Overcoming cisplatin resistance by mTOR inhibitor in lung cancer

Our data show that CCI-779 possess antiproliferative effects in both cisplatin sensitive and resistant cell lines, but shows no effect in P-gp1 and MRP1 overexpressing cell lines. Importantly, CCI-779 at 10 ng/ml (less that 10% of the growth inhibitory effect) can increase the growth inhibition of cisplatin by 2.5–6 fold. Moreover, CCI-779 also enhances the apoptotic effect of cisplatin in cisplatin resistant cell lines. In these resistant cells, adding CCI-779 decreases the amount of 4E-BP phosphorylation and p-70S6 kinase phosphorylation as well as lower the amount of elongation factor while cisplatin alone has no effect. However, CCI-779 can only reverse P-gp mediated drug resistance at a higher dose(1 ug/ml).We conclude that CCI-779 is able to restore cisplatin sensitivity in small cell lung cancer cell lines selected for cisplatin resistance as well as cell lines derived from patients who failed cisplatin. These findings can be further explored for future clinical use. On the other hand, CCI-779 at achievable clinical concentration, has no growth inhibitory effect in P-gp1 or MRP1 overexpressing cells. Furthermore, CCI-779 also appears to be a weak MDR1 reversal agent. Thus, it is not a candidate to use in MDR1 or MRP1 overexpressing cells.Cisplatin and its analog carboplatin have significant antitumor activity against a wide variety of solid tumors[1]. Furthermore, cisplatin also showed synergistic effect with other chemotherapeutic agents and therefore has been incorporated in many treatment regimens for solid tumors [1]. Like other chemotherapeutic agents, resistance to this drug is inevitable and often occurs after several cycles of treatment. Several laboratories have studied the mechanism(s) of cisplatin resistance in the past decades and many possible mechanism(s) have been identified [2-9]. These resistance mechanism(s) appears to fall into four major categories. The first category involves DNA damage/repair proteins. The second category involves drug r