engleski

Human laryngeal carcinoma cells resistant to carboplatin demonstrate lower constitutive FasL expression and increased expression of atp7a and nhe1 efflux pumps

Chronic exposure of tumor cells to carboplatin (CBP) results very often in development of acquired CBP resistance reducing the efficacy of tumor therapy. The analysis of parental human laryngeal carcinoma (HEp2) cell line and its CBP-resistant subline (7T) identified CBP-induced apoptosis as the cause of resistance. Upon CBP treatment of HEp2 and 7T cell lines we found similar pattern of Bcl-2, survivin and p-Bad expression. Bcl-2 silencing did not influence the sensitivity of both cell lines to CBP treatment therefore excluding a main role of the mitochondrial pathway in apoptosis induction. The constitutive level of FasL was higher in sensitive HEp2 as compared to resistant 7T cells. CBP more efficiently increased the transcription of fasL mRNA in HEp2 than in 7T cell line, indicating the role of death receptor pathway in apoptosis induction. After analyzing several signaling pathways which could be involved in decreased apoptosis of 7T cells, we present here the most promising model. Total cell and DNA platination upon CBP treatment were lower in resistant 7T as compared to sensitive HEp2 cells. The decreased platination delayed activation of SAPK/JNK and p38 in 7T cells. Reduced platination of 7T is very likely caused by an increased constitutive expression of ATP7A and NHE1 efflux pumps found in those cells as compared to HEp2 cells. Our results reveal transcriptional alterations in CBP resistant cells that could be involved in acquired drug resistance. Studies on the mechanisms of anticancer drug resistance provide important information about how to improve cancer chemotherapy.

carboplatin; drug resistance

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