VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim

Mustafa, Nurulhuda; Lee, Jeannie Xue Ting; Nee, Huey Fang Adina; Bi, Chonglei; Chung, Tae-Hoon; Hart, Stefan; Chng, Wee Joo

doi:10.18632/oncotarget.21988

Cited by 6 publications

(5 citation statements)

References 45 publications

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“…2 ). The genes identified encode surface (RARRES3, 31 TNFRSF10A, 32 PIK3R3, 33 TRAF1, 34 ), cytoplasmic (NCF2, 35 APOL3 36 ) and transporter (TAP1, TAP2) 37 proteins. A literature search of the 51 genes confirmed their role in cell death pathways in more detail ( Supplementary Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Autophagy Is Involved in Mesenchymal Stem Cell Death in Coculture with Chondrocytes

Paggi

Dudakovic

et al. 2020

CARTILAGE

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Objective Cartilage formation is stimulated in mixtures of chondrocytes and human adipose–derived mesenchymal stromal cells (MSCs) both in vitro and in vivo. During coculture, human MSCs perish. The goal of this study is to elucidate the mechanism by which adipose tissue–derived MSC cell death occurs in the presence of chondrocytes. Methods Human primary chondrocytes were cocultured with human MSCs derived from 3 donors. The cells were cultured in monoculture or coculture (20% chondrocytes and 80% MSCs) in pellets (200,000 cells/pellet) for 7 days in chondrocyte proliferation media in hypoxia (2% O2). RNA sequencing was performed to assess for differences in gene expression between monocultures or coculture. Immune fluorescence assays were performed to determine the presence of caspase-3, LC3B, and P62. Results RNA sequencing revealed significant upregulation of >90 genes in the 3 cocultures when compared with monocultures. STRING analysis showed interconnections between >50 of these genes. Remarkably, 75% of these genes play a role in cell death pathways such as apoptosis and autophagy. Immunofluorescence shows a clear upregulation of the autophagic machinery with no substantial activation of the apoptotic pathway. Conclusion In cocultures of human MSCs with primary chondrocytes, autophagy is involved in the disappearance of MSCs. We propose that this sacrificial cell death may contribute to the trophic effects of MSCs on cartilage formation.

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Section: Resultsmentioning

confidence: 99%

Autophagy Is Involved in Mesenchymal Stem Cell Death in Coculture with Chondrocytes

Paggi

Dudakovic

et al. 2020

CARTILAGE

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“…In the case of relapsed and refractory multiple myeloma (MM), the prognosis is poor. ( Mustafa et al, 2017 ) showed that VS-5584 may provide a longer-lasting chemotherapy response and may become a possible candidate for the combination therapy of relapsed and refractory patients. The reason is that in vivo , VS-5584 can significantly reduce the tumour burden of xenografts in MM mice.…”

Section: Purinesmentioning

confidence: 99%

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

Liang

et al. 2022

Front. Pharmacol.

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The PI3K-Akt-mTOR pathway is a viable target for cancer treatment and can be used to treat various malignant tumours, including follicular lymphoma and breast cancer. Both enzymes, PI3K and mTOR, are critical in this pathway. Hence, in recent years, an array of inhibitors targeting these two targets have been studied, showing dual PI3K/mTOR inhibition compared with single targeting small molecule inhibitors. Inhibitors not only inhibit cell proliferation but also promote cell apoptosis. These inhibitors show high potency and little drug resistance even at low doses, suggesting that PI3K/mTOR inhibitors are promising cancer drugs. Herein, we summarised the recent research of PI3K/mTOR dual inhibitors—for example, structure-activity relationship, pharmacokinetics, and clinical practice, and briefly commented on them.Clinical Trial Registration:https://clinicaltrials.gov.

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“…The PI3K/mTOR/AKT pathway is an integral regulator of this signaling network and its activation is related to survival and drug resistance in MM. VS-5584 is a synthesized purine analog and an equally potent inhibitor of both PI3K (all four isoforms of catalytic subunit p110 (α, β, γ, δ)) and mTORC1 and 2 [47]. VS-5584 effectively inhibits the growth of MM cell lines even in the presence of IL-6 and IGF-1 and this inhibition is partially dependent on Bim.…”

Section: Strategy For Enhancing the Anti-myeloma Effect Of Hdac Inmentioning

confidence: 99%

“…The tumor suppressor RARRES3 is downregulated with the progression of B-CLL, a mature B-cell malignancy [48]. Treating myeloma cells with VS-5584 was found to upregulate RARRES3 expression [47]. Furthermore, VS-5584 exerts synergistic anti-myeloma effects with the HDAC inhibitor panobinostat.…”

Section: Strategy For Enhancing the Anti-myeloma Effect Of Hdac Inmentioning

confidence: 99%

HDAC Inhibitors Exert Anti-Myeloma Effects through Multiple Modes of Action

Imai

Hirano

Kobayashi

et al. 2019

Cancers

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HDACs are critical regulators of gene expression that function through histone modification. Non-histone proteins and histones are targeted by these proteins and the inhibition of HDACs results in various biological effects. Moreover, the aberrant expression and function of these proteins is thought to be related to the pathogenesis of multiple myeloma (MM) and several inhibitors have been introduced or clinically tested. Panobinostat, a pan-HDAC inhibitor, in combination with a proteasome inhibitor and dexamethasone has improved survival in relapsing/refractory MM patients. We revealed that panobinostat inhibits MM cell growth by degrading the protein PPP3CA, a catalytic subunit of calcineurin. This degradation was suggested to be mediated by suppression of the chaperone function of HSP90 due to HDAC6 inhibition. Cytotoxicity due to the epigenetic regulation of tumor-associated genes by HDAC inhibitors has also been reported. In addition, HDAC6 inhibition enhances tumor immunity and has been suggested to strengthen the cytotoxic effects of therapeutic antibodies against myeloma. Furthermore, therapeutic strategies to enhance the anti-myeloma effects of HDAC inhibitors through the addition of other agents has been intensely evaluated. Thus, the treatment of patients with MM using HDAC inhibitors is promising as these drugs exert their effects through multiple modes of action.

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VS-5584 mediates potent anti-myeloma activity via the upregulation of a class II tumor suppressor gene, RARRES3 and the activation of Bim

Cited by 6 publications

References 45 publications

Autophagy Is Involved in Mesenchymal Stem Cell Death in Coculture with Chondrocytes

Autophagy Is Involved in Mesenchymal Stem Cell Death in Coculture with Chondrocytes

Recent Advances in Dual PI3K/mTOR Inhibitors for Tumour Treatment

HDAC Inhibitors Exert Anti-Myeloma Effects through Multiple Modes of Action

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