engleski

Determinants of increased sensitivity to lovastatin-induced apoptosis in cisplatin-resistant human laryngeal carcinoma cells

Cisplatin is one of the most effective and commonly used agents for the treatment of solid tumors. Nevertheless, acquired resistance to cisplatin represents a major obstacle to successful chemotherapy. We have observed that our cisplatin-resistant CA3ST and CK2 sublines display substantial alterations in cell morphology, adhesion and cytoskeleton organization comparing to their parental human laryngeal carcinoma HEp-2 cells. In addition, these sublines were more sensitive to lovastatin-induced apoptosis. Since HMG CoA-reductase inhibitors have already entered clinical trials for several types of cancer, we explored potential mechanisms of the increased sensitivity of the cisplatin-resistant cells to lovastatin. We used semiquantitative RT-PCR and Western blot to screen already known mechanisms that contribute to differential sensitivity of tumor cells to lovastatin, namely, the expression of P-glycoprotein, HMGCoA reductase, Bcl-2 and survivin, but found no correlation with the degree of sensitivity. In addition, statins with different lipophilicity gave the sensitivity pattern similar to the one of lovastatin, suggesting that the difference in sensitivity is not due to higher intracellular concentration of the active compound, which was confirmed by LC-MS. Nonetheless, lovastatin induced substantial increase in RhoB in all cell lines tested, while the expression of Rac1 and Cdc42 was decreased, especially in cisplatin-resistant sublines. Lovastatin toxicity was suppressed by the addition of geranylgeranyl PPi, and to less extent farnesyl PPi. In accordance, the alterations in the expression of Rho GTPases were also diminished. Since RhoB expression is downregulated in the cisplatin-resistant sublines, we presumed that this difference in basal RhoB level provides the difference in sensitivity. However, silencing of RhoB in HEp-2 cells with specific siRNA did not alter their sensitivity to lovastatin. Therefore, we conclude that increased susceptibility of cisplatin-resistant cells to lovastatin involves several geranylgeranylated proteins, among others Rac1 and Cdc42, which are presumably altered during the development of cisplatin resistance. Given that statins are safe and well tolerated even at higher doses, cancer treatment involving lovastatin could give superior results in patients that acquired resistance to cisplatin

Cisplatin; drug-resistance; RhoGTPases; RhoB

nije evidentirano