Cytotoxic effect of Efavirenz in BxPC‑3 pancreatic cancer cells is based on oxidative stress and is synergistic with ionizing radiation

Abstract

The non-nucleoside reverse transcriptase inhibitor (NNRTI) Efavirenz is frequently used in human immunodeficiency virus treatment, but also efficient against cancer in mouse models. Its radiosensitizing effect makes it a promising drug for combination with radiotherapy. The efficacy of Efavirenz combined with irradiation was assessed with immunostaining of DNA-damage markers and colony formation assays in BxPC-3 pancreatic cancer cells. Gene expression and protein phosphorylation of the Efavirenz-sensitive BxPC-3 cells was compared to the resistant primary fibroblasts SBL-5. Oxidative stress, mitochondrial damage and cell death were studied with live-cell microscopy and flow cytometry. Combined Efavirenz and radiation significantly increased the number of γH2AX and phospho-ataxia telangiectasia mutated foci. Efavirenz and ionizing radiation had a synergistic effect using the clonogenic survival assay. Efavirenz selectively induced cell death in the BxPC-3 cells. The differing gene expression of cell cycle and apoptotic regulator genes in both cell cultures after Efavirenz treatment match with this selective effect against cancer cells. In the phosphoprotein array, an early phosphorylation of extracellular signal-related kinase 1/2 and p38 mitogen-activated protein kinase was notably detected in the cancer cells. The phosphorylation of AKT decreased in the cancer cells whereas it increased in the fibroblasts. Oxidative stress and mitochondrial membrane depolarization appeared in the cancer cells immediately after Efavirenz treatment, but not in the fibroblasts. Efavirenz has an anti-cancer effect against pancreatic cancer mainly by the induction of oxidative stress. The antitumor potential of Efavirenz and radiotherapy are additive.

HIV‐1, HAART and cancer: A complex relationship

“…Another HAART class, non‐nucleoside reverse transcriptase inhibitors (NNRTIs) were also demonstrated to inhibit the growth of cancer cell lines and xenografts in rodents, among them, efavirenz is supposed to have the highest anticancer potential . NNRTIs can act on cancer cells through the induction of DNA damage, apoptosis, oxidative stress and downregulation of LINE‐1 expression . Similarly to PIs, exposure to NNRTIs was associated with the radiosensitizing effect …”

“…NNRTIs can act on cancer cells through the induction of DNA damage, apoptosis, oxidative stress and downregulation of LINE‐1 expression . Similarly to PIs, exposure to NNRTIs was associated with the radiosensitizing effect …”

“…158 LINE-1 propagation throughout the DNA may play a role in genome instability, mutagenesis and contribute to carcinogenesis. 163 Another HAART class, non-nucleoside reverse transcriptase inhibitors (NNRTIs) were also demonstrated to inhibit the growth of cancer cell lines and xenografts in rodents, 157,[164][165][166] among them, efavirenz is supposed to have the highest anticancer potential. 167 NNRTIs can act on cancer cells through the induction of DNA damage, 157 apoptosis, 168 oxidative stress 165 and downregulation of LINE-1 expression.…”

“…169 Similarly to PIs, exposure to NNRTIs was associated with the radiosensitizing effect. 165,170 HIV-integrase strand transfer inhibitors (INSTIs) may cause aberrant HIV-integration and rearrangements in the host DNA when used in low doses. 171,172 Low-dose INSTI may create the In cancer, PI3K/Akt activation inhibits apoptotic enzymes; promotes transcription regulation that increases growth, survival, proliferation, increases MMPs (migration, invasion and metastasis) and VEGF (angiogenesis) expression via mTOR and NF-κB axes; causes chemo/radiotherapy resistance by deregulation of DNA damage response.…”

Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization

“…Both nucleoside RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs) have demonstrated to be effective anticancer agents in several carcinoma cell lines (23)(24)(25)(26). Inspired by the combined structureactivity relationships of F2-DABO class of NNRTIs and of the related ADATs (27,28), a series of novel pyrimidinone derivatives were designed and screened for their antiproliferative effects in cancer cell lines.…”