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European Journal of Pharmacology 740 (2014) 364–378

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European Journal of Pharmacology
journal homepage: www.elsevier.com/locate/ejphar

Review

Cisplatin in cancer therapy: Molecular mechanisms of action
Shaloam Dasari, Paul Bernard Tchounwou n
Cellomics and Toxicogenomics Research Laboratory, NIH/NIMHD RCMI-Center for Environmental Health, College of Science,
Engineering and Technology, Jackson State University, 1400 Lynch Street, Box 18750, Jackson, MS 39217, USA

art ic l e i nf o

a b s t r a c t

Article history:
Received 27 March 2014
Received in revised form
13 July 2014
Accepted 14 July 2014
Available online 21 July 2014

Cisplatin, cisplatinum, or cis-diamminedichloroplatinum (II), is a well-known chemotherapeutic drug.
It has been used for treatment of numerous human cancers including bladder, head and neck, lung,
ovarian, and testicular cancers. It is effective against various types of cancers, including carcinomas, germ
cell tumors, lymphomas, and sarcomas. Its mode of action has been linked to its ability to crosslink with
the purine bases on the DNA; interfering with DNA repair mechanisms, causing DNA damage, and
subsequently inducing apoptosis in cancer cells. However, because of drug resistance and numerous
undesirable side effects such as severe kidney problems, allergic reactions, decrease immunity to
infections, gastrointestinal disorders, hemorrhage, and hearing loss especially in younger patients, other
platinum-containing anti-cancer drugs such as carboplatin, oxaliplatin and others, have also been used.
Furthermore, combination therapies of cisplatin with other drugs have been highly considered to
overcome drug-resistance and reduce toxicity. This comprehensive review highlights the physicochemical properties of cisplatin and related platinum-based drugs, and discusses its uses (either alone or in
combination with other drugs) for the treatment of various human cancers. A special attention is paid to
its molecular mechanisms of action, and its undesirable side effects.
& 2014 Elsevier B.V. All rights reserved.

Keywords:
Cisplatin
Platinum-based drugs
Mechanisms of action
Cancer treatment

Contents
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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Cisplatin and other platinum-containing drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Uses of cisplatin for cancer treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Cisplatin and lung cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Cisplatin and ovarian cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Cisplatin and carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Cisplatin and breast cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.
Cisplatin and brain cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Combination therapy of cisplatin with other cancer drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Cisplatin and paclitaxel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Cisplatin and tegafur-uracil (UFT) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Cisplatin and doxorubicin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.4.
Cisplatin and gemcitabine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.5.
Cisplatin and vitamin D. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.6.
Other possible drug combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Molecular mechanisms of cisplatin pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.1.
Cisplatin-induced oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.2.
Cisplatin modulation of calcium signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.3.
Cisplatin-induced cell apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.4.
Cisplatin and protein kinase C . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.5.
Cisplatin and mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
5.6.
Cisplatin and jun amino-terminal kinase (JNK) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Corresponding author. Tel.: þ 1 601 979 0777.
E-mail address: paul.b.tchounwou@jsums.edu (P. Bernard Tchounwou).

http://dx.doi.org/10.1016/j.ejphar.2014.07.025
0014-2999/& 2014 Elsevier B.V. All rights reserved.

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. . . It exhibits lower reactivity and slower DNA binding kinetics. . . . . Dasari. . . . . . . . . . . . . . . Toxicological effects of cisplatin . . . . . . Conclusions . . . . . . . Peyrone in 1844 and its chemical structure was first elucidated by Alfred Werner in 1893. . . Since the identification of cis-dichlorodiammineplatinum (II) (cisplatin. . 1 and 2). . . . . . . . . . . . . . . . . 2007). . . . . . It was the first FDA-approved platinum compound for cancer treatment in 1978 (Kelland. . . . . . . . . .7. . . and hence its effects are longer lasting (a retention half-life of 30 h for carboplatin. . . 2. . . Nine platinum analogs are currently in clinical trials around the world ormaplatin (tetraplatin). . . . . . . . . . . . . . . . . . . . . . 2014). . . . 5. . . . . . . . . . . . . . . . . . . and by the end of the 1970s it had earned a place as the key ingredient in the systemic treatment of germ cell cancers. . . . Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 5. . . . . . . . . . . . . . . . . . . DWA2114R. . . . . . . . . . . . 2006). . . . . . . . Among many chemotherapy drugs that are widely used for cancer. . . . . . .R-1. . . . . . . . . . . .1 g/mol. . Some studies show that cisplatin and carboplatin cause different morphological changes in MCF-7 cell lines while exerting their cytotoxic behavior (Natarajan et al. . . . . with the amine ligands on the left forming stronger interactions with the platinum ion. . . . . . . . . . . . . . . . . . . . . . . .6 h in the case of cisplatin). 1993). . . enloplatin. . . . . . . considerable interest has been generated in the use of coordination complexes of platinum. . . . . . . . carboplatin and oxaliplatin are composed of doubly charged platinum ion surrounded by four ligands. . we aim to provide a comprehensive review of the physicochemical properties of cisplatin and related platinum-based drugs. . . . .9. . . . . palladium. . . . . . . . . . . . . . . . . . . . . . . .. significant challenges remain with regard to their cure. . . . . . . . . . . . . . Cisplatin was first synthesized by M. . . . . . . . . . . . . . . . . . . . . From the molecular perspective. . Cyclobutanedicarboxylate (c-abl) and DNA damage response to cisplatin treatment . . . . . . . . . . . . and liposome-entrapped cis-bis-neodecanoato-trans-R. . . . . .N-dimethylformamide. . . . . . . CI-973 (NK-121). . . . . . . lobaplatin. . . . 2002). . . Introduction Cisplatin (CAS no. . . . . . . . . . 2014). . . . . . . . . . . .1-cyclobutanecarboxylato) platinum (II) is a chemotherapeutic drug used for cancers of ovaries. . . . ormaplatin and enloplatin. . . . . p53 and DNA damage response to cisplatin treatment . . . . . . . . . . . . . Although such cancers have recently received better prognosis and therefore have become less life threatening (Desoize and Madoulet. . . . . . . . . . . . . . . . . . . . . . . combination therapy of cisplatin with other cancer drugs has been applied as novel therapeutic strategies for many human cancers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . It is slightly soluble in water and soluble in dimethylprimanide and N. . . . . . . . . . . . . . . . . . . . . . . . r) as the agent responsible for this activity. . . . . . muscles. . . References . . . . . . . 6. . . . . . . . Cisplatin modulation of gene expression . . . 2010). . . 5. . . . . . . In this research. 2006). . . . which are the leaving groups in cisplatin (Figs. . . . . . . . . . . This has led to interest in platinum (II)—and other metal—containing compounds as potential anticancer drugs (Frezza et al. . . . . . . . . . . . . . . . 5. . . . . . . NCF-119875). . . . . . . several thousand analogs have been synthesized and tested for properties that would enhance its therapeutic index. . . . . . . . . . . . . . . . . . . head and neck. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11. . . . . . . . . . . JM-216. . . (1965) at Michigan State University pointed out that certain electrolysis products of platinum mesh electrodes were capable of inhibiting cell division in Escherichia coli created much interest in the possible use of these products in cancer chemotherapy. . . . . . . . . and other noble metals in the treatment of cancer. . . . Computational studies of cisplatin . Cisplatin and AKT . . . . . In terms of its structure. 5. . . . . cisplatinum. . . . . . 1 presents the chemical structures of cisplatin and four of its analogs including carboplatin. . . . . . .4. . . . . . . . . . . . . . . . cisplatin represents a perfect example of how a small alteration in chemical structure can significantly affect biological activity in target cell (Goodsell. . . . . . . . . . . . . . . . . . . . . .S. . . . . . cancers of soft tissue. . . .2. . . . . . although it forms the same reaction products in vitro at equivalent doses with cisplatin. . . . cisplatin is one of the most compelling ones. . . . . . . . . . . . . . . . . . . . . . . Also. . 5. . . . . . . Nephrotoxicity . . . . Other organ toxicity . . . . . Cisplatin and signaling for DNA damage . because of drug resistance and considerable side effects. . . . . . . . . . . . . . . . . . . . . It was discovered to have cytotoxic properties in the 1960s. . . . . . . . . . . . . . . . . . . . . . . . . . . . and blood vessels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5–3. . . The lower excretion rate of carboplatin means that more is retained in the body. . . . . . . . . . . . Cisplatin and other platinum-containing drugs Since the early seminal work in the preclinical and clinical development of cisplatin. . Akron. . . . . . . . . . . . 254-S. Fig. . . . . . . . . . . . . 6. the compound did not gain scientific investigations until the 1960s when the initial observations of Rosenberg et al. . . . . carboplatin differs from cisplatin in that it has a bidentate dicarboxylate (CBDCA) ligand in place of the two chloride ligands. .8. 1999). to discuss its uses (either alone or in combination with other 365 371 371 372 372 372 372 373 374 374 374 374 374 374 374 374 drugs) for the treatment of various human cancers. . . . . . . . . . . . . . . . . . . testes. . . . 15663-27-1. . . . . . . which are excreted. . . . but only one (carboplatin) has provided definite advantage over cisplatin and achieved worldwide approval. The diminished reactivity limits protein–carboplatin complexes. . . . . . . . . . . . . . . . . . . . . . . Cisplatin is clinically proven to combat different types of cancers including sarcomas. . . Cardiotoxicity . . . . . a melting point of 270 1C. . . . Carboplatin or Cis diammine (1. . . . . . . . . . .2-diaminocyclohexane platinum (II) (LNDDP)] (Weiss and Christian. . . . . . . . . . . . . . . . 6. . . . Acknowledgments . .12. . . . . . . Cisplatin and p38 mitogen-activated protein kinase (MAPK) . . . . . . . . . . . . . . . . . . . . . 1. . . . . . . . . . . . . . . . a density of 3. . . . . 2. . . . . . . .74 g/cm3. . . . . . . . . . . . . . . . . . . . . . . . . 6. . . . . . . . . . . oxaliplatin. . . . . . . . . . . . 5.53 g/ L at 25 1C (HSDB. . . . . . . . . . . . . . . . Cisplatin has a molecular weight of 301. . . . . . . . . . . . . . . . . . . . . . . to examine its molecular mechanisms of action. . . . . . . . . . . . and solid tumors of the head and neck. . 1981. . . . . As illustrated in Fig. . . . . . . bones. . . . . . . . . . . . . . . . . . . . . . P. . . . . . . . Unlike cisplatin. carboplatin may be susceptible to alternative mechanisms. . MF-Cl2H6N2Pt. . . . . . . . a log Kow of  2. . cisplatin.19 and a water solubility of 2. . . . 2009). . . . . It is a white or deep yellow to yellow–orange crystalline powder at room temperature. 7. . . . . . . . . . . . . . Cisplatin has been especially interesting since it has shown anticancer activity in a variety of tumors including cancers of the ovaries. . . . . . .10. . and to discuss it potential side effects. . . . . . . . . . compared to 1. . . . . . . . . . . 6. . . . . .1. . . . . also called cis-diamminedichloroplatinum(II). . . . . . . . . . . . . . . . . . . . . About 13 of these analogs have been evaluated in clinical trials. . . . . . . . . . . . . . . . . . . Cisplatin is stable under normal temperatures and pressures. . . .13. . . . . . . . . . . . . . . . lung. . .. . Hepatotoxicity . . . . . . . . . . and the chloride ligands or carboxylate compounds on the right forming leaving groups allowing the platinum ion to form bonds with DNA bases (Goodsell. . . . . . . However. . . . . . . . . . . . . . . . . is a metallic (platinum) coordination compound with a square planar geometry (The chemical book database. . .3. . . . . . . . . . but may transform slowly over time to the trans-isomer (IARC. . . . . . . . . . . . . . . . . oxaliplatin.

depending on the type of cancer. showing that although these compounds target the nuclei. sometimes as low as 10% of its usual production levels (Canetta et al. but more recent studies have focused on strategies to synthesize intrinsically fluorescent derivatives. this fluorescence is maintained after binding to oligonucleotides or DNA. these bile acid derivatives have shown increased cytotoxicity and ability to overcome resistance as compared to cisplatin in several cell lines. they form adduct with the DNA that are different from those due to cisplatin. in the last ten years. P. C-oxaliplatin. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 Fig.g. Because of this.. Fig. 2009) . once uptake of the drug occurs. The first generation of reporting Pt-compounds was based on linking a fluorescent molecule (e. but it is also this inertness that causes carboplatin to go right through the human body. that is. the activity of these compounds does not seem to be restricted to cycling cells but they also seem to kill resting cells (Rodriguez-Fernandez et al. and the chloride ligands or carboxylate compounds on the right forming leaving groups allowing the platinum ion to form bonds with DNA bases (Goodsell. Computational molecular structures of cisplatin. Chemical structures of selected platinum drugs: A-cisplatin. Carboplatin is less potent than cisplatin. 1985). The clinical standard of dosage of carboplatin is usually a 4:1 ratio compared to cisplatin.. These platinum compounds are composed of doubly charged platinum ion surrounded by four ligands. bile acid platinum compounds have shown fluorescence intensity that is stable at room temperature for a long time. for a dose that usually requires a particular dose of cisplatin. with the amine ligands on the left forming stronger interactions with the platinum ion. in contrast to cisplatin. The stable property of carboplatin is a mixed blessing.366 S. the binding mode of these compounds to DNA can be easily analyzed both by flow injection and fluorescence techniques. Accordingly. D-ormaplatin. the greatest benefit of carboplatin is its reduced side effects. 2006). its retention half-life is considerably longer than cisplatin. Pt-derivatives with reporting activity have also been synthesized. Relative to cisplatin. particularly the elimination of nephrotoxic effects. 1993). and up to 90% of the carboplatin given can be recovered in urine (Go and Adjei. E-enloplatin (Weiss and Christian. 2. Dasari. carboplatin and oxaliplation. B-carboplatin. four times more carboplatin is needed to achieve the same effectiveness. carboplatin may only be 1/8 to 1/45 as effective. 1. 1999). In order to overcome cisplatin resistance. In line with this. other platinum (Pt) compounds have been developed and. The main drawback of carboplatin is its myelo suppressive effect which causes the blood cell and platelet output of bone marrow in the body to decrease quite dramatically. Moreover. cyanine) to cisplatin.

followed by repetitive cycles of temozolomide (Stupp et al. Cisplatin is used in combination with other chemical agents or compounds to treat ovarian cancer in both the resistant and sensitive cell lines. A randomized comparison of cisplatin alone or in combination with methotrexate. Cisplatin and breast cancer Breast cancer is one of the leading causes of women mortality worldwide.3. Matsuki et al.. It has also been reported that a CD133 þ . carcinoma of salivary gland origin.. 3. Dhar et al. 2012).. Table 1 presents a synopsis of cisplatin combination therapy with other cancer drugs and targeted cancers. lung and refractory non-Hodgkin's lymphomas (Tsimberidou et al.4. 2001). squamous cell carcinoma of male genitial tract. 2009). a surface glycoprotein linked to organ-specific stem cells. 2008). is invariably fatal (Stupp et al. cervical. 1982). recurrence occurs in up to 75% of ovarian cancer patients. overcoming chemotherapy resistance of ovarian cancer cells by liposomal cisplatin (Koch et al.. including surgery.. The proposed mechanisms of cisplatin resistance include changes in cellular uptake and efflux of cisplatin. 2002). HNSCC is associated with a high mortality rate. most chemotherapeutic drugs effectively target rapidly dividing cells causing damage and are thus referred to as “cytotoxic drugs”. Chemotherapy is the only option for treating the malignant breast cancer and condition for increases the lifespan of the patient (Decatris et al. melanoma and pancreatic cancer cell lines. Dasari. Cisplatin derivatives are used as the mainline treatment of ovarian cancer.. biliary tract cancer.. 2008).. 2005).. Patients with recurrent ovarian cancer ultimately develop resistance to chemotherapy and eventually succumb to the disease (Agarwal and Kaye. 2003). The standard of care for localized non-small-cell lung cancer (NSCLC) is surgery followed by. recently showed an absolute 5-year survival benefit of 5. colon. The Lung Adjuvant Cisplatin Evaluation program.5. anal cancer (Ajani et al. doxorubicin. urothelial bladder cancer. 2013). 3. prostate. Cisplatin and carboplatin are two of the most common types of platinum based treatments used in SCLC chemotherapy (Go and Adjei. despite their severe side effects and development of resistance.. 3. 1999). to avoid renal toxicity. To overcome resistance. Cisplatin therapy is also used for recurrent childhood brain tumors(Khan et al. a pooled analysis of the five largest trials. and increase in DNA repair and antiapoptotic mechanisms (Gottesman et al.. Although this treatment regime is effective as the first-line treatment. drug resistance has been observed in many patients who have relapsed from cisplatin treatment. 2006). Paclitaxel has been demonstrated to be active against . Conventional treatment for late stages of ovarian cancers is surgical excision followed by platinum/taxane combination chemotherapy. The cytotoxic effect is likely a result of inhibition of replication by cisplatin-DNA adducts and induction of apoptosis (Siddik. cisplatin is often selected due to its strong antitumor activity. Combination therapy of cisplatin with other cancer drugs Cisplatin combination chemotherapy is the basis of treatment of many cancers.2.. Cisplatin is an important chemotherapeutic agent used widely or the treatment of a variety of malignancies.. 2009).. and leukemia (Previati et al.. Cisplatin and carcinoma 4. and cervical cancer. has been described as a marker of cancer-initiating cells in different tumor types.. epithelial-specific antigen-positive (CD133 þ ESA þ ) population is increased in primary non-small cell lung cancer (NSCLC) compared with normal lung tissue (Bertolini et al. In clinical practice. CD133. 2003). Cisplatin and brain cancer Glioblastomamultiforme (GBM) is the most common primary malignant brain tumor.3% with adjuvant chemotherapy as well as the NSCLC meta-analysis (Pignon et al. 2004). Cisplatin and ovarian cancer Ovarian cancer has the highest mortality among gynecologic cancers. adjuvant cisplatin-based chemotherapy. platinum based treatments are key drugs for SCLC (Abrams et al. 2005). including breast. 2013). carboplatin has been considered to be a substitute for cisplatin without any apparent loss of therapeutic efficacy since aggressive hydration is often problematic. Cisplatin and paclitaxel Head and neck squamous cell carcinoma (HNSCC) is a common malignant disease with more than 600.. The overall 5-year Paclitaxel is a mitotic agent that binds preferentially to microtubules (Parness et al.S. Small cell lung cancers (SCLCs) represent 15% of all lung cancers (Chen et al.as well as in other cancers such as gastric cancer (Koizumi et al. testicular. bladder. In clinical trials.1. 4. At present. 2009.5 months.. lung cancer (diffuse malignant pleural mesothelioma). The current standard of care for patients with GBMs consists of surgery and radiotherapy in combination with temozolomide. 2008). Despite improved treatment options. but its adverse effects include renal toxicity (Iwasaki et al. prostate. Hence. nausea and vomiting (Kosmas et al. and with rare exception. 3. For example cisplatin is used along with honey venom (Alizadehnohi et al.000 new cases registered worldwide every year (Parkin et al. 2013) 367 survival rate of approximately 50% has not changed over the last decades. while the remainder has hereditary background.. ovarian. 2009). Cisplatin alone is not an effective drug in treating the disease. Platinum responsiveness is high primarily but many cancer patients will ultimately relapse with cisplatinresistant disease.. Chemotherapeutic agents have been developed to counter the continuing breast cancer problem. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 3. Uses of cisplatin for cancer treatment 3. increased biotransformation and detoxification in the liver.1. the increase in overall median survival was only for 2. radiation and chemotherapy. 2011). gastric cancer.. in case of stage II and III disease. P. withaferin (Kakar et al. cisplatin is commonly used in combination with some other drugs in treating ovarian cancer. Most patients with ovarian cancer are diagnosed at late stages due to lack of effective screening strategies and specific symptoms associated with early-stage disease. trichostatin A or 5-aza-20 deoxycytidine (Meng et al. 2008). Cisplatin and lung cancer Lung cancer remains one of the most common types of fatal malignancies (Youlden et al. Although the survival advantage of this combined treatment regimen was still evident at 5 years. 2009). or are associated with breast and colon cancers (Lynch et al.. head and neck. 2005). urine volumes should be monitored and large-dose infusion is mandatory in cisplatin based chemotherapy.. 2012). vinblastine. and or gemcitabine in patients with metastatic urothelial carcinoma has been reported (Scher.. Therefore. lung. breast. 2003). 1981) and the resulting stabilization of microtubules inhibits the reorganization of the microtubule network. However. About 90% of ovarian cancers arise originally from ovaries with an unknown reason.. 1992.

1987). McGuire et al. insulin-like transforming growth factor family and their receptors (Saramaki et al.. 1991). 1994).. E-cadherin. 4. 1997) and colon cancer (Milczarek et al. (1999) Ichinose et al. The combination chemotherapy with paclitaxel. for all cytotoxic agents tested a synergistic antiproliferative effect was observed. Upon ligand activation and dimerization with retinoid X receptor (RXR).4. This effect was expressed as a significant decrease of the ID50 (inhibitory dose 50%) values for each cytotoxic agent applied after pretreatment of HL-60 cells with calcitriol or its analogs in comparison with the effect of cytotoxic agent applied alone (Siwinska et al. (2013) 4. (1991). (1991) Pinto-Leite. c-Myc oncogene. Einzig et al. 1999) 4. VDR–RXR heterodimers bind specific nucleotide sequences. A number of vitamin D target genes have been identified in several tumor cell types: p21. 2013). .2. honey bee venom in ovarian cancer cells (Alizadehnohi et al. 4. (1989). (1987) Valle et al. 1991). P.5.. vitamin D response elements (VDREs). 1991). head and neck carcinoma Paclitaxel and 5-FU UFT Doxorubicin Cyclophosphamide and doxorubicin Gemcitabine Osthole Honeybee venom Anvirzel Gastric and esophagogastric adenocarcinoma Non small lung carcinoma Diffuse malignant pleural mesothelioma Salivary gland advanced carcinoma Biliary cancer Lung cancer Ovarian cancer Breast..Holmes et al.3.McGuire et al. bevacizumab in non-small cell lung cancer mediated malignant pleural effusion (Du et al. Nagpal et al. Forastiere (1994) Kim et al. (2011) Minami et al... 1992. melanoma and pancreatic cancer cell lines (Apostolou et al. 2013). 2010).. 4. Moreover..368 S.. Combination chemotherapy comprised of oral UFT (a combination of tegafur and uracil) and cisplatin was shown to be an effective regimen for the treatment of advanced non-small cell lung carcinoma (Ichinose et al. (1991) Dreyfuss et al. Cisplatin and vitamin D Vitamin D and its analogs regulate gene expression by binding to specific vitamin D receptors (VDR). Cisplatin is used along with vitamin D in treating squamous cell carcinoma (Light et al. anvirzel in breast. It might be considered for palliation of symptomatic patients with diffuse malignant pleural mesothelioma DMPM (Ardizzoni et al. and cisplatin combination chemotherapy for advanced carcinomas of salivary gland origin showed encouraging results (Dreyfuss et al. 2013). c-Jun N-terminal kinase (JNK).. lung. 2006.. Kohn et al. vinblastine and bleomycin in metastatic granulosa cell tumor of the ovary (Colombo et al. et al. breast carcinoma. (2013) Dimery et al... 1991) as well as for head and neck carcinoma (Forastiere. (2012) Apostolou et al. Combination drug(s) Cancer type Reference(s) Paclitaxel Ovarian carcinoma.. doxorubicin and cyclophosphamide Metformin Oxaliplatin. Dasari.. (2013) Alizadehnohi et al. cisplatin plus gemcitabine was associated with a significant survival advantage without the addition of substantial toxicity. colon.. (1992).. prostate. Cisplatin and tegafur-uracil (UFT) UFT is an oral anticancer agent comprised of tegafur and uracil in a 1:4 fixed molar ratio and is absorbed very well from the small intestine (Fujii et al. Murphy et al. 2012). lung.. (1990) Lin et al. (1993). breast carcinoma (Holmes et al. (1994) Deng et al. (2013) Le et al. 1993). Cyclophosphamide.. (2013) Nessa et al. Published research has shown that pre-treatment for 72 h of human promyelocytic leukemia (HL-60) cells with calcitriol or its new analogs significantly potentiated their sensitivity to the antiproliferative effect in vitro of cisplatin. quercetin and thymoquinone Olaparib Tetra arsenic oxide Vindesine β-galactosyl-pyrrolidinyldiazeniumdiolate Lung adenocarcinoma Ovarian cancer PTEN deficient lung cancer Cervical cancer Non small lung carcinoma Glial cells of brain Human cervical cancer Gliosarcoma cell lines previously treated ovarian carcinoma (Sarosy et al.. doxorubicin or genistein. (1986) Dexeus et al. and melanoma (Legha et al. doxorubicin. (1991). Cisplatin and doxorubicin The combination of doxorubicin and cisplatin is effective and well tolerated. 1986). methotrexate. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 Table 1 Combination therapy of cisplatin and other cancer drugs.. (2013) Bevacizumab Vinbalstine and bleomycin Methotrexate and bleomycin Everolimus Fluorouracil. bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract (Dexeus et al. 2013). lung carcinoma (Murphy et al. Legha et al. Einzig et al.6. (1990). 1992). (2000) Ardizzoni et al. 2001). 1990. colon... 1989. (2013) Colombo et al.. Cisplatin and gemcitabine As compared with gemcitabine alone. 1979). (1992). 2000). 1993). melanoma and pancreatic cancer Non small lung carcinoma Metastatic granulosa cell tumors in ovary Advanced squamous cell carcinoma of the male genital tract Urothelial bladder cancer Salivary gland carcinoma Sarosy. 2005). (2013) Byun et al. lung carcinoma. prostate. Other possible drug combinations Cisplatin is also used in combination with natural compounds like osthole in lung cancer cell lines (Xu et al. Einzig et al. Cisplatin plus gemcitabine is an appropriate option for the treatment of patients with advanced biliary cancer (Valle et al. Einzig et al. melanoma. in target genes to activate or repress their expression (Baniahmad and Tsai. cisplatin and fluorouracil is an active and tolerable as first-line and second line therapies in Chinese patients with advanced gastric and esophagogastric junction adenocarcinoma which showed a better tolerance has also been reported (Kim et al. Du et al. (2010) Xu et al.

5.. Eisenberger.. In chondrosarcoma cells overexpression of EGFR contributed to cisplatin resistance (Song et al. It has been hypothesized that Rac1. doxorubicin. cells control reactive oxygen species levels by balancing the generation of reactive oxygen species with their elimination by scavenging system (reduced . 2002)...1. Cisplatin becomes activated once it enters the cell. pancreas. 1983. These complexes exhibit different numbers and types of excited states which are easily accessible upon light irradiation. with morphological changes including acquisition of a spindle-like fibroblastic phenotype. Genetic knockout of CTR1 results in cellular resistance to cisplatin in vivo. Cells with increased CTR1 expression exhibit increased platinum accumulation and. (Demonstrated that A549/CDDP cells acquired an epithelialmesenchymal transition (EMT) phenotype.. This hydrolyzed product is a potent electrophile that can react with any nucleophile.2-intrastrand d(ApG) adducts representing about 90% and 10% of adducts.. increased sensitivity to cisplatin. Dasari. 1994).. 1990). 2014). which is the administration of a photosensitiser followed by visible light activation. 2014). blocking cell division and resulting in apoptotic cell death. with morphological changes including acquisition of a spindle-like fibroblastic phenotype. overexpression of TMEM205 in CP-r cells may play a role in cellular resistance to platinum and would also be valuable as a biomarker or target in cancer chemotherapy (Shen et al. including the sulfhydryl groups on proteins and nitrogen donor atoms on nucleic acids.. Analysis of TMEM205 expression profiles in normal human tissues indicates a differential expression pattern with higher expression levels in the liver. cyclophosphamide. Due to loss of homeodomain-interacting protein kinase2 (HIPK2) contributes to cell proliferation and tumorigenesis in bladder cancer (Lin et al. Fluorouracil.. In ovarian carcinoma treatment. resulting in resistance to the drug (Lin et al. a Rho GTPase. the most revealing evidence being the hypersensitivity to cisplatin by both prokaryotic and eukaryotic cells deficient in DNA repair (Beck and Brubaker. subsequently giving rise to the formation of various photoproducts that can enable a distinct mode of action. 1997. 2014). downregulation of E-cadherin. 2012). Previous studies demonstrated that A549/CDDP cells acquired an epithelialmesenchymal transition (EMT) phenotype. So. Fraval et al. Cisplatin binds to the N7 reactive center on purine residues and as such can cause deoxyribonucleic acid (DNA) damage in cancer cells. The uptake of cisplatin is mediated by the copper transporter Ctr1 in yeast and mammals (Ishida et al.. respectively. AQP2. 1996). and the solute carrier importers (CTR1. 1978). It has been further confirmed in human cells that cisplatin triggers rapid degradation of the copper membrane transporter CTR1. 1981... in most instances. upregulation of mesenchymal markers (vimentin. Synergistic interactions have been reported for β-galactosyl-pyrrolidinyldiazeniumdiolate and cisplatin combination chemotherapy against glial cells of brain. 2011).2intrastrand cross-links of purine bases with cisplatin are the most notable among the changes in DNA. several molecular mechanisms leading to apoptosis have been implicated in cisplatin treatment of human cancers. Cisplatin resistance in colorectal 369 cancer is due to adaptive activation of Nrf2 may contribute to the development of acquired drug-resistance (Chian et al. and increased capability of invasion and migration in case of human lung cancer cell lines (Wang et al. 2014). ATP7A/B).. Cisplatin-induced oxidative stress Under normal physiological conditions. Cisplatin resistance is correlated with autophagy induction in a panel of ovarian cancer cells (Wang and Wu. von der et al..2intrastrand d(GpG) adducts 1. Photodynamic therapy (PDT).. and increased capability of invasion and migration in case of human lung cancer cell lines. the combination of cisplatin and paclitaxel produced a more encouraging response rate (73%) (McGuire et al. Cisplatin is known to have an additive or synergistic effect in combination with gemcitabine in a number of different tumor types (Crino et al. upregulation of mesenchymal markers (vimentin. 2013). Vindesine and cisplatin combination chemotherapy compared with vindesine as a single agent in the management of non-small cell lung cancer seemed to be more effective (Le et al. is implicated in HNSCC insensitivity to chemo-radiotherapy resulting in tumour recurrence development in head and neck squamous cell carcinoma (Skvortsov et al. Hence. In the cytoplasm the chloride atoms on cisplatin are displaced by water molecules. is a promising route to avoid damage to healthy cells and the surrounding tissue. 2013). The addition of cisplatin to cyclophosphamide and doxorubicin (CAP) has been recently associated with overall response rates of 57–00% and complete response rates of 26–75% in small series of patients (Creagan et al. P. MDR1 is an ATP-binding cassette transporter known for years as P-glycoprotein (Shen et al . 2013).. TMEM205. downregulation of E-cadherin. These include the 1.. Alberts et al. A single institutional Phase II trial using cisplatin and oral UFT administration in place of protracted intravenous injection of 5-FU yielded a 35% response rate and a median survival time of 11 months in 31 patients with advanced NSCLC (Ichinose et al.. with diminished influx of cisplatin. Transition metal complexes as photochemotherapeutic agents are an attractive option for further development in the field of photoactivated chemotherapy (PACT). 2005... 2006). 2013). As illustrated in Fig. 2014).. and cisplatin combination chemotherapy has been used in advanced or recurrent salivary gland carcinoma (Dimery et al... and AQP9). Holzer et al. 1. 2002. the mislocalization of the transporter exacerbates the cisplatin resistance phenotype (Shen et al. It is also indicated that AQP5 is associated with drug resistance of colon cancer (Shi et al. 5. 3. and adrenal glands. Platinum–diazido complexes are promising candidates for PACT due to the low cytotoxicity when irradiated with visible light (Shaili.. 1973. published research from many laboratories has implicated DNA as a critical target for cisplatin cytotoxicity. a membrane protein has been associated with cellular resistance to cisplatin was identified. 2013).. 2012.. The 1.. Metformin has been shown to enhance cisplatin cytotoxicity by suppressing Stat3 activity independently of the LKB1-AMPK pathway (Lin et al. 2014). Johnson et al.. Molecular mechanisms of cisplatin pharmacology Several membrane transporters of platinum compounds analogous to MDR1 including the efflux ATPases (MRPs. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 Everolimus combined with cisplatin has a potential role in treatment of urothelial bladder cancer (Pinto-Leite et al. Tetraarsenic oxide and cisplatin induce apoptotic synergism in cervical cancer (Byun et al. 1998). have been reported. human cervical and gliosarcoma cell lines (Deng et al. Hitt et al. 2012). Cisplatin and oxaliplatin in combination with quercetin and thymoquinone in human ovarian tumour models is the best combination to treat ovarian cancer (Nessa et al.3-intrastrand d(GpXpG) adducts and other adducts such as inter-strand crosslinks and nonfunctional adducts have been reported to contribute to cisplatin's toxicity. 1996). the SLCs. 2014). Snail and Slug). Glucose Transporter 1 (Glut1) is not proposed to directly transport cisplatin. 1985). 1995).S. 2014). Olaparib in combination with cisplatin has a synergistic effect on PTEN-Deficient lung cancer Cells (Minami et al. Snail and Slug).

Cell death occurs upon immediate activation of numerous signaling pathways. reactive oxygen species function to facilitate cytochrome c release by activating pore-stabilizing proteins (Bcl-2 and Bcl-xL) as well as inhibiting pore-destabilizing proteins (Bcl-2-associated X protein. 3. The formation of reactive oxygen species depends on the concentration of cis-diamminedichloro platinum(II) and the length of exposure (Brozovic et al. partly due to oncogenic stimulation. for degradation in lyposomes (Shrivastava et al. lipids and DNA. The mitochondrion is the primary target for cisplatin induced oxidative stress. Cisplatin modulation of calcium signaling Cisplatin. which is necessary for subsequent recruitment of Fas-associated protein with death domain and caspase 8 as well as apoptosis induction (Gupta et al. therefore generating reactive oxygen species (Desoize. 2010). 2011) 5. In the extrinsic pathway of apoptosis.2. 2004) Exposure to oxidative stress can upset regular biological functions. Oxidative stress is the one of most important mechanisms involved in cisplatin toxicity. Excessive reactive oxygen species can induce apoptosis through both the extrinsic and intrinsic pathways (Ozben. Under certain conditions a thiol group may lead to formation of thiyl radicals that in turn can interact with molecular oxygen. An even higher reactive oxygen species level can result in both apoptosis and necrosis in cancer cells (Hampton and Orrenius. Dasari. whereas the definite pathways depend on the (cancer) cell. P. increased metabolic activity and mitochondrial malfunction. Reactive oxygen species can also induce cell death through autophagy. excessive reactive oxygen species can damage cellular proteins. In the intrinsic pathway. But under oxidative stress conditions. Cancer cells exhibit greater reactive oxygen species stress than normal cells do. 2002). which is a self-catabolic process involving sequestration of cytoplasmic contents (exhausted organelles and protein aggregates).370 S. 1997). Cisplatin also induces reactive oxygen species that trigger cell death besides DNA damage. 2002). resulting in loss of mitochondrial protein sulfhydrl group. has been shown to hydrolyze into variously charged reactive .. glutathione-GSH... Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 Fig. Overview of molecular mechanisms of cisplatin in cancer treatment. 2007). 2012). calcium uptake inhibition and reduction of mitochondrial membrane potential (Saad et al. under low intracellular chloride ion concentrations. Bcl-2 homologous antagonist/killer) (Martindale and Holbrook. and catalase-CAT). leading to fatal lesions in cells that contribute to carcinogenesis. superoxide dismutase-SOD.. reactive oxygen species are generated by Fas ligand as an upstream event for Fas activation via phosphorylation. The intracellular redox homeostasis is maintained by the thiol group (–SH) containing molecules.

Yeh et al. 1995). declines with cisplatin treatment. These hydrolyzed forms of cisplatin have been shown to be 1000 times more reactive than normal cisplatin. phosphatidylserine externalization.. membrane budding. including DNA damage. Cisplatin and mitogen-activated protein kinase (MAPK) Mitogen activated protein kinases are a family of structurally related serine/threonine protein kinases that coordinate various extra cellular signals to regulate cell growth and survival (Chang and Karin. such as DNA damage. Cisplatininduced extracellular-signal-regulated kinase (ERK) activation precedes p53-mediated DNA damage response since ERK directly phosphorylates p53 causing up regulation of p21. 1980). Aggarwal et al.. 5. they become inactivated. the p38 MAPK pathway plays a critical role in regulating cisplatininduced apoptosis. 1990. especially nephrotoxicity. These events damage the cells through mitochondrial damage. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 species including monoaqua [cis-(NH)PtCI(HO)] þ and diaquated [cis-(NH)Pt(HO)]2 þ forms (Jennerwein and Andrews. by activating p38 MAPK family.. When the SH-groups of enzymes are not maintained in a reduced form. 1999. 2002. which can contribute to apoptosis or chemo resistance. Cisplatin primarily induces cell death by apoptosis and a defect in apoptotic signaling could also confer cisplatin resistance. inhibition of mitochondrial function. Therefore.7.. Cisplatin has been shown to cause activation of ERK in several cell types although there are controversies whether activation of ERK prevents or contributes to cisplatin induced cell death (Tang et al. There have been contrasting on reports whether activation or down regulation of PKC is necessary for cisplatin sensitization (Isonishi et al. 1997. Cisplatin and p38 mitogen-activated protein kinase (MAPK) Environmental stress is an important moderator of cisplatininduced apoptosis.. This probably leads to apoptosis and tissue necrosis..3. 2010). 2000). it seems that elevated calcium levels. which leads to DNA fragmentation. Cisplatin and AKT Akt belongs to a family of serine/threonine kinases which act downstream of phosphoinositide 3-kinase (P13K) and plays a critical role in the cell survival (Brazil and Hemmings. Caspases are either initiators or executioners of apoptosis.4. 2000). and activation of these caspases results in activation of downstream or executioner caspases such as caspases 3 and 7 (Salvesen and Abrams. Cisplatin induced toxicities. 2002. via calcium supplementation. 371 regulating the release of mitochondrial cytochrome c in response to DNA damage. 1995). Johnson and Lapadat. There are two major pathways of apoptotic cell death (Nunez et al.... 2002. may act as another means of cytoprotection. 2001). The effects of PKC on cellular sensitivity/resistance to cisplatin depend on the pattern of the PKC isozymes as well as on the cellular context (Basu and Krishnamurthy. 1998). this depletion of GSH and NADH appears to result in the inhibition of some dehydrogenases. 2004). a p38 MAPK-regulated protein. Wang et al. 2007).8. including those that activate plasma membrane death receptors (caspase 8) and cause mitochondrial dysfunction (caspase 9). Caspase activation is the key step in the beginning of apoptosis. and activation of a family of cysteine proteases called caspases (Salvesen and Dixit. p38 MAPK has been shown to mediate its effect via p18 (Hamlet). Both cis and trans forms of cisplatin activate the JNK pathway. 2000. Kischkel et al. Mitochondrial glutathione (GSH) seems to be essential in the regulation of inner mitochondrial permeability and enzyme function by keeping SH in the reduced state. Consequently. 1993). 5. and several stimuli activate caspases. p73. 1999.. 2010. Bcl-2 family proteins regulate DNA damage-induced apoptosis by c-Jun N-terminal kinase or stress activated protein kinase is activated by various stress stimuli. This result in an efflux of calcium from the mitochondria and a temporary increase in the cellular calcium levels. 2001). 5.. 2003. This process becomes autolytic and causes severe damage to membrane integrity (Aggarwal. Thus. 2006). Persons et al. Cummings et al. which interacts with p53 and stimulates the transcription of proapoptotic genes PUMA and NOXA to induce apoptosis (Cuadrado et al. which helps to maintain SH groups. and hence cell function. resulting in release of cytochrome-c from the mitochondria causing activation of procaspase-9 through the interaction with apoptosis promoting activating factor-1 (APAF-1) and formation of an active apoptosome complex. 5. by competing for binding sites with cisplatin and prevent various toxicities associated with it.5. 2007. chromatin condensation. Cisplatin-induced genotoxic stress activates multiple signal transduction pathways. depletion of adenosine triphosphate (ATP) and other cofactors. 1995. a proapoptotic member of p53 forms a complex with JNK leads to cisplatin induced apoptosis (Jones et al. Initiator caspases include caspases 8 and 9. Nowak. It has been demonstrated that cisplatin-induced DNA damage caused phosphorylation of BAD at ser136 via Akt (Hayakawa et al. These free radicals attack polyunsaturated lipids and proteins and initiate lipid per oxidation. resulting in the uncoupling of oxidative phosphorylation leading to hydroxyl radical formation and oxidative stress. 1992).6.S. 45kd-growth arrest and DNA damage (GADD45). Dasari. including cleavage and activation of poly (ADP-ribose) polymerase and of the inhibitor of caspase activator domain protein.. P.. Executioner caspases are accountable for many of the biochemical characteristics of apoptosis. In summary. The extrinsic pathway is initiated when ligands bind to the tumor necrosis factor-α (TNFα) receptor super family followed by oligomerization and recruitment of procaspase8 via adapter molecules to form the death-inducing signaling complex (DISC). Marshall. 5. activation of ERK may cause cell cycle arrest allowing time for the repair of cisplatininduced DNA damage via p53.. Nishizuka. Hayakawa et al. Newton. Cisplatin-induced cell apoptosis 5. and mouse double minute 2 homolog (Mdm2) (DeHaan et al. which is thought to play a significant role in the disruption of normal calcium homeostasis. Basically. and act through the inhibition of mitochondrial respiration by uncoupling oxidative phosphorylation (Aggarwal. It has already been identified that EGFR as a substrate for p38 MAPK and cisplatin-induced receptor internalization was triggered by p38mediated phosphorylation of the receptor (Winograd-Katz et al. BAD is phosphorylated in cells with . 1993). 1998. cisplatin's disruption of calcium homeostasis initiates primary events such as lipid per oxidation and enzyme inhibition. Cisplatin and protein kinase C Protein kinase C [PKC] is a family closely related phospholipid dependent enzymes that play critical roles in signal transduction and cell regulation (Basu and Sivaprasad. 2001. The intrinsic pathway is initiated by cellular stress.Thus. Nicotinamide adenine dinucleotide (NADH). Basu. 1993. 2007). Basu and Tu. Hirata et al. seem to be related to a decrease in the intracellular concentrations of GSH and protein bound SH-groups.. Cisplatin and jun amino-terminal kinase (JNK) Apoptosis is a controlled type of cell death which is energydependent leading to cell shrinkage. 2005)..

372 S. up. Cisplatin modulation of gene expression In vitro studies suggest that cisplatin resistance can result from epigenetic changes at the molecular and cellular levels. the microphthalmia-associated transcription factor. p53 and DNA damage response to cisplatin treatment p53 is a short lived protein. RhoB. preventing proteasomal degradation of p73 and results in the recruitment of p300 to trigger transcription of proapoptotic genes (Levy et al... 2004). the nuclear transcription factor. P. DNA once is damaged is followed by activation of cell cycle check points. cytotoxicity.. 2010). 5. HSP60 was significantly expressed in both human cervical and liver carcinoma (Shen et al. 2004). changes in DNA methylation status. Previous study showed that cisplatininduced DNA damage triggers the phosphorylation of both BAD Ser-112 via an ERK cascade and BAD Ser-136 via a PI-3 K-PKB/Akt cascade (Hayakawa et al. zinc finger factor 143. and RhoA was detected in human cisplatin-resistant cells in association with decreased accumulation of radiolabeled compounds (Shen et al. 2008). Upon DNA damage..induced DNA damage and this BAD phosphorylation is required for cell viability after cisplatin treatment in both cisplatin resistant and -sensitive cells. 2000. Significant reductions in platinum-DNA adduct formation (9-fold) and ribosomal RNA gene-specific interstrand crosslink formation (12-fold) have been reported in studies with human hepatoma cisplatin-resistant 7404-CP20 cells. increased expression in GCF2-transfected KB-3-1 cells results in reduced RhoA expression. . colon cancer (Belfi et al. and apoptosis in response to cisplatin treatment compared with control cells (Cho et al....ḱB. play a major role in cisplatin resistance (Shen et al. It is also demonstrated that activation of c-Abl and JNK is conditional upon the recognition of cisplatin induced DNA damage by the mismatch repair (MMR) system since c-Abl response is absent in MMR-deficient cells (Nehme et al. 5. there by delaying the cell cycle progression either to repair or to permanently eliminate the cells by inducing cell death. 1999. cisplatin induced phosphorylation of both BAD Ser-112 and Ser-136 is involved in maintaining cell viability after cisplatin treatment.. The MMR/c-Abl binds to p73. As a consequence of reduced uptake or retention.9. Loss of Nrf2 or inhibition by siRNA resulted in increased cell death. including reduced accumulation of the platinum compounds by either active efflux/sequestration/secretion or impaired influx. HSP70.. alterations of membrane protein trafficking as a result of defective organization and distribution of the cytoskeleton. while cisplatin-induced phosphorylation of BAD Ser. 2012). This complex activates jun aminoterminal kinase /stress-activated protein kinases (JNK/SAPK) (Kharbanda et al. The low molecular weight GTP-binding proteins of the Rho family. All these results suggest that the ERK and PI-3K-Akt signaling cascades converge at BAD to suppress the apoptotic effect of BAD (Hayakawa et al. This suggests the existence of alternate pathway for this event to occur upon stress. GRP78. 1999)...136 is PI-3K-Akt-dependent. In human breast cancer MCF-7 cells. breast cancer (VargasRoig et al.. Ohta et al.. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 cisplatin. direct binding and counteracting the antiapoptotic function of B-cell lymphoma-extra-large (Bcl-xL). Dasari. 2007). cervical HeLa cells (Huang et al. ectopic L37 over expression can attenuate the DNA damage response mediated by p53 (Llanos and Serrano. It has been reported that transcription factors such as Y-box binding protein-1. detoxification by GSH conjugates.. and HSP90 have been reported to be involved in CP-r ovarian cancer (Arts et al. and Rac. 1999). Moreover. DNA repair and apoptosis. Iinhibition of either of these cascades sensitizes ovarian cancer cells to cisplatin (Hayakawa et al. Also. inactivation (Shen et al. p53 negative cells also respond to cisplatin induced DNA damage. reducing cytotoxicity.. 2006). HSP72.. metallothioneins and other antioxidants. the forkhead transcription factor O. 2002).. 2008).or down-regulated expression of microRNA (miRNA1). 5.. 2000). It was first found that the levels of nuclear factor (ErythroidDerived 2)-like 2 (Nrf2) expression in Nrf2-deficient murine embryonic cells and human ovarian cancer SK-OV cisplatin-resistant cells correlate with the extent of resistance to cisplatin. 2012). Liu et al. RhoC. which is E3 ubiquitin ligase. Up-regulation of HSP27. Because cisplatin is a DNA-damaging agent and an inducer of apoptosis. it is reasonable to expect changes in HSPs in the development of cellular resistance to the drug. 2004). 1996). In addition. C-Jun will enhance the p73 stability by binding to transcription co activator Yap1. reduced expression of the ribosomal protein P0 was found by proteomic analysis (Smith et al.12. transcription factors and small GTPases. 5. and mitochondrial transcription factor A. However the removal rates of the total platinum-DNA adducts and genespecific interstrand cross-links were similar to those in their parental 7404 cells (Johnson et al. 2000). which is activated (phosphorylation) by Ataxia telangiectasia mutated (ATM) on DNA damage signal. Although p53 plays an important role in cisplatin induced DNA damage response. Rac1. the formation of platinum-DNA adducts is correspondingly decreased. CCAAT-binding transcription factor 2. 2010). p53 can transactivate genes involved in cell cycle progression. 2006).. The response of cells to cisplatin induced DNA damage will decide the fate of a cell to live or die (Basu and Krishnamurthy. 1998). 2012). overexpression of chaperones. Phosphorylation and stabilization of p73 can increase its proapoptotic function by disassociating from p63. Cyclobutanedicarboxylate (c-abl) and DNA damage response to cisplatin treatment c-Abl is tyrosine kinase receptor and contains nuclear localization motifs and nuclear export signals.10. The ribosomal protein L36 was found to present cisplatin resistance in human carcinoma cells (Shen et al.. c-Abl is recruited from cytoplasm to nucleus. 2001).Cisplatin can trigger cleavage of c-Abl which is a substrate for caspase and proteolytic cleavage of c-Abl was shown to be important for cisplatin-induced apoptosis (Machuy et al. 2010). 2003). another p53 family member (Basu and Krishnamurthy. It has been demonstrated that cisplatin-induced phosphorylation of BAD Ser-112 is MEK-dependent. disruption of actin-filamin dynamics. Reduced expression of small GTPases such as Rab5. p53 can regulate cisplatin induced cell death by several mechanisms like: degradation of flice-like inhibitory protein (FLIP). Cisplatin and signaling for DNA damage Mutations are caused by several signals associated with stress.. activating transcription factor 4.11. Cisplatin also induces endoplasmic reticulum stress and nucleus-independent apoptotic signaling (Mandic et al. all belong to the Ras tumor suppressor gene family.. a member of p53 family to start apoptosis (Gong et al. including RhoA. resulting in more resistance to the platinum compound. 2010). 2000) and laryngeal carcinoma cells (Brozovic et al. 1999). increased levels of DNA damage repair (nucleotide excision repair and mismatch repair). over expression of phosphatase and tensin homolog (PTEN) and inhibition of AMPK (Basu and Krishnamurthy.. later associate with and phosphorylates MEK kinase 1. The activated p53 now in turn activates Mdm2..

Pt(NH3)23 þ was used as the fragment that interacted with the bases. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 mislocalization of the membrane protein MRP1. the thermodynamics of the various possible adducts. since DNA is the primary target of the drug. especially in the case of anionic ligands. resulting in either deactivation of the drug and/or disruption of normal biochemical pathways. This study revealed that kinetically N-donor ligands were preferred over S-donors. it was demonstrated that the trans isomer is favored over the cis isomer in all cases due to reduction in ligand–ligand repulsion. Later. 1986). was performed (Pavankumar et al. 1996). but also of other complexes such as Pt (II)-based cisplatin analogs.. An intriguing question had been the preferential antitumor activity of the cis isomer over the trans isomer.. To enable comparison of the binding of Pt(II) to various positions in the four nucleobases in DNA and to keep computational costs to a minimum. which is somewhat surprising because it could be argued that the inductive effects of the electron-withdrawing oxo group at the C6 position of guanine should reduce the electron density at N7 compared to adenine that has an electron-donating amino group at the C6 position. Lau and Deubel. 2001. Cisplatin binds to other cellular components. Following the finding of its antitumor activity over three decades ago. electronic.and sulfur-donor ligands as models of competing ligands encountered in a biological system (Deubel.and transplatin and related hydrolysis product (Carloni et al. followed by an MP2-based energy analysis (Nikolov et al. These differences become negligibly small when favorable hydrogen bonding interactions are possible between the ammine ligands and the other labile ligands (Basch et al.and N-containing ligands that are expected have the greatest affinity for platinum based on good hardness. describes the interaction of transplatin and the fragments trans-PtCl2(NH3) þ and Pt(NH3)23 þ with G:C and A:T base pairs using DFT. a fact then attributed to the steric effects of binding DNA bases. including pure ECP and hybrid ECP with various electron correlation methods up to the MP4 level.. significant efforts have focused on understanding the binding of cisplatin with other entities found in the cells. 2006). strong research has been carried out to reveal the details of its cytotoxic activity and to design analogs with reduced side effects (Mantri and Baik. 2006). 2006). Results suggested that the replacement of the chloride ligands of cisplatin by carboxylate ligands in carboplatin resulted in a greater stability of the metalligand bonds in the latter. 2006) Density functional theory was applied to provide new insights into the structure and reactivity of cis. cisplatin–DNA interactions are the next theoretical studies. Cisplatin has been known to bind to guanine with much greater preference over adenine. and DFT. a more comprehensive 373 study comparing the geometric. N3. the kinetics of the substitution reaction of various nitrogen. Mantri and Baik. and the binding and recognition of HMG domain and/or DNA repair proteins to these adducts (Mantri and Baik. where a common approach adopted has been to use DFT to optimize the geometries of the key intermediates and reevaluate their energies using higher level ab initio methods. leading to 3-fold resistance to cisplatin (Shen et al. 1999). and N7 atoms (Mantri and Baik. In another study. 1986). The ranking of the bases followed the order: G(N7) 4C(N3)4C(O2)4G(O6)4A(N3)EA(N1)4A(N7)4G(N3)4T(O4) 4T(O2). other transition metal complexes. leading to potentially higher activation energy for substitution reactions. sophisticated. This hydrolysis was studied by several others using various levels of theory. the N7 position of guanine—in particular intrastrand binding to two adjacent guanines—was confirmed as the preferred binding site. The presence of the N1 proton diminishes the delocalization of electron density over the nitrogen lone pairs of the purine skeleton resulting in greater localization of electron density on the N3 and N7 atoms of guanine. the ineffectiveness of transplatin. 5. computational studies have been conducted to complement experimental works. 2000) and also to compare the electronic structures of cisplatin and its second-generation analog carboplatin (Carloni and Andreoni. based on differential Pt(II) binding energies. The very first computational studies on cisplatin aimed at better understanding the hydrolysis of cisplatin. 2006. . both quantum mechanical and molecular mechanical methods are being used. with the selectivity originating from electrostatic rather than orbital-based interaction (Deubel. and reduction in cisplatin accumulation. In an attempt to identify yet another subtle electronic feature that could help in distinguishing between the reactivity of adenine and guanine. Recently. to study the thermodynamics and kinetics of not only cisplatin–DNA complexes. The hydrolysis process of cisplatin which activates the drug was the goal of past research. 2012). 2005). while adenine exposes an N1 lone pair. and/or adding solvation corrections based on continuum dielectric models. and vibrational properties of cisplatin using different basis sets.. At present..and sulfur ligands with the activated cisplatin complex was modeled using DFT. 2004). 2002). the directional preference in the formation of the bifunctional adducts. it was discovered that the [Pt] fragment is a poor π-donor. Zhang et al. 1994. the effect of cisplatin binding on the dynamics of DNA. the disruption of base stacking and other local distortions. and the extended Huckel method for deriving charge distributions and electronic energies were studied. 2006). However. There is increasing awareness now that one important reason for cisplatin's performance is associated to the high mobility group (HMG) proteins that bind to DNA and protect the drug–DNA adducts against excision repair (Wang and Lippard. 2006). Thermodynamics of hydrolysis of cisplatin and bis(ethylenediamine) dichloroplatinum(II) using a combination of molecular mechanics for obtaining optimized geometries of the reactants and products. thus making the N7 of guanine less nucleophilic compared to adenine (Mantri and Baik. because the activation by hydrolysis had long been established as the rate-limiting step (Basch et al. The major difference between guanine and adenine is that N1 of guanine is protonated. Dasari. Thus.. which resulted in a large kink in the DNA helix.S. On the basis of the ranking above and the fact that most of the potential binding sites are in reality unavailable for binding due to Watson–Crick base pairing. Other areas of active study on cisplatin are degree of local bending/unwinding upon cisplatin binding.. in full agreement with experimental evidence (Mantri and Baik. Computational models have made significant contributions to understanding the nature and reactivity of cisplatin and allowed for delineating many features of how it binds to DNA. causing polymerases to be stalled at the kink. compared to adenine where the electron density is delocalized over the N1. nitrogen. P. in particular S.softness matching. 2005). It was reported a thorough DFT study which compared the Pt–L bond strengths of a series of tri. Future research is aiming at elucidating the role of repair enzymes in modulating the cytotoxic activity of DNA binding agents (Mantri and Baik.ammine platinum(II) complexes with oxygen-.13. The combination of dramatically improved computer hardware and robust. and DNA binding organic molecules. 2006). Computational studies of cisplatin Cisplatin is one of the most effective anticancer drugs currently in use. and numerically efficient modeling software has allowed for employing high levels of theory to examine various aspects of cisplatin chemistry using computational chemistry techniques. thus π-back donation does not appear to play a major role (Mantri and Baik. It was eventually discovered that the cis orientation of the leaving groups allowed binding of two adjacent guanine bases on the same strand.

Cardiotoxicity Leakage of lactate dehydrogenase (LDH) and creatine kinase (CK) from cardiac myocytes is due to cardiotoxicity could be a secondary event following cisplatin-induced lipid peroxidation of cardiac membranes. Other organ toxicity Other cisplatin-induced organ toxicities such as ototoxicity. ovarian. 6.J. 2006). 2003). The cisplatin concentration in proximal tubular epithelial cells is about 5 times the serum concentration (Kuhlmann et al.. 2010). which is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids to generate metabolic energy. N. 2007). combinatorial strategies which target multiple mechanisms. Kidney damage is caused by the inhibition of Carnitine synthesis and also by the Carnitine reabsorption by the proximal tubule of nephron. 2009).K. 2004.. T.3. 2003) 7. In general.. 1053–1073.. myelosuppression. 6. However. cisplatin and other platinum-based compounds are considered as cytotoxic drugs which kill cancer cells by damaging DNA. R. 2007. Hence. breast.M. L. Later. hepatotoxicity and Cardiotoxicity (Al-Majed.1.K. 6. arrhythmias.. Bernard Tchounwou / European Journal of Pharmacology 740 (2014) 364–378 6.. 2005). such as selenium (Liao et al. Pryer. 471–478. 2004). which is due to declined production of Carnitine.. Cisplatin treatment has been associated with several toxic side effects including nephrotoxicity (de Jongh et al.. Ishida et al. G12MD007581) through the RCMI Center for Environmental Health at Jackson State University. cardiotoxic. 2008) and vitamin E (Naziroglu et al. are major alterations in the cisplatin toxicity (Kart et al. Moving forward. 2010. Many cardiac events have been reported in many case reports including electrocardiographicchanges. down-regulation of proto-oncogenes and anti-apoptotic proteins. combination therapies of cisplatin with other drugs are common practice in the treatment of human cancers.2. Elevation of the hepatic enzymes level in serum and bilirubin are the indicators for impaired liver functions (Iseri et al. kidney and testicular cancers. leukemia. et al. Cisplatin is cleared by the kidney by both glomerular filtration and tubular secretion (Yao et al. Cancer Ther. S.. 2007).4. 2007). cisplatin chemotherapy is also associated with substantial side effects that include hepatotoxic. P. Conclusions Cisplatin is one of the most effective anticancer agents widely used in the treatment of solid tumors. Recent studies have focused on methods for protection of cisplatin-induced Hepatotoxicity using various agents. nephrotoxic. Studies in recent years have identified two different membrane transporters capable of transporting cisplatin into cells: Ctr1 and OCT2 (Ishida et al.. A histochemical approach to the mechanism of action of cisplatin and its analogues.. 1998. References Abrams. and inducing apoptotic cell death. 2000. Toxicological effects of cisplatin Cisplatin interacts with DNA. cardiomyopathy and congestive heart failure (Yousef et al.. Several molecular mechanisms of action including induction of oxidative stress as characterized by reactive oxygen species production and lipid peroxidation. Also. also many studies reported that there were a significant elevation in the hepatic malonaldehyde (MDA) and reduction in the level of antioxidant enzymes in rats treated with cisplatin (Yilmaz.Observed histopathological changes will be necrosis and degeneration of hepatocytes with inflammatory cells infiltration around portal area with sinusoidal dilatation (Kart et al. 41. induction of p53 signaling and cell cycle arrest.Oxidative stress is the main reason for cisplatininduced toxicity possibly due to depletion of reduced glutathione GSH (Yilmaz et al. 2004). The most sensitive biomarkers directly concerned in causing the cellular damage and toxicity are transaminases. Cetin et al. 2003). 2009). 502–516.. 2. and activation of both intrinsic and extrinsic pathways of apoptosis.. ... S. including antioxidant enzymes and non enzymatic molecules. Murray. 2006).The disproportionate accumulation of cisplatin in kidney tissue contributes to cisplatin-induced nephrotoxicity (Arany and Safirstein. Hepatotoxicity High dosage of cisplatin may lead to hepatotoxicity (dos Santos et al. J.B. Findings of several studies have suggested that other compounds combined with cisplatin constitute the best therapeutic approach to overcome drug resistance and reduce the undesirable side effects. Nephrotoxicity The kidney accumulates cisplatin to a greater degree than other organs and is the major route for its excretion. Aggarwal. because they are cytoplasmic in location and are released into the circulation after cellular damage. Based Drugs 5. 2003.. Met. Iraz et al.. neurotoxic and/or hematotoxic damage. Ovarian cancer: strategies for overcoming resistance to chemotherapy. may offer the best chance for clinically meaningful prevention. Histochem. Agarwal. some patients may relapse from cisplatin treatment with their cancers being refractory to cisplatin regimen. 1997). S... 6. Cisplatin hepatotoxicity was shown to be exacerbated by increased expression of cytochrome P450-2E1 enzyme (Caro and Cederbaum. gastrotoxicity. myocarditis. cisplatin is biotransformed in the kidney into cysteinyl glycine conjugates and other high thiols by some localized enzymes. Calcium modulation of toxicities due to cisplatin. Cherrington. 2002). 1993. Acknowledgments The research described in this publication was made possible by a grant from the National Institutes of Health (Grant no.J. Cancer 3. 2006). brain. Nat.B.. Kaye. J. Mansour et al.. 2005. and forms covalent adduct with purine DNA bases and this platinum compound. 2003. L. Decrease in antioxidant defense system is reported due to oxidative stress through the generation of reactive oxygen species...374 S.K.. Aggarwal. It has been extensively used for the cure of different types of neoplasms including head and neck. such as reducing cisplatin uptake and reducing inflammation. Dasari. Biosynthesis of amino acid lysine and methionine yields a quaternary ammonium compound called Carnitine. Rev. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Lee. allergic reactions and some reproductive toxic effects have also been reported (Hartmann et al. Cytochem. inhibiting DNA synthesis and mitosis. Mol.. Degeneration and necrosis of cardiac muscle fiber cells with fibrous tissue reaction and vacuolated cytoplasm of many muscle cells and blood vessels are inflated with blood are the histological changes of cisplatin induced toxicology (Al-Majed et al.. Hartmann and Lipp. interaction is the root cause for cytotoxic effect of cisplatin (Yousef et al.. Cisplatin concentrations within the kidney exceed those in blood suggesting an active accumulation of drug by renal parenchymal cells. reduced glutathione. 77–81. lung.. 2002).

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