Abstract
Bcl2 and IAP families are anti-apoptotic proteins deregulated in multiple myeloma (MM) cells. Pharmacological inhibition of each of these families has shown significant activity only in subgroups of MM patients. Here, we have examined a broad-spectrum Bcl2 family inhibitor Obatoclax (OBX) in combination with a Smac mimetic LCL161 in MM cell lines and patient cells. LCL161/OBX combination induced synergistic cytotoxicity and anti-proliferative effects on a broad range of human MM cell lines. The cytotoxicity was mediated through inhibition of the IAPs, activation of caspases and up regulation of the pro-apoptotic proteins Bid, Bim, Puma and Noxa by the drug combination. In addition, we observed that OBX caused ER stress and activated the Unfolded Protein Response (UPR) leading to drug resistance. LCL161, however inhibited spliced Xbp-1, a pro-survival factor. In addition, we observed that OBX increased GRP78 localization to the cell surface, which then induced PI3K dependent Akt activation and resistance to cell death. LCL161 was able to block OBX induced Akt activation contributing to synergistic cell death. Our results support clinical evaluation of this combination strategy in relapsed refractory MM patients.
Keywords:
Bcl-2; GRP78; IAP; apoptosis; myeloma.
MeSH terms
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins
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Caspases / metabolism
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Cell Line, Tumor
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Down-Regulation
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Drug Resistance, Neoplasm
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Drug Synergism
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum Stress / drug effects*
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Heat-Shock Proteins / metabolism
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Humans
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Indoles
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Intracellular Signaling Peptides and Proteins / agonists
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Mitochondrial Proteins / agonists
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Multiple Myeloma / drug therapy*
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Multiple Myeloma / pathology
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Neoplasm Recurrence, Local / drug therapy*
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Neoplasm Recurrence, Local / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyrroles / pharmacology*
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Pyrroles / therapeutic use
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Thiazoles / pharmacology*
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Thiazoles / therapeutic use
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Unfolded Protein Response / drug effects
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Up-Regulation
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X-Box Binding Protein 1 / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2 protein, human
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DIABLO protein, human
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Endoplasmic Reticulum Chaperone BiP
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HSPA5 protein, human
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Heat-Shock Proteins
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Indoles
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Intracellular Signaling Peptides and Proteins
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LCL161
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Mitochondrial Proteins
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Proto-Oncogene Proteins c-bcl-2
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Pyrroles
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Thiazoles
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X-Box Binding Protein 1
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XBP1 protein, human
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Proto-Oncogene Proteins c-akt
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Caspases
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obatoclax