Inhibitory Effect of Etravirine, a Non-Nucleoside Reverse Transcriptase Inhibitor, via Anterior Gradient Protein 2 Homolog Degradation against Ovarian Cancer Metastasis

Abstract

Anterior gradient protein 2 homolog (AGR2), an endoplasmic reticulum protein, is secreted in the tumor microenvironment. AGR2 is a member of the disulfide isomerase family, is highly expressed in multiple cancers, and promotes cancer metastasis. In this study, we found that etravirine, which is a non-nucleoside reverse transcriptase inhibitor, could induce AGR2 degradation via autophagy. Moreover, etravirine diminished proliferation, migration, and invasion in vitro. Moreover, in an orthotopic xenograft mouse model, the combination of etravirine and paclitaxel significantly suppressed cancer progression and metastasis. This drug may be a promising therapeutic agent for the treatment of ovarian cancer.

Exploring Darunavir, Rilpivirine and Etravirine as Potential Therapies for Bladder Cancer: Efficacy and Synergistic Effects

“…The latter is likely due to the interaction of AGR2 secreted from cancer cells with VEGF and FGF2, a bond that eases angiogenesis and, consequently, metastasis [38]. The concentrations at which ETV showed results were 5-10 µM at different time points [30], which is slightly lower than the results obtained here for 24 and 48 h, but accordant to those obtained for 72 h, which can be attributed to different cancer cell types.…”

“…In this study, DRV, RPV, and ETV, three antiretroviral drugs, were studied in UM-UC-5 bladder cancer cells. These drugs have been selected because they have been shown to have effects on cancer in studies found in the literature, namely ETV in ovarian cancer metastasis [ 30 ], RPV in pancreatic cancer [ 31 ], and DRV has demonstrated in silico evidence of inhibiting enzymes overexpressed in several cancer types [ 32 ]. Overall, the best drug tested in this study was ETV, in a concentration and time-dependent manner, having a relatively low IC 50 at 24 and 48 h (24.76 µM and 32.77 µM), but with the overall lowest IC 50 being at 72 h (5.923 µM).…”

“…This protein is a disulfide isomerase expressed in the endoplasmic reticulum that regulates protein folding and is related to the initiation of carcinogenesis, its progression, and resistance to therapy [ 36 ], and is overexpressed in bladder cancer cells and can be related to the local spread of cancer, and the secretion of this protein by bladder cancer cells can be used as a biomarker [ 37 ]. ETV in ovarian cancer cells was able to decrease AGR2 levels, as well as induce autophagy by increasing a key component in its pathway (LC3-B), suppressing cell proliferation, migration, and invasion when used alone, in vitro and in vivo tumor growth and metastasis when used in combination with the antineoplastic drug paclitaxel [ 30 ]. The latter is likely due to the interaction of AGR2 secreted from cancer cells with VEGF and FGF2, a bond that eases angiogenesis and, consequently, metastasis [ 38 ].…”

“…These two drugs are similar, as they are both second-generation diarylpyrimidine NNRTIs, which can contribute to their high synergy, as they can potentiate each other. Another factor can be that, as mentioned above, ETV shows the inhibition of AGR2 and a decrease in its connection with VEGF [ 30 ], while RPV inhibits VEGFR-2 [ 44 ]. These effects of each drug on different points of the VEGFs–VEGFRs pathway can be the cause of this high synergy between the two drugs, with them potentiating the effect of each other, with a greater effect and with less concentration the more time they are left to act on bladder cancer cells.…”

Future of epigenetic immunotherapy in kidney cancer

“…Ненуклеозидный ИОТ этравирин, вызывающий деградацию AGR2 (белок эндоплазматической сети, секретируемый опухолевым микроокружением), in vitro подавлял пролиферацию, миграцию и инвазию опухолевых клеток. На моделях мышей комбинация паклитаксела с этравирином более эффективно ингибировала прогрессирование рака яичника [44]. На клетках сПКК была продемонстрирована способность ненуклеозидных ИОТ эфавиренза и невирапина инду-цировать иммуногенность опухоли и приводить к дифференцировке клеток [45].…”