A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib

被引：589

作者：

Chauhan, D

Catley, L

Li, GL

Podar, K

Hideshima, T

Velankar, M

Mitsiades, C

Mitsiades, N

Yasui, H

Letai, A

Ovaa, H

Berkers, C

Nicholson, B

Chao, TH

Neuteboom, STC

Richardson, P

Palladino, MA

Anderson, KC ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol,Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA

[2] Nereus Pharmaceut, San Diego, CA 92121 USA

来源：

CANCER CELL | 2005年 / 8卷 / 05期

关键词：

D O I：

10.1016/j.ccr.2005.10.013

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Bortezomib therapy has proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM); however, prolonged treatment is associated with toxicity and development of drug resistance. Here, we show that the novel proteasome inhibitor NPI-0052 induces apoptosis in MM cells resistant to conventional and Bortezomib therapies. NPI-0052 is distinct from Bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, and toxicity profile against normal cells. Moreover, NPI-0052 is orally bioactive. In animal tumor model studies, NPI-0052 is well tolerated and prolongs survival, with significantly reduced tumor recurrence. Combining NPI-0052 and Bortezomib induces synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating NPI-0052, alone and together with Bortezomib, to improve patient outcome in MM.

引用

页码：407 / 419

页数：13

共 39 条

[1]

Adams J, 1999, CANCER RES, V59, P2615

[2] Preclinical and clinical evaluation of proteasome inhibitor PS-341 for the treatment of cancer [J].

Adams, J .

CURRENT OPINION IN CHEMICAL BIOLOGY, 2002, 6 (04) :493-500

[3] The proteasome: A suitable antineoplastic target [J].

Adams, J .

NATURE REVIEWS CANCER, 2004, 4 (05) :349-360

[4]

Anderson Kenneth C, 2004, Curr Hematol Rep, V3, P65

[5] Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib [J].

Berkers, CR ;

Verdoes, M ;

Lichtman, E ;

Fiebiger, E ;

Kessler, BM ;

Anderson, KC ;

Ploegh, HL ;

Ovaa, H ;

Galardy, PJ .

NATURE METHODS, 2005, 2 (05) :357-362

[6] Substrate binding and sequence preference of the proteasome revealed by active-site-directed affinity probes [J].

Bogyo, M ;

Shin, S ;

McMaster, JS ;

Ploegh, HL .

CHEMISTRY & BIOLOGY, 1998, 5 (06) :307-320

[7] Apoptosis: checkpoint at the mitochondrial frontier [J].

Bossy-Wetzel, E ;

Green, DR .

MUTATION RESEARCH-DNA REPAIR, 1999, 434 (03) :243-251

[8] Proteasome inhibition in multiple myeloma: Therapeutic implication [J].

Chauhan, D ;

Hideshima, T ;

Anderson, KC .

ANNUAL REVIEW OF PHARMACOLOGY AND TOXICOLOGY, 2005, 45 :465-476

[9] Cytochrome c-dependent and -independent induction of apoptosis in multiple myeloma cells [J].

Chauhan, D ;

Pandey, P ;

Ogata, A ;

Teoh, G ;

Krett, N ;

Halgren, R ;

Rosen, S ;

Kufe, D ;

Kharbanda, S ;

Anderson, K .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1997, 272 (48) :29995-29997

[10] JNK-dependent release of mitochondrial protein, Smac, during apoptosis in multiple myeloma (MM) cells [J].

Chauhan, D ;

Li, GL ;

Hideshima, T ;

Podar, K ;

Mitsiades, C ;

Mitsiades, N ;

Munshi, N ;

Kharbanda, S ;

Anderson, KC .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (20) :17593-17596

← 1 2 3 4 →