Overcoming cisplatin resistance by mTOR inhibitor in lung cancer

Chunjing Wu,Theodore Lampidis,Marcus Tien Kuo,Niramol Savaraj,Medhi Wangpaichitr,Lynn Feun,Carlos Robles

doi:10.1186/1476-4598-4-25

Abstract

BackgroundCisplatin resistance is complex and involves several different mechanisms. Employing cDNA microarray analysis, we have found that cisplatin resistant cells share the common characteristic of increase in ribosomal proteins and elongation factors. We hypothesize that in order to survive cisplatin treatment, cells have to synthesize DNA repair proteins, antiapoptotic proteins and growth-stimulating proteins. Thus, by blocking the translation of these proteins, one should be able to restore cisplatin sensitivity. We have studied the role of CCI-779, an ester analog of rapamycin which is known to inhibit translation by disabling mTOR, in restoring cisplatin sensitivity in a panel of cisplatin resistant cell lines. We have also determined the role of CCI-779 in P-gp1 and MRP1 mediated resistance.ResultsOur 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).ConclusionWe 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.

Highlights

Cisplatin and its analog carboplatin have significant antitumor activity against a wide variety of solid tumors[1]
Using microarray analysis in our cisplatin resistant cell lines as well as reviewing the available microarray data published in other laboratories, we have found that the there are many gene(s) which are overexpressed in these cisplatin resistant cell lines including those involved in DNA repair, signal transduction, invasion and metastasis, and antiapoptosis {for review see ref. [2]}
It is well known that mTOR known as FRAP, RAFT, or RAPT is important in regulating translation of a set of mRNA which encode ribosomal proteins and elongation factor [10,11,12]

Summary

Introduction

Cisplatin and its analog carboplatin have significant antitumor activity against a wide variety of solid tumors[1]. While different cisplatin resistant cell lines often overexpressed different genes involved in DNA repairs and/or signal transduction, antiapoptosis, a majority of cisplatin resistant cells overexpress elongation factor alpha and genes which are involved in ribosomal biogenesis These findings have led us to hypothesize that after DNA damage by cisplatin, the surviving cells have to develop the ability to generate repair proteins and/or survival proteins to prepare for the insult. The common theme to survive cisplatin in these resistant cell lines is to increase these mRNAs. if ribosomal proteins and/or elongation factor can be inhibited, one should be able to restore cisplatin sensitivity. We have studied the role of CCI-779, an ester analog of rapamycin which is known to inhibit translation by disabling mTOR, in restoring cisplatin sensitivity in a panel of cisplatin resistant cell lines. We have determined the role of CCI-779 in P-gp and MRP1 mediated resistance

Methods

Results

Discussion

Conclusion