Approaches to repurposing reverse transcriptase antivirals in cancer.

This review highlights the role of reverse transcriptase (RT) inhibition in cellular regulation associated with non-terminal repeat retrotransposons and endogenous retroviruses. Based on their pleiotropic characteristics, RT inhibitors (RTIs) are discussed as potential anticancer agents. Both the nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) display cytotoxicity in cancer cells which are likely mediated by endogenous RT inhibition and not necessarily by differing molecular structures. Three features of RTIs are evident in inducing cytotoxicity in cancer cells. Firstly, NRTIs and NNRTIs induce cell cycle arrest. Secondly, they suppress transposable elements, inhibit long interspersed nuclear elements (LINE)-1, with RTI key in cytotoxicity in cancer cells. Thirdly, the cyclic GMP-AMP-synthase-stimulator of interferon genes (cGAS-STING) pathway can be activated by LINE-1-derived cytoplasmic DNA with promotion of p21-dependent cell cycle arrest and cell-mediated immune response. This suggests that RTIs induce DNA strand breaks with incomplete retrotransposition, initiate cell cycle arrest and an immune response. Additionally, poly (ADP-ribose) polymerase 1 and 2 (PARP1, PARP2) and its relationship with DNA methylation is highlighted in the context of LINE-1 retrotransposition. There is a need to examine the relationship between PARP1, PARP2 and mutated BRCA proteins in normal and abnormal LINE-1 retrotransposition. This review explores how efavirenz and related RT inhibitors suppress endogenous reverse transcriptase, providing a basis for preclinical evaluation of RT inhibitors as potential repurposed drugs for cancer treatment.