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

Hecht, Markusa; Harrer, Thomasb; Büttner, Maikec; Schwegler, Manuelaa; Erber, Sonjaa; Fietkau, Rainera; Distel, Luitpold V.a

doi: 10.1097/QAD.0b013e3283625444
Basic Science

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.

aDepartment of Radiation Oncology

bDepartment of Internal Medicine 3

cDepartment of Pathology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.

Correspondence to Markus Hecht, Department of Radiation Oncology, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nuremberg, Universitätsstraße 27, D-91054 Erlangen, Germany. Tel: +49 9131 854 4247; fax: +49 9131 853 9335; e-mail:

Received 27 September, 2012

Revised 1 April, 2013

Accepted 17 April, 2013

© 2013 Lippincott Williams & Wilkins, Inc.