Inhibitors of mTOR overcome drug resistance from topoisomerase II inhibitors in solid tumors

The present study was performed to investigate the possible role of mTOR inhibitors in restoring chemosensitivity to adriamycin/cisplatin and elucidate the underlying mechanism. Combining adriamycin/cisplatin with torisel synergistically inhibited the cell proliferation in human oropharyngeal carcinoma cell line KB and its multidrug-resistant subclone KB/7D. Combining adriamycin and torisel inhibited the phosphorylation of 4EBP-1 and p70S6 K, the proteins involved in mTOR pathway, increased expression of γH2AX indicative of DNA damage, triggered cell cycle arrest at G2/M and apoptosis. We conclude that chromatin decondensation by DNA damage provided an easy access for torisel to block the translation of proteins essential for DNA repair thereby restoring the chemosensitivity.

► Combination of mTOR inhibitors with Topoisomerase II inhibitors. ► Combination is synergistic in head and neck and breast cancer cells. ► mTOR inhibitor sensitizes adriamycin/cisplatin resistant cells. ► DNA repair is required after induction of DNA damage by topoisomerase II inhibitors. ► mTOR inhibitor restores chemosensitivity by blocking the translation of proteins.