Modulation of Cell Differentiation, Proliferation, and Tumor Growth by Dihydrobenzyloxopyrimidine Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

A series of 5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl)propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives (3a-h) belonging to the F(2)-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) are endowed with a strong antiproliferative effect and induce cytodifferentiation in A375 melanoma cells. Among tested compounds, the most potent is 3g (SPV122), which also induces apoptosis in a cell-density-dependent manner and antagonizes tumor growth in animal models. All these effects are similar or even more pronounced than those previously reported for other nucleoside or non-nucleoside inhibitors of reverse transcriptase or by functional knockout of the reverse-transcriptase-encoding long interspersed element 1 by RNA interference (RNAi). Taken together with our previously reported results, these data further confirm our idea that cellular alterations induced by NNRTIs are a consequence of the inhibition of the endogenous reverse transcriptase in A375 cells and support the potential of NNRTIs as valuable agents in cancer therapy.

Activation of LINE-1 Retrotransposon Increases the Risk of Epithelial-Mesenchymal Transition and Metastasis in Epithelial Cancer

“…An important conclusion emerging from this study was that prolonged L1 inhibition maintained the tumors in a repressed, non-invasive state. Recently, another type of NNRTIs drug belonging to the F2-DABO class (5-alkyl-2-(alkylthio)-6-(1-(2,6-difluorophenyl) propyl)-3,4-dihydropyrimidin-4(3H)-one derivatives or SPV122 compound) has been shown to have a strong anti-proliferative effect and induce differentiation in melanoma cells [65]. This drug also induced apoptosis in a cell-density-dependent manner and antagonized tumor growth in animal models.…”

LINE-1 Retrotransposons and Their Role in Cancer

“…There is growing evidence indicating a high level of endogenous RT activity associated with transformed/tumorigenic phenotypes in mammalian cells. Additionally inhibition of L1 RT through nuclear or non-nuclear inhibitors has been suggested as a promising approach in cancer therapy (Sbardella et al 2011;Carlini et al 2010;Jones et al 2008). For example it has been demonstrated that ethyl-substituted derivatives 3a-h, belonging to the F2-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors, have an anti-proliferating role on A375 melanoma cells (Sbardella et al 2011).…”

“…Additionally inhibition of L1 RT through nuclear or non-nuclear inhibitors has been suggested as a promising approach in cancer therapy (Sbardella et al 2011;Carlini et al 2010;Jones et al 2008). For example it has been demonstrated that ethyl-substituted derivatives 3a-h, belonging to the F2-DABOs class of non-nucleoside HIV-1 reverse transcriptase inhibitors, have an anti-proliferating role on A375 melanoma cells (Sbardella et al 2011). In contrast, a study on the effect of different RT inhibitors against L1 RT activity and retrotransposition indicated that L1 RT is sensitive to nucleoside analog inhibitors (NRTIs), but non-nucleoside inhibitors (NNRTIs) inhibit L1 RT less efficiently.…”

Epigenetics Territory and Cancer

“…Additionally inhibition of L1 RT through nuclear or non-nuclear inhibitors has been suggested as a promising approach in cancer therapy (Sbardella et al 2011;Carlini et al 2010;Jones et al 2008). There is growing evidence indicating a high level of endogenous RT activity associated with transformed/tumorigenic phenotypes in mammalian cells.…”