Enhanced induction of apoptosis in a radio-resistant bladder tumor cell line by combined treatments with X-rays and wortmannin.
ABSTRACT The radiosensitizing effect of wortmannin (WM) treatment during and after irradiation was studied in radioresistant bladder tumor cell lines with normal (MGH-U1 cells) or defective p53 activity (RT112 cells). WM modulated G(2)/M cell cycle arrest induced by higher X-ray doses (10 Gy) in both cell lines, although the alteration was significant only in RT112 cells. The observation suggests that WM activity is independent of p53. Constitutive expression of DNA-PKcs was found to be higher in RT112 cells than in MGH-U1. Treatment with WM enhanced radiation-induced apoptosis significantly in RT112 cells while it had no effect on MGH-U1 cells. Although a variety of PI3-kinases and PI3-K like kinases (including ATM) could be inhibited by WM, our observation of increased early lethality by WM treatment in RT112 is in agreement with previous results. They suggest that the WM-dependent radiosensitization of RT112 is a direct consequence of the inhibition of DNA-PK, resulting in the inhibition of DSB repair in the fast component. This early effect in the p53 deficient cell line could also indicate that processes other than apoptosis may contribute to the increased radiosensitization. In our opinion, the expression level of DNA-PKcs in human tumor cells may be a good predictor for the success of DNA-PKcs inhibitors when used as radiosensitizers.
SourceAvailable from: Xiaodong Liu[Show abstract] [Hide abstract]
ABSTRACT: Traditional Chinese medicine (TCM) has been demonstrated to have potent cytotoxic activity against certain malignant tumors. Ionizing radiation (IR) is one of the most effective methods used in the clinical treatment of cancer. The drawback of a single formula is that it limits the treatment efficacy for cancer, while comprehensive strategies require additional theoretical support. However, a combination of different antitumor treatment modalities is advantageous in restricting the non-specific toxicity often observed with an extremely high dose of a single regimen. The induction of apoptotic cell death is a significant process in tumor cells following radiotherapy or chemotherapy, and resistance to these treatments has been linked to a low propensity for apoptosis. Autophagy is a response of cancer cells to IR or chemotherapy, and involves the prominent formation of autophagic vacuoles in the cytoplasm. In this review, the synergistic effects of TCM and radiotherapy are summarized and the underlying mechanisms are illustrated, providing new therapeutic strategies for cancer.Oncology letters 05/2013; 5(5):1439-1447. DOI:10.3892/ol.2013.1245 · 0.99 Impact Factor
Academic Journal of Second Military Medical University 11/2010; 29(11):1217-1220. DOI:10.3724/SP.J.1008.2009.01217
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ABSTRACT: Glioblastoma, one of the deadliest forms of brain tumor, responds poorly to available therapies. This highlights the intense search for new treatment approaches, and an emerging strategy is based on molecular targets. In the present work, we aimed to study whether glioblastoma cells can be sensitized by cisplatin combined with LY294002 (LY), which is an inhibitor of PI3K-related family (ATM, ATR, DNA-PK). We observed that cisplatin caused a pronounced reduction in cell proliferation in U343 and U87 cells, and LY significantly increased the cytotoxic effects caused by cisplatin under these conditions. Differently of U343, U87 cells did not show a significant induction of apoptosis. The phosphorylation level of damage response proteins was analyzed after drug-treatment either with/without LY. The presence of γH2AX foci and phosphorylation of TP53(ser15) and CHK1(ser317) were shown in U343 cells, compatible with cisplatin-induced DNA damage. Similarly, the level of ATR phosphorylation (ser428) was also increased (24 h). The transcript expression profiles of drug-treated compared with untreated U343 cells showed significant changes in the expression of 108 genes, while 274 genes were modulated by cisplatin+LY. The combined treatment caused a high proportion of down-regulated genes, which were mainly involved with DNA repair, cell death and cell cycle control/proliferation, metabolism, transcription regulation and cellular adhesion. Altogether, the present results indicate that most probably, PI3K-related kinases may play an important role in the resistance of glioblastomas cells to cisplatin, and the combination with LY can, at least in part, sensitize these cells to drug treatment.Molecular Biology Reports 11/2013; DOI:10.1007/s11033-013-2849-z · 1.96 Impact Factor