The natural antioxidant gallic acid (GA) was isolated from fruits of a medicinal Indonesian plant, Phaleria macrocarpa (Scheff.) Boerl. The structure was identified on the basis of spectroscopic analysis and comparison with authentic compound. GA demonstrated a significant inhibition of cell proliferation in a series of cancer cell lines and induced apoptosis in esophageal cancer cells (TE-2) but not in noncancerous cells (CHEK-1). Observation of the molecular mechanism of apoptosis showed that GA up-regulated the proapoptosis protein, Bax, and induced caspase-cascade activity in cancer cells. On the other hand, GA down-regulated antiapoptosis proteins such as Bcl-2 and Xiap. In addition, GA also induced down-regulation of the survival Akt/mTOR pathway. In non-cancerous cells, we observed delayed expression of pro-apoptosis related proteins. Our results suggest that GA might be a potential anticancer compound. However, in depth in vivo studies are needed to elucidate the exact mechanism.

No abstract

No abstract

No abstract

Alterations of the Akt/mTOR pathway have been observed in numerous types of cancer, thus this pathway represents an exciting new target for molecular therapeutics. We investigated the expression of activated Akt (p-Akt) and mTOR (p-mTOR) in patients with adenocarcinoma of the cervix and the involvement of the p-Akt/p-mTOR pathway in response to combination of inhibitor agents, rapamycin and LY294002, with conventional therapy, cisplatin, in vitro. Immunohistochemistry analysis of p-Akt and p-mTOR was conducted in 26 patients with adenocarcinoma of the cervix. Western blot analysis was performed to determine the protein expression involved in response to chemotherapy in cervical cancer cell lines. The results showed that p-Akt and p-mTOR were identified in 50% and 53.8% of adenocarcinoma of the cervix. The expression of p-mTOR was a significant independent marker for prognosis. A significant correlation between p-Akt and p-mTOR was observed. There was no correlation between their expressions with any of clinicopathological factors. In the in vitro study, cisplatin at CPI(50) targets both the apoptosis and survival pathway by activating the caspase-cascade; inhibiting Akt, mTOR, p70S6K, and 4EBP1. Combination of rapamycin with cisplatin induced synergistic interaction. On the other hand, combination with LY294002 resulted in either synergistic or antagonistic effect depending on the doses given. Rapamycin pretreatment potentiated cisplatin-induced apoptosis cell death and enhanced blocking of the survival pathway. Overall, the expression of p-mTOR is a significant prognostic marker of adenocarcinoma of the cervix and a potential molecular target for the treatment of cervical cancer. Inhibition of the mTOR pathway contributes to cisplatin-induced apoptosis in cervical cancer cell lines.

To our knowledge, this study is the first in which the expression of RhoA and RhoC at the mRNA level in ESCC was examined and compared with its normal counterpart. Our results suggest that rhoA and rhoC are involved in ESCC progression and useful as prognostic markers. Further study will be needed to examine the therapeutic potential of the Rho GTPase inhibitor as a promising anticancer therapy, especially in ESCC.

Clear cell adenocarcinoma of the ovary has a poor prognosis due to chemoresistance and early metastasis to the lymph nodes. It also can result in endometriosis and is the second most frequent type of ovarian cancer in Japan. Serous adenocarcinoma of the ovary is another common epithelial cancer tissue subtype in Japan, and it is highly sensitive to chemotherapy. In the current study, we examined the differential expression of genes in these types of ovarian cancer and tried to analyze their functions, especially as they relate to chemoresistance. We used differential display to compare clear cell carcinoma and serous adenocarcinoma of the ovary. We identified sperm protein 17 (SP17) as a candidate gene related to the chemoresistance of clear cell carcinoma. Its differential expression was confirmed by real-time polymerase chain reaction. Because the function of the SP17 gene in ovarian cancer is not known, we examined the effect of small interfering RNA targeting the SP17 gene on the chemoresistance and proliferation of ES-2 ovarian cancer cells to paclitaxel, currently the most effective treatment for ovarian cancer. We found that this treatment decreased the chemoresistance of these cells to paclitaxel. Our results strongly suggest that SP17 plays a role in the resistance of clear cell carcinoma to chemotherapy without influencing their ability to proliferate.

Differential sensitivity was observed in human ESCC cell lines in response to paclitaxel treatment. G2/M arrest occurs with a prior to paclitaxel-induced apoptosis and might be mediated by the mitochondrial (intrinsic) apoptosis pathway in human ESCC cells.