TY - JOUR
T1 - Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma
AU - Ramakrishnan, Vijay
AU - Gomez, Marcus
AU - Prasad, Vivek
AU - Kimlinger, Teresa
AU - Painuly, Utkarsh
AU - Mukhopadhyay, Bedabrata
AU - Haug, Jessica
AU - Bi, Lintao
AU - Vincent Rajkumar, S.
AU - Kumar, Shaji
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Bcl-2
KW - GRP78
KW - IAP
KW - Myeloma
UR - http://www.scopus.com/inward/record.url?scp=84984911623&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84984911623&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.11028
DO - 10.18632/oncotarget.11028
M3 - Article
C2 - 27494845
AN - SCOPUS:84984911623
SN - 1949-2553
VL - 7
SP - 56253
EP - 56265
JO - Oncotarget
JF - Oncotarget
IS - 35
ER -