Antiproliferative effects of HIV integrase strand transfer inhibitors (INSTIs) in experimental models for cancer research: a narrative review

A growing body of literature suggests that Integrase Strand Transfer Inhibitors (INSTIs), a cornerstone of antiretroviral therapy for the treatment of Human Immunodeficiency Virus (HIV) infection, seem to possess antiproliferative properties against some types of cancer and/or anti-invasion effects. Preclinical studies describe as INSTIs, including Dolutegravir (DTG), Raltegravir (RAL), Cabotegravir (CAB) and Elvitegravir (EVG) and some 1,2,3-Triazole derivatives, can inhibit the growth of various cancer cell lines and some of them seem to also have direct inhibitory effects on human endogenous retrovirus (HERV) reactivation. This review comprehensively synthesizes and analyzes this evidence, detailing the proposed multi-mechanistic actions behind these effects, such as induction of DNA damage, inhibition of key oncogenic pathways, triggering of oxidative stress and diverse cell death modalities. All described compounds seem to have potential effects on cancerous cells, and these effects may be also independent from their antiretroviral activity, that is, may be separated from the mere effect on suppression of HERV reactivation in cancerous cells. Although the type of target cancer, the mechanisms of action (i.e. enzyme or protein inhibition, oxidative stress, DNA methylation, DNA damage) or the ultimate effects (i.e. cell proliferation, migration or invasion) were different in most of the studies and sometimes inconsistent, all these studies suggest several potential targets of INSTIs that deserve further investigations. Although the incidence of many cancers is higher in people with HIV infection compared to the general population, the relative risk has been decreasing over time for many cancers. Further studies are then needed to assess the effects of INSTI therapies on malignancies in people living with HIV (PLWH).