Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341

Teru Hideshima, Constantine Mitsiades, Masaharu Akiyama, Toshiaki Hayashi, Dharminder Chauhan, Paul Richardson, Robert Schlossman, Klaus Podar, Nikhil C Munshi, Nicholas Mitsiades, Kenneth C Anderson
Blood 2003 February 15, 101 (4): 1530-4
We have recently shown that proteasome inhibitor PS-341 induces apoptosis in drug-resistant multiple myeloma (MM) cells, inhibits binding of MM cells in the bone marrow microenvironment, and inhibits cytokines mediating MM cell growth, survival, drug resistance, and migration in vitro. PS-341 also inhibits human MM cell growth and prolongs survival in a SCID mouse model. Importantly, PS-341 has achieved remarkable clinical responses in patients with refractory relapsed MM. We here demonstrate molecular mechanisms whereby PS-341 mediates anti-MM activity by inducing p53 and MDM2 protein expression; inducing the phosphorylation (Ser15) of p53 protein; activating c-Jun NH(2)-terminal kinase (JNK), caspase-8, and caspase-3; and cleaving the DNA protein kinase catalytic subunit, ATM, and MDM2. Inhibition of JNK activity abrogates PS-341-induced MM cell death. These studies identify molecular targets of PS-341 and provide the rationale for the development of second-generation, more targeted therapies.

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