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https://doi.org/10.18632/oncotarget.21988
Title: | VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim | Authors: | Mustafa, N Ting Lee, J.X Adina Nee, H.F Bi, C Chung, T.-H Hart, S Chng, W.J |
Keywords: | 5 (9 isopropyl 8 methyl 2 morpholino 9h purin 6 yl) 2 pyrimidinamine beta catenin BIM protein bortezomib caspase 3 cyclin D2 cyclin dependent kinase 4 cytochrome c dexamethasone dickkopf 1 protein mammalian target of rapamycin melphalan messenger RNA nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase panobinostat phosphatidylinositol 3 kinase protein Bax protein bcl xl protein kinase B protein S6 survivin Akt signaling animal experiment animal model antineoplastic activity apoptosis Article cancer inhibition cell viability cellular distribution concentration response controlled study cytosol down regulation drug cytotoxicity drug effect drug efficacy drug mechanism drug potentiation enzyme activation enzyme activity female G1 phase cell cycle checkpoint gene expression profiling gene expression regulation gene silencing human human cell IC50 in vivo study mouse multiple myeloma multiple myeloma cell line nonhuman protein cleavage protein expression protein phosphorylation RARRES3 gene therapeutic index tumor suppressor gene tumor volume tumor xenograft upregulation |
Issue Date: | 2017 | Citation: | Mustafa, N, Ting Lee, J.X, Adina Nee, H.F, Bi, C, Chung, T.-H, Hart, S, Chng, W.J (2017). VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim. Oncotarget 8 (60) : 101847-101864. ScholarBank@NUS Repository. https://doi.org/10.18632/oncotarget.21988 | Abstract: | The PI3K/mTOR/AKT pathway is an integral regulator of survival and drug resistance in multiple myeloma (MM). VS-5584 was synthesized with dual-specific and equipotent activity against mTORC1/2 and all four Class I PI3K isoforms so as to durably inhibit this pathway. We show that VS-5584 is highly efficacious against MM cell lines even in the presence of IL-6 and IGF-1 and that this growth inhibition is partially dependent on Bim. Importantly, VS-5584 triggers apoptosis in patient cells with a favorable therapeutic index. Gene expression profiling revealed a VS-5584-induced upregulation of RARRES3, a class II tumor suppressor gene. MM patient databases, UAMS and APEX, show that RARRES3 is under-expressed in 11q13 subsets which correlates with the reduced effectiveness of VS-5584 in 11q13 cell lines. Silencing RARRES3 expression significantly rescues VS-5584-induced cell death and increases cyclin D2 expression but not cyclin D1 or other cyclins implying a role for RARRES3 in cell cycle arrest. In vivo, VS-5584 significantly reduces the tumor burden of MM mouse xenografts. We further identified that VS-5584 synergised with Dexamethasone, Velcade, and exceptionally so with HDAC inhibitor, Panobinostat. Interestingly, this was consistently observed in several patient samples, proposing a promising novel clinical strategy for combination treatment especially in relapsed/refractory patients. © Mustafa et al. | Source Title: | Oncotarget | URI: | https://scholarbank.nus.edu.sg/handle/10635/173800 | ISSN: | 19492553 | DOI: | 10.18632/oncotarget.21988 |
Appears in Collections: | Staff Publications Elements |
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