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Smac模拟物LCL161克服了由 obatoclax 诱导的保护性内质网应激，协同导致多发性骨髓瘤细胞死亡。

Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma.

作者信息

Ramakrishnan Vijay, Gomez Marcus, Prasad Vivek, Kimlinger Teresa, Painuly Utkarsh, Mukhopadhyay Bedabrata, Haug Jessica, Bi Lintao, Rajkumar S Vincent, Kumar Shaji

机构信息

Division of Hematology, Mayo Clinic, Rochester, MN, USA.

4th Department of Internal Medicine-Hematology, University Hospital Hradec Kralove and Charles University in Prague, Faculty of Medicine in Hradec Kralove, Czech Republic.

出版信息

Oncotarget. 2016 Aug 30;7(35):56253-56265. doi: 10.18632/oncotarget.11028.

DOI:10.18632/oncotarget.11028
PMID:27494845
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5302912/
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.

摘要

Bcl2和IAP家族是在多发性骨髓瘤（MM）细胞中失调的抗凋亡蛋白。对这些家族中每个家族的药理学抑制仅在MM患者的亚组中显示出显著活性。在此，我们在MM细胞系和患者细胞中研究了一种广谱Bcl2家族抑制剂Obatoclax（OBX）与一种Smac模拟物LCL161的联合作用。LCL161/OBX联合用药对多种人类MM细胞系诱导了协同细胞毒性和抗增殖作用。细胞毒性是通过抑制IAPs、激活半胱天冬酶以及该药物组合上调促凋亡蛋白Bid、Bim、Puma和Noxa来介导的。此外，我们观察到OBX引起内质网应激并激活未折叠蛋白反应（UPR），从而导致耐药性。然而，LCL161抑制了剪接的Xbp-1，一种促生存因子。此外，我们观察到OBX增加了GRP78在细胞表面的定位，进而诱导PI3K依赖性的Akt激活和对细胞死亡的抗性。LCL161能够阻断OBX诱导的Akt激活，从而导致协同性细胞死亡。我们的结果支持对复发难治性MM患者进行这种联合治疗策略的临床评估。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/4db2bd8d8f3a/oncotarget-07-56253-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/1dd1b6e828ca/oncotarget-07-56253-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/5472848e510c/oncotarget-07-56253-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/5225ea85ab7f/oncotarget-07-56253-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/4c463c0b986e/oncotarget-07-56253-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/a298499f9ce3/oncotarget-07-56253-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/4db2bd8d8f3a/oncotarget-07-56253-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/1dd1b6e828ca/oncotarget-07-56253-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/5472848e510c/oncotarget-07-56253-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/5225ea85ab7f/oncotarget-07-56253-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/4c463c0b986e/oncotarget-07-56253-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/a298499f9ce3/oncotarget-07-56253-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9df2/5302912/4db2bd8d8f3a/oncotarget-07-56253-g006.jpg

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