The mitochondria-independent cytotoxic effect of nelfinavir on leukemia cells can be enhanced by sorafenib-mediated mcl-1 downregulation and mitochondrial membrane destabilization.

Molecular Cancer
Ansgar BrüningKlaus Friese

Abstract

Nelfinavir is an HIV protease inhibitor that has been used for a long period of time to treat HIV-infected individuals. It has recently emerged that nelfinavir could represent a prospective new anti-cancer drug, prompting us to test the effect of nelfinavir on leukemia cells. By combining in vitro and ex vivo studies, the effect of nelfinavir on leukemia cells and non-malignant, bone marrow-derived tissue cells was analyzed. At a concentration of 9 microg/ml, nelfinavir induced death of 90% of HL60, IM9, and Jurkat cells. At the same concentration and treatment conditions, less than 10% of aspirated human bone marrow cells showed nelfinavir-induced cell damage. Nelfinavir-induced death of leukemia cells was accompanied by activation of caspases 3, 7, and 8. Despite caspase activation, the upregulation of the anti-apoptotic bcl-2 family member protein mcl-1 that resulted from nelfinavir treatment stabilized the mitochondrial membrane potential, resulting in primarily mitochondria-independent cell death. Pharmacological downregulation of mcl-1 expression by treatment with sorafenib (2 microg/ml) significantly enhanced nelfinavir-induced apoptosis even at lower nelfinavir concentrations (5 microg/ml), but did not have additional d...Continue Reading

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Citations

Jul 3, 2010·Breast Cancer Research : BCR·Ansgar BrüningIoannis Mylonas
Sep 9, 2011·Trends in Pharmacological Sciences·Nadezda ApostolovaJuan V Esplugues
Jun 10, 2020·Pharmaceutical Research·Vineela ParvathaneniVivek Gupta
Nov 24, 2016·Oncology Reports·Ansgar BrüningIoannis Mylonas
Apr 30, 2020·Cancers·Dominika FassmannováKlára Grantz Šašková
May 22, 2020·Seminars in Cancer Biology·Itishree KaushikSanjay K Srivastava
Nov 25, 2020·Cancers·Mahbuba R Subeha, Carlos M Telleria
Jan 25, 2012·Journal of Proteome Research·Vibeke Hervik BullBernd Thiede

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Methods Mentioned

BETA
fluorescence microscopy
electrophoresis
phase contrast microscopy
FACS
PCR

Software Mentioned

Quantity One
FACScan

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