Efavirenz and Lopinavir/Ritonavir Alter Cell Cycle Regulation in Lung Cancer

Abstract

Highly active anti-retroviral treatment (HAART) is currently the most effective treatment for HIV/AIDS. Additionally, HIV positive patients receiving HAART have a better health-related quality of life (HRQoL). Cancers previously associated with HIV/AIDS also known as the AIDS defining cancers (ADCs), such as Kaposi's sarcoma and non-Hodgkin's lymphoma have been on the decline since the introduction of HAART. However, non-AIDS defining cancers (NADCs), in particular, lung cancers have been documented to be on the rise. The association between the use of HAART components and lung carcinogenesis is poorly understood. This study aimed at elucidating the effects of two HAART components [efavirenz (EFV), and lopinavir/ritonavir (LPV/r)] on lung cancer. This was achieved through the use of in vitro cell biological approaches to assess cell health, including cell viability, Real Time Cell Analysis (RTCA) growth monitoring, evaluation of the cell cycle, and progression to apoptosis, following on drug treatments. At plasma level concentrations, both EFV and LPV/r induced S-phase arrest, while at lower concentrations both drugs promoted the progression of cells into G2/M phase following cell cycle FACS analysis. At higher concentrations although cell viability assays reflected anti-proliferative effects of the drugs, this was not statistically significant. RTCA showed a significant decline in cell viability in response to the highest dose of LPV/r. Dual staining by Annexin V-FITC and PI confirmed significant pro-apoptotic effects were promoted by LPV/r. Both EFV and LPV/r exert double-edged oncogenic effects on MRC-5 and A549 lung cells, acting to either promote cell proliferation or to enhance apoptosis. This is affected by EFV and LPV/r altering cell cycle progression, with a significant S-phase arrest, this being an indication of cellular stress, cytotoxicity, and DNA damage within the cell.

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“…While lopinavir-ritonavir treatment is a standard therapy in HIV patients, studies in the last decade have examined these drugs as a possible anti-cancer treatment ( Dalva-Aydemir et al, 2015 ; Kast et al, 2016 ; Okubo et al, 2019 ; Marima et al, 2020 ). Lopinavir and ritonavir induce apoptosis in glioma, lung cancer, and other tumor cell lines, likely by downregulating pro-survival factors such as AKT while increasing endoplasmic reticulum (ER) and mitochondrial stress ( Kast et al, 2016 ; Okubo et al, 2019 ; Marima et al, 2020 ). Lopinavir and ritonavir also demonstrate some cytotoxicity in in kidney proximal tubule cells, another target of aminoglycoside-induced damage ( Walker et al, 1990 ; Humes, 1999 ; Vidal et al, 2006 ).…”

Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?

“…For instance, this combination causes, in urological cancer cells, endoplasmic reticulum stress and increases the expression levels of AMP-activated protein kinase and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor [132]. In lung cancer cells, the same combination induces cell cycle arrest, downregulates cell viability, and induces apoptosis [133]. Additionally, as a single treatment Lopinavir and its generated Lopinavir nitric oxide derivative inhibit cell proliferation, cause morphological changes, and induce reactive oxygen species production and apoptosis in melanoma [134].…”

“…Ample evidence supports the repurposing of Efavirenz for cancer therapy. In vitro, Efavirenz inhibits the progression of different cancer types, including colorectal, pancreatic [152,153], lung cancer [133], as well as to Glioblastoma [152], and leukemia [154]. Interestingly, this drug is not only effective as a single treatment but is also shown to synergize the effect of radiation therapy [155].…”

Drug Repurposing in Non-Small Cell Lung Carcinoma: Old Solutions for New Problems

“…This combination is being tested in the treatment of lung cancer. It was shown that Lopinavir and Ritonavir exposure causes cell cycle arrest, decreased cell viability, and apoptosis in lung cancer cells [115]. Efavirenz is another antiretroviral drug that downregulates the synthesis of viral DNA by binding the viral reverse transcriptase [116].…”