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Biomedicine & Pharmacotherapy 60 (2006) 349–352

http://france.elsevier.com/direct/BIOPHA/

Review

Anticancer activity of polyoxomolybdate


H. Yanagiea,*, A. Ogatab, S. Mitsuib, T. Hisaa, T. Yamaseb, M. Eriguchia
a
Department of Intellectual Property, Project of Cancer Metastasis Inhibition,
Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan
b
Chemical Research Laboratory, Tokyo Institute of Technology, R1-21,
4259 Nagatsuta, Midori-ku, Yokohama 226-8503, and “Creation of bio-devices and bio-systems with chemical and biological molecules for medical use”,
CREST, Japan Science and Technology Agency (JST), Japan

Received 8 February 2006; accepted 22 February 2006


Available online 30 June 2006

Abstract
Anticancer polyoxomolybdates have been investigated for medical application of polyoxometalates as discrete cluster anions of metal oxides.
[NH3Pri]6[Mo7O24]·3H2O (PM-8) has been recognized as one of significant antitumoral polyoxomolybdates. PM-8 had shown the growth sup-
pression against several tumors, for examples, Co-4, human colon cancer, MX-1, human breast cancer, and OAT, human lung cancer. PM-8
showed the tumor growth suppression for MKN-45 human gastric cancer in tumor bearing mice. PM-8 inhibited the cell growth of AsPC-1
which depended on the dose with showing DNA ladder formation and DNA fragmentation, and positive Hoechst staining indicating apoptosis.
The ratio of apoptotic cells on flow cytometry analysis were 35%, and 57% with treatment of PM-8 after 48, and 72 h, respectively. One of the
anti-tumor activity of PM-8 result from the activation of apoptotic pathway. It is thought that polyoxomolybdates will be applied as a novel anti-
tumor agent especially against cancers which are difficult to be treated clinically.
© 2006 Elsevier SAS. All rights reserved.

Keywords: Polyoxomolybdate; Cancer growth inhibition; Apoptosis; Redox reaction

1. Background Yamase [15,16] had reported that significant antitumoral effect


of polyoxomolybdates, especially [NH3Pri]6[Mo7O24]·3H2O
Polyoxometalates, the discrete polymeric anions of early (PM-8) was found against MX-1 murine mammary cancer cell
transition metal oxide, form a large class of inorganic com- line, Meth A sarcoma and MM46 adenocarcinoma. The structure
pound with great molecular diversity and significant potential the anion of PM-8 is constructed large open circles oxygen atoms
applications in analytical chemistry, material science, catalysis, and small closed circles represent Mo atoms [17]. PM-8 is water-
and medicine. Polyoxometalates are negatively charged inor- soluble and structurally stable in aqueous solutions at pH 5–7
ganic substances which contain early transitional metal ions [18]. The polyoxometalates can usually be isolated as ammonium
such as tungsten (W), molybdenum (Mo), vanadium (V), nio- metallic, or organometallic salts [19].
bium (Nb), antimony (Sb), etc., and which make a cluster with In vivo or in vitro anti-tumor activity of cyclopentadienyl
the surrounding oxygen atoms. titanium-containing polyoxotungstates has been investigated
Several polyoxometalates has been reported to inhibit the along with the modification of the well-known antitumoral
replication of the human immunodeficiency virus (HIV) [1– organo-titano compound [20–23].
6], herpes simplex virus (HSV) [7–10], influenza virus (fluV)
[11], and respiratory syncytial virus (RSV) [12]. Also, the anti- 2. Cancer cell cytotoxicity and tumor growth suppression
bacterial activities against methicillin-resistant Staphylococcus of polyoxomolybdate
aureus (MRSA) [13], Streptococcus pneumoniae [14].
Some polyoxometalates such as PM-8, PM-17, PM-26, and
* Correspondingauthor. Tel.: +81 3 5452 5436; fax: +81 3 5452 5434. PM-32 were found to exhibit anti-tumor activities against Co-4,
E-mail address: yanagie@ip.rcast.u-tokyo.ac.jp (H. Yanagie). MX-1, OAT human cancers and Meth A mouse sarcoma using
0753-3322/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.biopha.2006.06.018
350 H. Yanagie et al. / Biomedicine & Pharmacotherapy 60 (2006) 349–352

SRC assay on tumor bearing mice [24]. It had been reported that tion potential (≈–0.10-[HXMo7O24]6–. The plausible redox
[NH4]6–[Mo7O24]·4H2O and K6[Mo7O24]·4H2O were effective, reaction between [HxMo7O24]6– and host cells results in
whereas [NH3Pri]Cl was ineffective against Meth A tumor bear- [Mo7O24]6– formation and cytotoxicity (due to the reduction
ing mice [24]. Especially, hexakis (isopropylammonium) hepta- of the host cells). [Mo7O24]6– produced in the host cells will
molybdate (V1) [NH3Pri]6[Mo7O24]·3H2O exhibited a signifi- be transmitted to the tumor cells and contribute to the tumor
cant inhibition on the growth of Meth A sarcoma. The results cell killing due to the reproduction of [HxMo7O24]6– as a result
indicate that the polyoxomolybdate structure of the Mo7O24 is of the redox reaction with the tumor cells.
apparently of critical significance for the antitumor activity. [NH3Pri]6–[HxMo7O24] exhibited a significant inhibition on
Anderson structural polyoxometalates and V-shaped heptamo- growth of Meth A sarcoma. This results indicated that the
lybdates have been recognized to exhibit antitumor activities at structure of the [Mo7O24]6– is apparently important for antic-
non-cytotoxic doses in vivo. If the polyoxometalates exhibit ancer activity [16].
their redox reactions and adsorption ability in/on the cell, it is PM-8 inhibited the cell growth of AsPC-1 with showing
necessary to modify the electron-transfer net work in the biolo- DNA ladder formation and DNA fragmentation, apoptotic
gical system [15,16,19,24]. small bodies on Hoechst staining and TUNEL staining. The
Polyoxotungstate CoW11(CpTi) remarkably decreased flow cytometry analysis reveals that the ratio of apoptotic
tumor weight of the rats bearing SSMC-7721 (liver cancer cells increased with the duration of the PM-8 treatment: 35%
cell), HL-60 (leukemia) and HLC (colon cancer cell) in in after 48 h of the PM-8 treatment, and 57% after 72 h, while
vivo model. The in vivo antitumor activity of CoW11(CpTi) there were no apoptotic cells in control. These results indicated
resembles the antitumor drugs of clinical practice cyclopho- that one of the mechanisms of cancer cell cytotoxicity is apop-
sphamide (CP) and 5-fluorouracil (5-FU), but the toxicity of tosis in the cancer cells. The apoptosis was induced in the man-
CoW11(CpTi) is much lower than the latter [13]. ner of concentrations of PM-8 [25].
Cytotoxic effects of PM-8 on the proliferation of human PM-8 exhibited non-specific weak interaction with DNA
gastric cancer cell line, MKN45 reveals that IC50 values of [26]. PM-8 can be distinguished from the antitumor mechanism
PM-8 for 24 and 48 h-treatments were 0.90 and 0.50 mg/ml, of a mononuclear metal complex such as CDDP and other
respectively. The tumor growth suppression on MKN45 tumor organometallic compounds, because in case of CDDP the dis-
bearing mice by PM-8 became twice compared to the control sociation of chloride ligands is followed by binding to N-7
groups after 70 days incubation. PM-8 did not induced any atoms of guanine bases in DNA and formation of DNA inter-
adverse effects such as body weight loss in the host mice. strand crosslinks at clinically achievable concentration [27,28].
The cytotoxic effects of PM-8 on the proliferation of human It has been shown that [Mo7O24]6– interacts with flavinmo-
pancreatic cancer cell line, AsPC-1 reveals that IC50 values of nonucleotide (FMN) to yield the 1:1 [Mo7O24]6-–FMN com-
PM-8 for 24 and 48 h-treatments were 1.65 and 0.50 mg/ml, plex [8,24]. Since FMN is a prosthetic group in a flavoprotein
respectively [25]. and acts as an electron carrier for the electron transfer (from
NADH to coenzyme Q) coupled with the ATP generation at
3. Anticancer mechanisms of polyoxomolybdate the site 1 [16], therefore, it has been proposed that the forma-
tion of the 1:1 [Mo7O24]6––FMN complex in mitochondria on
the tumor cell inhibits ATP generation with a resultant antitu-
Antitumor mechanism of polyoxometalates is based on the mor activity [8,11,20]. Therefore, it may be point out that the
redox reaction. The MoVO5(OH) site in the Mo7O24 framework induction of apoptosis by PM-8 is due to blocking the signal
exhibits a strong toxicity in contrast to the d0-configurated pathway derived from the response of mitochondria. These
MoVIO6 site but the antitumoral potency of the former is simi- hypothesis reveals that the apoptotic pathway may be asso-
lar to that of the latter. This provides a clue to the mechanism
ciated with this redox hypothesis [15,19,29].
of the antitumor activity of the [Mo7O24]6– to [Mo7O23(OH)]6–
It is well known that the PM-8 exhibited non-specific weak
is involved in the antitumor mechanism, which leads to
interaction with DNA, different from the case of 5-FU, or cis-
repeated cycles of the redox reaction of Eq. (1) in tumor cells
platin (CDDP). The mechanism of anti-tumor activity of 5-FU
[16]:
is unformulation of RNA, and that of CDDP is the DNA inter-
½Mo7 O24 6 þ e þ Hþ !½Mo7 O23 ðOHÞ6 (1) strand crosslinks derived from adduction of guanine bases [27,
28]. It is also well known that there are several pathways for
Yamase et al. had been reported that the modification of the apoptosis, such as induction of cytochrome C to caspase 9,
polyoxometalates is described as follows; (1) the [NH3Pri] the induction of caspase 8 to caspase 3 from external stimula-
cation was replaced by [NH4]+ and K+; (2) the [Mo7O24]6– tions or nuclear signalings, and bcl 2 pathway inductions [30].
anion was replaced by Cl–; (3) the reduction of [Mo7O24]6– to A novel polyoxotungstate [CoW11O39(CpTi)7–(Cp = η5–C5H5)
[HXMo7O24]6– in the tumor cells, leading to the specificity of exhibits the highest antitumor activity in vitro among the
tumor cell killing by [HXMo7O24]6–, seems to reflect the anti- cyclopentadienyltitanium substituted polyoxometalates investi-
tumor potency of [Mo7O24]6–. The strong toxicity of the d1 gated and has a remarkable inhibitory action on three types of
configuration in the Mo7O24 framework may be explained by human cancer cells, SSMC-7721, HL-60 and HLC, in vivo. It
the reduction of the host cells due to the highly negative oxida- has been reported that β-SiW9(CpTi)3 can degrade the genomic
H. Yanagie et al. / Biomedicine & Pharmacotherapy 60 (2006) 349–352 351

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