Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myeloma Article Swipe
Vijay Ramakrishnan
,
Marcus V. Gomez
,
Vivek Prasad
,
Teresa K. Kimlinger
,
Utkarsh Painuly
,
Bedabrata Mukhopadhyay
,
Jessica Haug
,
Lintao Bi
,
S. Vincent Rajkumar
,
Shaji Kumar
·
YOU?
·
· 2016
· Open Access
·
· DOI: https://doi.org/10.18632/oncotarget.11028
YOU?
·
· 2016
· Open Access
·
· DOI: https://doi.org/10.18632/oncotarget.11028
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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- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.18632/oncotarget.11028
- http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=11028&path%5B%5D=34926
- OA Status
- diamond
- Cited By
- 24
- References
- 54
- Related Works
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- OpenAlex ID
- https://openalex.org/W2485413676
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2485413676Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.18632/oncotarget.11028Digital Object Identifier
- Title
-
Smac mimetic LCL161 overcomes protective ER stress induced by obatoclax, synergistically causing cell death in multiple myelomaWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2016Year of publication
- Publication date
-
2016-08-02Full publication date if available
- Authors
-
Vijay Ramakrishnan, Marcus V. Gomez, Vivek Prasad, Teresa K. Kimlinger, Utkarsh Painuly, Bedabrata Mukhopadhyay, Jessica Haug, Lintao Bi, S. Vincent Rajkumar, Shaji KumarList of authors in order
- Landing page
-
https://doi.org/10.18632/oncotarget.11028Publisher landing page
- PDF URL
-
https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=11028&path%5B%5D=34926Direct link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
diamondOpen access status per OpenAlex
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-
https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=11028&path%5B%5D=34926Direct OA link when available
- Concepts
-
Hematology, Medicine, Apoptosis, Multiple myeloma, Programmed cell death, Cancer research, Internal medicine, Oncology, Pharmacology, Biology, GeneticsTop concepts (fields/topics) attached by OpenAlex
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24Total citation count in OpenAlex
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2025: 1, 2024: 3, 2023: 2, 2022: 4, 2021: 2Per-year citation counts (last 5 years)
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54Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.MM | 28, 49, 69, 179 |
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| abstract_inverted_index.in | 8, 25, 41, 48, 176 |
| abstract_inverted_index.of | 15, 17, 27, 67, 78, 82, 87, 172 |
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| abstract_inverted_index.we | 31, 102, 130 |
| abstract_inverted_index.Akt | 146, 160 |
| abstract_inverted_index.IAP | 2 |
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| abstract_inverted_index.and | 1, 52, 60, 84, 94, 109, 148 |
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| abstract_inverted_index.the | 79, 88, 97, 111, 138 |
| abstract_inverted_index.was | 74, 154 |
| abstract_inverted_index.(MM) | 11 |
| abstract_inverted_index.Bcl2 | 0, 36 |
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| abstract_inverted_index.Bim, | 92 |
| abstract_inverted_index.Noxa | 95 |
| abstract_inverted_index.PI3K | 144 |
| abstract_inverted_index.Puma | 93 |
| abstract_inverted_index.Smac | 45 |
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| abstract_inverted_index.then | 142 |
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| abstract_inverted_index.(UPR) | 115 |
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| abstract_inverted_index.death. | 152, 166 |
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| abstract_inverted_index.strategy | 175 |
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| abstract_inverted_index.Obatoclax | 39 |
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| abstract_inverted_index.increased | 134 |
| abstract_inverted_index.inhibited | 122 |
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| abstract_inverted_index.inhibition | 14, 77 |
| abstract_inverted_index.refractory | 178 |
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| abstract_inverted_index.resistance | 149 |
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| abstract_inverted_index.Pharmacological | 13 |
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| cited_by_percentile_year.min | 90 |
| corresponding_author_ids | https://openalex.org/A5026574827 |
| countries_distinct_count | 3 |
| institutions_distinct_count | 10 |
| corresponding_institution_ids | https://openalex.org/I4210125099 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8500000238418579 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.88223674 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |