Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

Abstract

BackgroundCancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo.MethodsCytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data.ResultsThe in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5μmol/l (= 9944ng/ml), Nevirapine 239μmol/l (= 63786ng/ml), Etravirine 89.0μmol/l (= 38740ng/ml), Lersivirine 543μmol/l (= 168523ng/ml), Delavirdine 171μmol/l (= 78072ng/ml), Rilpivirine 24.4μmol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162–15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856–8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients.ConclusionAll studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer.

Combination of tenofovir and emtricitabine with efavirenz does not moderate inhibitory effect of efavirenz on mitochondrial function and cholesterol biosynthesis in human T lymphoblastoid cell line

“…CEM cells treated with either EFV alone or in combination with TDF/FTC showed a higher proportion of non-viable cells (Figure 1A) and increased apoptosis (Figure 1B) in time- and dose-dependent manner. These findings are consistent with other reports; EFV has been reported to decrease cell viability and increase apoptosis in different cell types –primary human hepatocytes and HepG2 cell line (8, 36), pancreatic cancer cell lines (37), human endothelial cell lines (38), human T lymphocytes (Jurkat cell lines) (39), and PBMCs (39). Mitochondrial function depends on intact mitochondrial membrane (40).…”

HIV-Associated Gastrointestinal Cancer

“…As many of the patients in the studies from Europe and North America were treated with antiretrovirals, it could be speculated that there was a possible induction of carcinoma by these drugs. However, the use of non-nucleoside reverse transcriptase inhibitors seem to have an inhibitory effect on the growth of pancreatic tumor cells [21]. This was also shown in a clinical setting using the protease inhibitor nelfinavir, which showed activity against pancreatic cancer and neuroendocrine tumors in adults [22].…”

HIV‐1, HAART and cancer: A complex relationship

“…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.…”