Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma
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Vijay Ramakrishnan1,*, Marcus Gomez1,*, Vivek Prasad1, Teresa Kimlinger1, Utkarsh Painuly1,2, Bedabrata Mukhopadhyay1, Jessica Haug1, Lintao Bi1,3, S. Vincent Rajkumar1 and Shaji Kumar1
1 Division of Hematology, Mayo Clinic, Rochester, MN, USA
2 4th Department of Internal Medicine-Hematology, University Hospital Hradec Kralove and Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic
3 The Department of Hematology and Oncology, China-Japan Union Hospital, Jilin University, Changchun, Jilin, China
* These authors have contributed equally to this work
Shaji Kumar, email:
Keywords: IAP, Bcl-2, myeloma, apoptosis, GRP78
Received: June 30, 2016 Accepted: July 23, 2016 Published: August 02, 2016
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.
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