AIDS. 2013 Aug 24;27(13):2031-40.

Cytotoxic effect of efavirenz is selective against cancer cells and associated with the cannabinoid system.

Hecht M, Harrer T, Büttner M, Schwegler M, Erber S, Fietkau R, Distel LV.

1 Department of Radiation Oncology, 2 Department of Internal Medicine, 3 Department of Pathology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.



BACKGROUND: Recently, a regression of precancerous lesions in HIV-1-infected patients after initiation of HAART was reported. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) as efavirenz (EFV) might be mediators of this effect, as they are known to have a cytotoxic effect on tumour cells. A potential mechanism involved in this effect may be the activation of the cannabinoid receptor to mediate tumour toxicity.

METHODS: Several tumour-derived and fibroblast cell lines were studied. Cytotoxicity of EFV was evaluated by Annexin-Pi staining. The expression of the cannabinoid receptors CB1, CB2 and GPR55 was analysed by western blot, quantitative reverse transcriptase (qRT-PCR) and fluorescence activated cell sorting. The influence of the cannabinoid agonists and antagonists on the effects of EFV was investigated. Furthermore, the effect of EFV on the phosphorylation state of the growth factors Erk, Akt and the tumour suppressor protein p53 was tested.

RESULTS: EFV revealed a selective cytotoxic effect on several tumour cell lines, whereas primary fibroblasts were not affected. The cytotoxic effect was associated with the expression of CB1. The combination of EFV with cannabinoid agonists showed an increase in toxicity. The phosphorylation state of Erk and Akt was not affected by EFV, whereas p53 showed an increased phosphorylation.

CONCLUSION: EFV has a selective cytotoxic effect on several tumour cells. Furthermore, EFV led to an activating phosphorylation of the tumour suppressor protein p53 going in line with earlier reports that EFV may be antitumourigenic and a potential cytostatic drug. The observed synergistic effect with cannabinoid agonists implicates an involvement of the cannabinoid system.

PMID: 23612009



With modern antiretroviral drugs the HI-virus itself can be controlled very well in HIV-1-infected patients. Consequently, live expectancy of HIV-1-infected patients is no longer limited by their infection. As these patients get older, the prevention and therapy of comorbidities plays a larger role. Nowadays, one third of all deaths in HIV-1-infected patients are cancer related [1]. In this context a toxic potential of antiretroviral drugs against cancer cells is encouraging.

In this paper the NNRTI Efavirenz was toxic against several cancer cell lines, whereas primary fibroblasts were resistant to Efavirenz treatment. Apoptosis and necrosis was analyzed with Annexin-V-FITC / Propidium Iodide (PI) staining and flow cytometry. A representative plot of T98G glioblastoma cells and SBL-5 primary fibroblasts is shown in figure 1. Furthermore Efavirenz lead to an accumulation of cells in G1/G0-phase of the cell cycle and a phosphorylation of the tumor suppressor protein p53 in cancer cells. The idea of the mechanism of action was based on the observation that in patients taking Efavirenz drug screening for cannabis is often false positive and cannabinoids are toxic against cancer cells [2, 3]. Efavirenz toxicity correlated with the expression of the cannabinoid receptor 1 and there was a synergistic effect with cannabinoid agonists. Conversely there was no effect on the intracellular downstream signals Erk and Akt. It can be concluded that the cannabinoid system seems to be involved in Efavirenz toxicity, but is not the primary mechanism of action.

These results lead to the idea, that EFV could be used as cytotoxic drug against cancer also in vivo. Clinical observations of regressions of precancerous lesions, regressions of lymphomas or a case of long term survival of a patient with small cell lung cancer under Efavirenz treatment support this idea [4-6]. In order to clarify whether this in vitro effect can be translated in cancer therapy clinical trials will be necessary.
Fig 1. Apoptosis and Necrosis was analyzed with Annexin-V-FITC / Propidium Iodide (PI) staining and flow cytometry. Annexin / PI double negative cells are alive, Annexin positive / PI negative cells are apoptotic and Annexin / PI double positive cells are necrotic. T98G glioblastoma cells (A,B) were compared to SBL-1 primary fibroblasts (C,D) after Efavirenz (EFV) treatment (60µmol/l). The glioblastoma cells became necrotic after Efavirenz treatment (B), whereas the primary fibroblasts were resistant (D).



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