Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells.

Blood
Dharminder ChauhanKenneth C Anderson

Abstract

Bortezomib (PS-341), a selective inhibitor of proteasomes, induces apoptosis in multiple myeloma (MM) cells; however, prolonged drug exposure may result in cumulative toxicity and the development of chemoresistance. Here we show that combining PK-11195 (PK), an antagonist to mitochondrial peripheral benzodiazepine receptors (PBRs), with bortezomib triggers synergistic anti-MM activity even in doxorubicin-, melphalan-, thalidomide-, dexamethasone-, and bortezomib-resistant MM cells. No significant cytotoxicity was noted in normal lymphocytes. Low-dose combined PK and bortezomib treatment overcomes the growth, survival, and drug resistance conferred by interleukin-6 or insulin growth factor within the MM bone marrow milieu. The mechanism of PK + bortezomib-induced apoptosis includes: loss of mitochondrial membrane potential; superoxide generation; release of mitochondrial proteins cytochrome-c (cyto-c) and Smac; and activation of caspases-8/-9/-3. Furthermore, PK + bortezomib activates c-Jun NH2 terminal kinase (JNK), which translocates to mitochondria, thereby facilitating release of cyto-c and Smac from mitochondria to cytosol. Blocking JNK, by either dominant-negative mutant (DN-JNK) or cotreatment with a specific JNK inhibito...Continue Reading

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