Reverse transcriptase inhibitors reduce tumor growth in vivo and induce cell differentiation

Abstract

3134 Background: Endogenous, nontelomeric reverse transcriptase (RT) is encoded by two classes of genomic repeated elements: retrotransposons and endogenous retroviruses. Expression of RT-coding genes is generally repressed in differentiated non pathological tissues, yet is active in the germ-line, embryonic tissue and tumor cells. We reported that nevirapine, a non-nucleosidic RT inhibitor, reduces cell growth and induces differentiation in murine and human cell lines. Furthermore, nevirapine treatment causes a reprogramming of gene expression in murine transformed cells: particularly significant changes occur in genes involved in cell cycle control, such as down-regulation of cyclin D1 and up-regulation of p16, (Mangiacasale, Oncogene 2003). Finally, RT inhibitors are currently used in the treatment of HIV patients and epidemiological studies suggested that these drugs induce a dramatic decrease in the incidence of HIV-related neoplasms. Results: We report that treatment with two RT inhibitors, nevirapine and efavirenz, effectively induces a reversible inhibition of cell growth in human prostate (PC3), colon (HT29), small-cell lung (H69) cancer cell lines as well as in human melanoma (A-375) and glioma (U343), in vitro. Neither drug displays significant cytotoxic effects, producing minimal induction of necrosis and apoptosis. The inhibition of cell growth correlates with the accumulation of cells in the G0/G1 phase of cell cycle, concomitant with decrease in S-phase cells. Moreover, treated cells acquire a differentiated phenotype. Tumor xenografts from human prostate, colon, melanoma and small-cell lung cancer cells in nude mice treated with efavirenz show a strong reversible inhibition of growth. Maximal inhibition of cancer growth is obtained with a dose of 20 mg/kg b.w., which is within the therapeutical dose range used to achieve RT inhibition in patients with retrovirus infections such as HIV. Conclusions: These findings suggest that endogenous RT may represent a novel target in human cancer therapy and support the proposal that efavirenz could be tested as a new safe drug in association with standard anti-cancer treatments in humans. No significant financial relationships to disclose.