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

Background: Nelfinavir is an HIV protease inhibitor that has been
used for a long period of time to treat HIVinfected 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. Methods: 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.
Results: At a concentration of 9 mu g/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 mu g/ml)
significantly enhanced nelfinavir-induced apoptosis even at lower
nelfinavir concentrations (5 mu g/ml), but did not have additional
detrimental effects on non-malignant bone marrow cells.
Conclusions: The ability of nelfinavir to induce apoptosis in
leukemia cells as a single agent in a mitochondria-independent
manner might suggest it could be used as a second or third line of
treatment for leukemia patients for whom standard
mitochondria-directed treatment strategies have failed. Combination
treatment with nelfinavir and sorafenib might further enhance the
efficacy of nelfinavir even on chemo-resistant leukemia cells.