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- PMID: 32066201
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Article: Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma
Title | Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma |
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Authors | |
Keywords | bortezomib myeloma S63845 synergistic effect venetoclax |
Issue Date | 2020 |
Publisher | John Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/WileyCDA/WileyTitle/productCd-JPHP.html |
Citation | Journal of Pharmacy and Pharmacology, 2020, v. 72 n. 5, p. 728-737 How to Cite? |
Abstract | Objectives:
Venetoclax, an orally available BCL2‐selective inhibitor, has demonstrated promising single‐agent anti‐tumour activity in myeloma especially patients with t(11;14). Herein, whether venetoclax sensitivity could be enhanced or restored in combination with bortezomib or S63845, a novel MCL1‐selective inhibitor, was examined in human myeloma cell lines (HMCLs), including bortezomib‐resistant HMCLs.
Methods:
By MTS assay, half‐maximal inhibitory concentration (IC50) and hence sensitivity/resistance to venetoclax, bortezomib and S63845 were determined.
Key findings:
Venetoclax (IC50 ≥100 nm), bortezomib (IC50 ≥50 nm) and S63845 (IC50 ≥100 nm) resistance was observed in nine (75%), three (25%) and six (50%) HMCLs, respectively. Moreover, venetoclax sensitivity was independent of bortezomib (R2 = 0.1107) or S63845 (R2 = 0.0213) sensitivity. Venetoclax sensitivity correlated with high mRNA ratio of BCL2/MCL1 (P = 0.0091), BCL2/BCL2L1 (P = 0.0182) and low MCL1 expression (P = 0.0091). In HMCLs sensitive to both venetoclax and bortezomib/S63845, venetoclax combined with S63845 showed stronger synergistic effect than combined with bortezomib. Moreover, in venetoclax‐resistant HMCLs, S63845, but not bortezomib, significantly restored venetoclax sensitivity. Conversely, bortezomib combined with S63845 did not result in augmented bortezomib sensitivity or abolishment of bortezomib resistance.
Conclusions:
Regardless of t(11;14), combination of venetoclax with S63845 is a promising strategy in enhancing venetoclax sensitivity or overcoming venetoclax resistance in myeloma therapy, hence warrant future clinical studies. |
Persistent Identifier | http://hdl.handle.net/10722/281224 |
ISSN | 2023 Impact Factor: 2.8 2023 SCImago Journal Rankings: 0.648 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Wong, KY | - |
dc.contributor.author | Chim, CS | - |
dc.date.accessioned | 2020-03-09T09:51:48Z | - |
dc.date.available | 2020-03-09T09:51:48Z | - |
dc.date.issued | 2020 | - |
dc.identifier.citation | Journal of Pharmacy and Pharmacology, 2020, v. 72 n. 5, p. 728-737 | - |
dc.identifier.issn | 0022-3573 | - |
dc.identifier.uri | http://hdl.handle.net/10722/281224 | - |
dc.description.abstract | Objectives: Venetoclax, an orally available BCL2‐selective inhibitor, has demonstrated promising single‐agent anti‐tumour activity in myeloma especially patients with t(11;14). Herein, whether venetoclax sensitivity could be enhanced or restored in combination with bortezomib or S63845, a novel MCL1‐selective inhibitor, was examined in human myeloma cell lines (HMCLs), including bortezomib‐resistant HMCLs. Methods: By MTS assay, half‐maximal inhibitory concentration (IC50) and hence sensitivity/resistance to venetoclax, bortezomib and S63845 were determined. Key findings: Venetoclax (IC50 ≥100 nm), bortezomib (IC50 ≥50 nm) and S63845 (IC50 ≥100 nm) resistance was observed in nine (75%), three (25%) and six (50%) HMCLs, respectively. Moreover, venetoclax sensitivity was independent of bortezomib (R2 = 0.1107) or S63845 (R2 = 0.0213) sensitivity. Venetoclax sensitivity correlated with high mRNA ratio of BCL2/MCL1 (P = 0.0091), BCL2/BCL2L1 (P = 0.0182) and low MCL1 expression (P = 0.0091). In HMCLs sensitive to both venetoclax and bortezomib/S63845, venetoclax combined with S63845 showed stronger synergistic effect than combined with bortezomib. Moreover, in venetoclax‐resistant HMCLs, S63845, but not bortezomib, significantly restored venetoclax sensitivity. Conversely, bortezomib combined with S63845 did not result in augmented bortezomib sensitivity or abolishment of bortezomib resistance. Conclusions: Regardless of t(11;14), combination of venetoclax with S63845 is a promising strategy in enhancing venetoclax sensitivity or overcoming venetoclax resistance in myeloma therapy, hence warrant future clinical studies. | - |
dc.language | eng | - |
dc.publisher | John Wiley & Sons Ltd. The Journal's web site is located at http://www.wiley.com/WileyCDA/WileyTitle/productCd-JPHP.html | - |
dc.relation.ispartof | Journal of Pharmacy and Pharmacology | - |
dc.rights | Preprint This is the pre-peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Postprint This is the peer reviewed version of the following article: [FULL CITE], which has been published in final form at [Link to final article using the DOI]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. | - |
dc.subject | bortezomib | - |
dc.subject | myeloma | - |
dc.subject | S63845 | - |
dc.subject | synergistic effect | - |
dc.subject | venetoclax | - |
dc.title | Venetoclax, bortezomib and S63845, an MCL1 inhibitor, in multiple myeloma | - |
dc.type | Article | - |
dc.identifier.email | Wong, KY: kwanumu@hku.hk | - |
dc.identifier.email | Chim, CS: jcschim@hku.hk | - |
dc.identifier.authority | Chim, CS=rp00408 | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1111/jphp.13240 | - |
dc.identifier.pmid | 32066201 | - |
dc.identifier.scopus | eid_2-s2.0-85079725083 | - |
dc.identifier.hkuros | 309255 | - |
dc.identifier.volume | 72 | - |
dc.identifier.issue | 5 | - |
dc.identifier.spage | 728 | - |
dc.identifier.epage | 737 | - |
dc.identifier.isi | WOS:000524181900007 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 0022-3573 | - |