Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma

Al-Odat, Omar S.; Suskil, Max Von; Chitren, Robert; Elbezanti, Weam Othman; S, Srivastava; Budak-Alpddogan, Tulin; Jonnalagadda, Subash C.; Aggarwal, Bharat B.; Pandey, Manoj K.

doi:10.3389/fphar.2021.699629

Cited by 27 publications

(23 citation statements)

References 117 publications

(155 reference statements)

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“…A substantial portion of the genes (21%) resulted in being unfavorable prognostic markers of overall survival in at least two MM patient cohorts ( Figure 5 E). A prominent example was shown for MCL1 ( Figure 5 F), an anti-apoptotic protein highly expressed in MM with a crucial role in disease progression [ 57 ]. A further literature review identified nine genes implicated in promoting drug resistance in MM cells, including CDK6 [ 58 ], HIF1A [ 59 ], MCL1 [ 60 ], MITF [ 61 ], PPP3CA [ 62 ], PTP4A3 [ 63 ], RUNX3 [ 64 ], SGK1 [ 27 , 65 ], and USP14 [ 66 ] ( Supplementary Table S4 ).…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, MM cells in the transwell exhibited substantial changes in the regulome as compared to the monoculture. In particular, we identified a subset of genes where BMSCs induced an increase in chromatin accessibility at multiple regulatory sites, including genes known to promote drug resistance such as ABCA1 [ 56 ], SGK1 [ 27 ], and MCL1 [ 57 ]. These signature genes were enriched in biological processes related to IL6 signaling, apoptosis, angiogenesis, unfolded protein stress, and the transcription response to drugs.…”

Section: Discussionmentioning

confidence: 99%

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Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma

Dziadowicz

Wang

Akhter

et al. 2022

Cancers

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Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in the transcriptome and develop de novo multi-drug resistance. As a critical component in transcriptional regulation, how the chromatin landscape is transformed in MM cells exposed to BMSCs and contributes to the transcriptional response to BMSCs remains elusive. We profiled the transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells that coexisted with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in the JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with increasing accessibility at multiple regulatory sites were preferentially induced by BMSCs; these genes were enriched in functions linked to responses to drugs and unfavorable clinic outcomes. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulate the BMSC-induced transformation of the regulome linked to the transcriptional response. Together, we characterized the BMSC-induced transcriptome and regulome signatures of MM cells to facilitate research on epigenetic mechanisms of BMSC-induced multi-drug resistance in MM.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma

Dziadowicz

Wang

Akhter

et al. 2022

Cancers

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“…The study also needs in-vitro with invivo animal studies for the con rmation of these phytochemicals as a potent inhibitor of MCL1 and PKM2 towards cancer treatment. Figure 2 the intrinsic and extrinsic processes that lead to programmed cell death in healthy mammalian cells [14].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, caspase-8 and caspase-10 activate Bid, which activates Bak and Bax to induce MOMP. MOMP is a link between extrinsic and intrinsic signaling pathways [14].…”

Section: Introductionmentioning

confidence: 99%

Classes of Mormordicoside with potent and selective tumor cell growth inhibitory activity: prediction of Pyruvate kinase muscle isozyme 2 (PKM 2) and Anti-apoptotic Myeloid leukemia 1 (MCL1) inhibitor through machine learning.

Ibisanmi

Aribisala

Odjegba

et al. 2022

Preprint

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Background The difficulty in treating cancer resides in the ability to target abnormal proliferation while protecting normal proliferation, a feat that necessitates a thorough comprehension of both the normal and malignant mechanisms that promote cell growth and proliferation. Targeting cell death signaling pathways such as glycolytic and mitochondrial apoptosis is hallmark of many cancers the aim in which this research is ready to evaluate. Methods Atomistic molecular dynamics simulation of top hits after molecular docking and ADMET profiling of the ligands were performed for main protease-hit complexes. Results Docking scores of ligands used against PKM2 ranges from – 9.36 to – 12.1 kcal/mol, wherein, Mormordicoside-F2 had the highest score (-12.1kcal/mol) performing better than the FDA approved drug Benserazide(-7kcal/mol). Likewise, the scores ranged between – 8.51 and – 12.05kcal/mol for Anti-apoptotic Myeloid leukemia 1 (MCL-1), with Mormordicoside-F1 being the highest ranked compound performing better than the FDA approved drug Venetoclax(-8.6 kcal/mol). The RMSD plots obtained depicted stable trajectories with consistent and minor fluctuations implying that the protein (PKM2 and MCL1) backbone underwent minor structural perturbations. In addition, several significant peaks of increased fluctuations (RMSF) were also observed, indicating their increased interaction potential implying that the ligands could adapt effectively in the binding pocket of the protein. SASA analysis results shows that ligands used retained inside their shallow binding pocket. The phylogenetic tree obtained implies likelihood of reoccurring result of the Insilco profiling. Conclusion This research unveils that Mormordicoside F1 shows acceptable stability with Anti-apoptotic Myeloid leukemia 1 (MCL-1), likewise Mormordicoside F2 against PKM2. These hits may offer a more advantageous repurposing alternative.

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“…Moreover, Mcl-1 dependent cancers are resistant to pan Bcl-2/Bcl-xL inhibitors (ABT-737), and venetoclax [ 186 ]. Therefore, Mcl-1 is an attractive target for MM [ 187 , 188 , 189 ]. There are several clinical trials ongoing for Mcl-1 inhibitors, for example MIK665 (also named S64315) is tested in phase I trials for refractory or relapsed lymphoma or MM patients [ 190 ].…”

Section: Glance Into the Futurementioning

confidence: 99%

Past, Present, and a Glance into the Future of Multiple Myeloma Treatment

et al. 2023

Self Cite

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Multiple myeloma (MM) is a challenging hematological cancer which typically grows in bone marrow. MM accounts for 10% of hematological malignancies and 1.8% of cancers. The recent treatment strategies have significantly improved progression-free survival for MM patients in the last decade; however, a relapse for most MM patients is inevitable. In this review we discuss current treatment, important pathways for proliferation, survival, immune suppression, and resistance that could be targeted for future treatments.

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Mcl-1 Inhibition: Managing Malignancy in Multiple Myeloma

Cited by 27 publications

References 117 publications

Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma

Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma

Classes of Mormordicoside with potent and selective tumor cell growth inhibitory activity: prediction of Pyruvate kinase muscle isozyme 2 (PKM 2) and Anti-apoptotic Myeloid leukemia 1 (MCL1) inhibitor through machine learning.

Past, Present, and a Glance into the Future of Multiple Myeloma Treatment

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