Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341

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 i...

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Veröffentlicht in:Blood 2003-02, Vol.101 (4), p.1530-1534
Hauptverfasser: Hideshima, Teru, Mitsiades, Constantine, Akiyama, Masaharu, Hayashi, Toshiaki, Chauhan, Dharminder, Richardson, Paul, Schlossman, Robert, Podar, Klaus, Munshi, Nikhil C., Mitsiades, Nicholas, Anderson, Kenneth C.
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Sprache:eng
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Zusammenfassung: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 NH2-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.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2002-08-2543