|
|
Blood, 15 October 2004, Vol. 104, No. 8, pp. 2458-2466.
Prepublished online as a Blood First Edition Paper on June 24, 2004; DOI 10.1182/blood-2004-02-0547.
 Previous Article | Table of Contents | Next Article 
NEOPLASIA
Targeting mitochondria to overcome conventional and bortezomib/proteasome inhibitor PS-341 resistance in multiple myeloma (MM) cells
Dharminder Chauhan,
Guilan Li,
Klaus Podar,
Teru Hideshima,
Constantine Mitsiades,
Robert Schlossman,
Nikhil Munshi,
Paul Richardson,
Finbarr E. Cotter, and
Kenneth C. Anderson
From the Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; and the Department of Experimental Haematology, The Royal London School of Medicine, London, United Kingdom.
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 inhibitor SP600125, abrogates both PK + bortezomib–induced release of cyto-c/Smac and induction of apoptosis. Together, these preclinical studies suggest that combining bortezomib with PK may enhance its clinical efficacy, reduce attendant toxicity, and overcome conventional and bortezomib resistance in patients with relapsed refractory MM.
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. M. Huber, A. Tagwerker, D. Heininger, G. Mayer, A. R. Rosenkranz, and K. Eller
The proteasome inhibitor Bortezomib aggravates renal ischemia-reperfusion injury
Am J Physiol Renal Physiol,
August 1, 2009;
297(2):
F451 - F460.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Sung, A. B. Kunnumakkara, G. Sethi, P. Anand, S. Guha, and B. B. Aggarwal
Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model
Mol. Cancer Ther.,
April 1, 2009;
8(4):
959 - 970.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Lu, J. Yang, X. Song, S. Gong, H. Zhou, L. Guo, N. Song, X. Bao, P. Chen, and J. Wang
Point Mutation of the Proteasome {beta}5 Subunit Gene Is an Important Mechanism of Bortezomib Resistance in Bortezomib-Selected Variants of Jurkat T Cell Lymphoblastic Lymphoma/Leukemia Line
J. Pharmacol. Exp. Ther.,
August 1, 2008;
326(2):
423 - 431.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. S. Carew, S. T. Nawrocki, V. K. Reddy, D. Bush, J. E. Rehg, A. Goodwin, J. A. Houghton, R. A. Casero Jr, L. J. Marton, and J. L. Cleveland
The Novel Polyamine Analogue CGC-11093 Enhances the Antimyeloma Activity of Bortezomib
Cancer Res.,
June 15, 2008;
68(12):
4783 - 4790.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Santidrian, A. M. Cosialls, L. Coll-Mulet, D. Iglesias-Serret, M. de Frias, D. M. Gonzalez-Girones, C. Campas, A. Domingo, G. Pons, and J. Gil
The potential anticancer agent PK11195 induces apoptosis irrespective of p53 and ATM status in chronic lymphocytic leukemia cells
Haematologica,
December 1, 2007;
92(12):
1631 - 1638.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Hurt, S. B. Thomas, B. Peng, and W. L. Farrar
Integrated molecular profiling of SOD2 expression in multiple myeloma
Blood,
May 1, 2007;
109(9):
3953 - 3962.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Podar, M. S. Raab, G. Tonon, M. Sattler, D. Barila, J. Zhang, Y.-T. Tai, H. Yasui, N. Raje, R. A. DePinho, et al.
Up-Regulation of c-Jun Inhibits Proliferation and Induces Apoptosis via Caspase-Triggered c-Abl Cleavage in Human Multiple Myeloma
Cancer Res.,
February 15, 2007;
67(4):
1680 - 1688.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Chauhan, P. Neri, M. Velankar, K. Podar, T. Hideshima, M. Fulciniti, P. Tassone, N. Raje, C. Mitsiades, N. Mitsiades, et al.
Targeting mitochondrial factor Smac/DIABLO as therapy for multiple myeloma (MM)
Blood,
February 1, 2007;
109(3):
1220 - 1227.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. T. Nawrocki, J. S. Carew, K. Dunner Jr., L. H. Boise, P. J. Chiao, P. Huang, J. L. Abbruzzese, and D. J. McConkey
Bortezomib Inhibits PKR-Like Endoplasmic Reticulum (ER) Kinase and Induces Apoptosis via ER Stress in Human Pancreatic Cancer Cells
Cancer Res.,
December 15, 2005;
65(24):
11510 - 11519.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. B. Walter, J. L. Pirga, M. R. Cronk, S. Mayer, F. R. Appelbaum, and D. E. Banker
PK11195, a peripheral benzodiazepine receptor (pBR) ligand, broadly blocks drug efflux to chemosensitize leukemia and myeloma cells by a pBR-independent, direct transporter-modulating mechanism
Blood,
November 15, 2005;
106(10):
3584 - 3593.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Chauhan, G. Li, K. Podar, T. Hideshima, P. Neri, D. He, N. Mitsiades, P. Richardson, Y. Chang, J. Schindler, et al.
A Novel Carbohydrate-Based Therapeutic GCS-100 Overcomes Bortezomib Resistance and Enhances Dexamethasone-Induced Apoptosis in Multiple Myeloma Cells
Cancer Res.,
September 15, 2005;
65(18):
8350 - 8358.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Hideshima, D. Chauhan, P. Richardson, and K. C. Anderson
Identification and Validation of Novel Therapeutic Targets for Multiple Myeloma
J. Clin. Oncol.,
September 10, 2005;
23(26):
6345 - 6350.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Yasui, T. Hideshima, N. Raje, A. M. Roccaro, N. Shiraishi, S. Kumar, M. Hamasaki, K. Ishitsuka, Y.-T. Tai, K. Podar, et al.
FTY720 Induces Apoptosis in Multiple Myeloma Cells and Overcomes Drug Resistance
Cancer Res.,
August 15, 2005;
65(16):
7478 - 7484.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. B. Rabson and D. Weissmann
From Microarray to Bedside: Targeting NF-{kappa}B for Therapy of Lymphomas
Clin. Cancer Res.,
January 1, 2005;
11(1):
2 - 6.
[Full Text]
[PDF]
|
|
|
|
|
