engleski

Lovastatin overcomes cisplatin resistance in human laryngeal carcinoma cells

Greater insight into the molecular mechanisms regarding modulation of the cellular response to anti-cancer drugs could help to develop and optimize therapeutic strategies. The aim of the present study was (i) to examine and compare the cytotoxic effect of lovastatin on human laryngeal carcinoma HEp2 cell line and its cisplatin resistant CA3ST and CK2 sublines, (ii) to examine whether it can overcome resistance to cisplatin, and (iii) to delineate the underlying mechanisms. The results show that CA3ST and CK2 cells were more sensitive to this statin than their parental HEp2 cells. Lovastatin induced drastic changes in cell morphology in both, parental and cisplatin resistant laryngeal carcinoma cells, time- and concentration-dependent arrest of cells in G1 phase (more pronounced in cisplatin resistant than parental HEp2 cells), and at later time points apoptosis in CA3ST and CK2 cells. In addition, lovastatin pretreatment overcame resistance of CA3ST and CK2 cells to cisplatin by priming these cells to undergo apoptosis. Increased sensitivity of CA3ST and CK2 cells to lovastatin was reduced by addition of geranylgeranyl pyrophosphate (GGPP), and to a smaller degree by farnesyl pyrophosphate (FPP). Geranylgeranyl transferase inhibitor (GGTI-286) induced similar sensitivity pattern as lovastatin, while farnesyl transferase inhibitor (FTI-I) had no significant effect, suggesting that lovastatin-caused inhibition of geranylgeranylation of target proteins is the predominant mechanism of lovastatin-induced reversion of cisplatin resistance. The most important targets for geranylgeranylation are Rho proteins, key molecules involved in essential cellular processes. Their lipid modification is essential for their localization to cell membrane and their biological functions. As a support that Rho proteins are the target of lovastatin activity, we demonstrated that lovastatin decreased the translocation of RhoA and Rac1 from cytosol to membrane fraction in HEp2, CA3ST and CK2 cells. Thus, blockage of the mevalonate pathway, particularly inhibition of protein geranylgeranylation, has the critical role in lovastatin reversion of cisplatin resistance in laryngeal carcinoma cells. This data could suggest new clinical strategies aimed to improve efficacy of chemotherapy of specific tumor types with cisplatin.

cisplatin; drug-resistance; lovastatin; resistance-reversion; laryngeal carcinoma cells

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