Related Experiment Video
Updated: Mar 16, 2026
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in
Vijay Ramakrishnan1, Marcus Gomez1, Vivek Prasad1
1Division of Hematology, Mayo Clinic, Rochester, MN, USA.
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.
Insights
Combining Obatoclax (OBX) and LCL161 shows synergistic effects against multiple myeloma (MM) cells by targeting anti-apoptotic proteins. This combination therapy holds promise for treating relapsed refractory MM patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bcl2 and IAP families are anti-apoptotic proteins often deregulated in multiple myeloma (MM).
- Targeted inhibition of these families shows activity in only some MM patients.
- Broad-spectrum inhibitors combined with Smac mimetics may offer enhanced therapeutic strategies.
Purpose of the Study:
- To investigate the synergistic effects of Obatoclax (OBX), a Bcl2 family inhibitor, and LCL161, a Smac mimetic, in multiple myeloma (MM).
- To elucidate the mechanisms underlying the combination therapy's efficacy and resistance pathways.
Main Methods:
- Treatment of human MM cell lines and patient cells with OBX and LCL161, individually and in combination.
- Assessment of cytotoxicity, anti-proliferative effects, caspase activation, and expression of pro-apoptotic proteins.
- Analysis of ER stress, Unfolded Protein Response (UPR) activation, GRP78 localization, and Akt signaling pathways.
Main Results:
- The LCL161/OBX combination demonstrated synergistic cytotoxicity and anti-proliferative effects across various MM cell lines.
- Cytotoxicity was mediated by IAP inhibition, caspase activation, and upregulation of pro-apoptotic proteins (Bid, Bim, Puma, Noxa).
- OBX induced ER stress and UPR, leading to resistance via GRP78 cell surface localization and Akt activation, which LCL161 effectively inhibited.
Conclusions:
- The combination of LCL161 and OBX exhibits potent synergistic anti-myeloma activity through multiple mechanisms.
- LCL161 counteracts OBX-induced resistance pathways, enhancing overall therapeutic efficacy.
- This combination strategy warrants clinical evaluation for relapsed refractory multiple myeloma.
