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Your search keyword '"Chauhan, Dharminder"' showing total 22 results
Start Over Author "Chauhan, Dharminder" Journal oncogene
22 results on '"Chauhan, Dharminder"'

20. Molecular characterization of PS-341 (bortezomib) resistance: implications for overcoming resistance using lysophosphatidic acid acyltransferase (LPAAT)-ßinhibitors.

Author

Hideshima, Teru, Chauhan, Dharminder, Ishitsuka, Kenji, Yasui, Hiroshi, Raje, Noopur, Kumar, Shaji, Podar, Klaus, Mitsiades, Constantine, Hideshima, Hiromasa, Bonham, Lynn, Munshi, Nikhil C, Richardson, Paul G, Singer, Jack W, and Anderson, Kenneth C

Subjects
APOPTOSIS, CELL death, MONOCLONAL gammopathies, ANTHRACYCLINES, LYSOPHOSPHOLIPIDS, ACYLTRANSFERASES
Abstract

PS-341 (bortezomib, Velcade™) is a promising novel agent for treatment of advanced multiple myeloma (MM); however, 65%of patients with relapsed refractory disease in a phase II study do not respond to PS-341. We have previously shown that lysophosphatidic acid acyltransferase (LPAAT)-ßinhibitor CT-32615 triggers caspase-dependent apoptosis, and can overcome resistance to conventional therapeutics (i.e., dexamethasone, doxorubicin, melphalan) in MM cells. In this study, we therefore determined whether CT-32615 could also overcome resistance to PS-341. We first characterized molecular mechanisms of resistance to PS-341 in DHL-4 cells. DHL-4 cells express low levels of caspase-3 and caspase-8; furthermore, no cleavage in caspase-8, caspase-9, caspase-3, poly ADP-ribose polymerase (PARP), or DNA fragmentation factor 45 was triggered by PS-341 treatment. We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH2-terminal kinase (JNK), which subsequently induces caspase-dependent apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis. We here show that phosphorylation of SEK-1, JNK, and c-Jun are not induced by PS-341 treatment, suggesting that PS-341 does not trigger a stress response in DHL-4 cells. Importantly, CT-32615 inhibits growth of DHL-4 cells in a time- and dose-dependent fashion: a transient G2/M cell cycle arrest induced by CT-32615 is mediated via downregulation of cdc25c and cdc2. CT-32615 triggered swelling and lysis of DHL-4 cells, without caspase/PARP cleavage or TUNEL-positivity, suggesting a necrotic response. Our studies therefore demonstrate that LPAAT-ßinhibitor CT-32615 triggers necrosis, even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.Oncogene (2005) 24, 3121-3129. doi:10.1038/sj.onc.1208522 Published online 21 February 2005 [ABSTRACT FROM AUTHOR]

Published
2005
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21. Biologic sequelae of c-Jun NH2-terminal kinase (JNK) activation in multiple myeloma cell lines.

Author

Hideshima, Teru, Hayashi, Toshiaki, Chauhan, Dharminder, Akiyama, Masaharu, Richardson, Paul, and Anderson, Kenneth

Subjects
CANCER cells, CELL lines, MULTIPLE myeloma, BONE marrow cells, NF-kappa B
Abstract

Although c-Jun NH2-terminal kinase (JNK) is activated by treatment with therapeutic agents, the biologic sequelae of inhibiting constitutive activation of JNK has not yet been clarified. In this study, we examine the biologic effect of JNK inhibition in multiple myeloma (MM) cell lines. JNK-specific inhibitor SP600125 induces growth inhibition via induction of G1 or G2/M arrest in U266 and MM.1S multiple myeloma cell lines, respectively. Neither exogenous IL-6 nor insulin-like growth factor-1 (IGF-1) overcome SP600125-induced growth inhibition, and IL-6 enhances SP600125-induced G2/M phase in MM.1S cells. Induction of growth arrest is mediated by upregulation of p27Kip1, without alteration of p53 and JNK protein expression. Importantly, SP600125 inhibits growth of MM cells adherent to bone marrow stromal cells (BMSCs). SP600125 induces NF-?B activation in a dose-dependent fashion, associated with phosphorylation of I?B kinase a (IKKa) and degradation of I?Ba. In contrast, SP600125 does not affect phosphorylation of STAT3, Akt, and/or ERK. IKK-specific inhibitor PS-1145 inhibits SP600125-induced NF-?B activation and blocks the protective effect of SP600125 against apoptosis. Our data therefore demonstrate for the first time that inhibiting JNK activity induces growth arrest and activates NF-?B in MM cells.Oncogene (2003) 22, 8797-8801. doi:10.1038/sj.onc.1206919 [ABSTRACT FROM AUTHOR]

Published
2003
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22. Activation of NF-KB and upregulation of intracellular anti-apoptotic proteins via the IGF-1/Akt signaling in human multiple myeloma cells: therapeutic implications.

Author

Mitsiades, Constantine S., Mitsiades, Nicholas, Poulaki, Vassiliki, Schlossman, Robert, Akiyama, Masaharu, Chauhan, Dharminder, Hideshima, Teru, Treon, Steven P., Munshi, Nikhil C., Richardson, Paul G., and Anderson, Kenneth C.

Subjects
SOMATOMEDIN, PHOSPHORYLATION, MYELOMA proteins
Abstract

Presents a study that demonstrated the functions of insulin-like growth factor-1. Inducement of phosphorylation of the FKHRL-1 Forkhead transcription factor; Upregulation of a series of intracellular anti-apoptotic proteins; Effect on Apo2L/TRAIL-sensitivity of multiple myeloma cells.

Published
2002
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