engleski

Expression of apoptotic genes in low, clinically relevant levels of drug resistance

Background and purpose: Recent publications have demonstrated that chemotherapeutic agents exert their cytotoxicity, at least partially, by inducing apoptosis. This observation has led to the concept the failure to activate this pathway in cancer cells may confer resistance to chemotherapy. The aim of the present study was to examine whether altered expression of apoptotic genes is involved also in low levels of drug-resistance that correspond to those detected in clinical samples. Materials and methods: We compared the p53 status and constitutive expression of several pro-apototic (p53, Bax, Fas and FasL) and anti-apoptotic (Bcl-2 and survivin) proteins in parental laryngeal carcinoma HEp2, cervical carcinoma HeLa and glioblastoma A1235 cells and their drug resistant cell lines: VA3, 7T, CK2 and VK2 (laryngeal carcinoma cells), HeLaCK and HeLaCA (cervical carcinoma cells) and CT (glioblastoma cells). Determination of DNA sequence (exons 5-9) was performed by Sanger dideoxy method, while expression of apoptotic genes was determined by Western blot method. Results: P53 status and constitutive expression of p53 was not changed in drug-resistant cells. The level of anti-apoptotic protein Bcl-2 increased in drug-resistant VA3, VK2 and 7T cells, while the level of proapoptotic protein Bax decreased in drug-resistant HeLa CA and HeLa CK cells. Constitutive levels of survivin, Fas and FasL were not altered in drug-resistant cell lines. No change in the expression of any of examined apoptotic genes was observed in drug-resistant CT or CK2 cells. Conclusion: In low, but clinically relevant levels of resistance to anticancer drugs, altered expression of apoptotic genes may cause/participate in drug-resistance of tumor cells. However, other mechanisms, such as increased activity of cellular protective mechanisms and/or altered expression of other apoptotic genes should be involved in low-level drug-resistance of tumor cells as well.

Drug resistance; Tumor cells; Apoposis; Low doses

nije evidentirano