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Green tea and other natural products induced apoptosis

in cervical cancer cells


Study I:
Jean M. Feugang, Francisco Garcia, Chaofeng Sun, Jian Wang, Andrew Abalos, Sui
Zhang and Changping Zou

University of Arizona, Dept of OB/GYN, Tucson, AZ, MD Anderson Cancer Center, Dept of
Cardiovascular, Houston, TX, Arizona Cancer Ctr., University of Arizona, Tucson, AZ

Cervical cancer is the third most common gynecologic malignancy in the world,
accounting for 15% of all cancers diagnosed in women. Cervical cancer has a well-
characterized pre-malignant phase, cervical intraepithelial neoplasia (CIN). CIN is
detectable using readily available well-established techniques including exfoliative
cervical cytology (Pap smear), human papillomavirus (HPV) testing, and colposcopy.
These facts make cervical cancer/CIN an ideal target for chemoprevention. Cancer
chemoprevention is the administration of chemical agents to prevent or delay the
development of cancer, in which chemical agents are used to prevent cancer in normal
and/or high-risk populations. However, the number of currently available preventive
agents is limited and the chemical agents are costly. Natural products, such as certain
herbs have demonstrated anti-cancer effects. We investigated Arizona cactus extracts and
green tea compounds (EGCG and polyphenol E) for their anti-cancer effects in cultured
immortalized cervical epithelial cells and cervical cancer cells. Green tea compound and
aqueous extracts of cactus pear were used to treat immortalized cervical epithelial cells
and cervical cancer cells. The cactus mix and green tea compounds were used at six
concentrations 0, 0.5, 1, 5, 10 or 25% and 0, 1, 5, 10, 25, 50 µg/ml, respectively. Growth
inhibition, apoptosis induction, and cell cycle were analyzed in these cells. Cells exposed
to these two natural products had a significant increase in apoptosis, especially cactus mix
and tea-EGCG. Tea-poly E had a little effect on apoptosis induction at concentration of
50 µg/ml; however it increased G1 and decreased S phases. Natural products effectively
inhibited immortalized cervical epithelial cells and cervical cancer cells growth, and
induced apoptosis. The mechanism of the anti-cancer effects of natural products needs to
be elucidated in future studies. Supported by the Women’s Fund for Health, Education
and Research, and the National Institutes of Health, National Cancer Institute (NIH/NCI),
grant number NOI-CN-35158.
Study II:
OBJECTIVE: The purpose of this article is to estimate the anti-cancer effects of the
major components of the green tea (polyphenols, catechin and EGCG) and the
mechanism of EGCG on different cervical cancer cell lines. METHODS: Six cervical
cancer cell lines (HeLa, HeLaS3, Caski, SiHa, HT3 and C33A) were treated with 20
microgram/ml green tea polyphenols (GTPs), 50 micrometer catechin and various
concentrations of (-)-epigallo- catechin-3-gallate (EGCG). The viabilities were
determined by trypan blue exclusion assay, neutral red assay and 3-[4,5-dimethylthiazol-
2-yl]-2,5-diphenyltetrazolium bromide assay. DNA fragmentation and nuclear
condensation were used to see whether EGCG-induced anti-proliferation effect was due
to apoptosis. RESULTS: Both GTPs, catechin and EGCG had growth inhibition effects
on cervical cancer cell lines, but EGCG appeared to be the most effective. What's more,
the sensitivity of each cell lines to EGCG was different. HT3 cells (HPV negative, mutant
type p53) were most sensitive to EGCG (estimate IC50: 10 micrometer). Caski (HPV-16
positive, wild type p53) and HeLaS3 cells (HPV-18 positive, wild type p53) were less
sensitive (estimate IC50: 35 and 70 micrometer respectively). EGCG-induced apoptosis
can be seen in all the cell lines and it happened as early as 8 hours after EGCG treatment.
CONCLUSION: Green tea or EGCG alone will be beneficial to the cervical cancer
patients. Affiliation:
Department of Oncology, Harbin Red Cross Central Hospital, Harbin, China.
Chungnam National University Cancer Research Institutes, Chungnam National
University, Taejon, Korea.
Department of obstetrics and Gynecology, College of medicine, Chungnam National
University, Taejon, Korea.
Department of Obstetrics and Gynecology, College of Medicine, The Catholic University
of Korea, Seoul, Korea.
STUDY III:
The increasing recognition of green tea and tea polyphenols as cancer preventives has
created a need for a study of their bioavailability. For this purpose, we synthesized [3H]
(-)-epigallocatechin gallate ([3H]EGCG) with a specific activity of 48.1 GBq/mmol and
directly administered the solution into the stomachs of CD-1 female or male mice.
Radioactivity in the digestive tract, various organs, blood, urine and feces was measured
with an oxidizer at various times after administration and significant radioactivity was
found in the previously reported target organs of EGCG and green tea extract (digestive
tract, liver, lung, pancreas, mammary gland and skin), as well as other organs (brain,
kidney, uterus and ovary and testes) in both sexes. Incorporation of radioactivity in the
cells was confirmed by microautoradiography. Within 24 h, 6.6 (females) and 6.4%
(males) of total administered radioactivity was excreted in the urine and 37.7 and 33.1%
in feces. HPLC analysis of urine from both sexes revealed that 0.03-0.59% of
administered [3H]EGCG, along with at least five metabolites, was excreted. In addition,
we found that a second, equal administration to female mice after a 6 h interval enhanced
tissue levels of radioactivity in blood, brain, liver, pancreas, bladder and bone 4-6 times
above those after a single administration. These results suggest that frequent consumption
of green tea enables the body to maintain a high level of tea polyphenols and this paper is
the first pharmacological evidence of a wide distribution of [3H]EGCG in mouse organs,
indicating a similar wide range of target organs for cancer prevention in humans.