MCL-1 inhibition in cancer treatment

Xiang, Weidong; Yang, Chao‐Yie; Bai, Longchuan

doi:10.2147/ott.s146228

Cited by 125 publications

(110 citation statements)

References 91 publications

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“…Taken together, compounds with potent activity for eliminating Bcl-2 or Mcl-1 in cancer cells are of great interest as good candidates for targeted therapy. In agreement with the use of Mcl-1 as a target for cancer therapy [11], our previous study highly supported this concept, where in our experiments, the treatment of RT in an NSCLC cell line (H460) resulted in apoptotic cell death through an Mcl-1 proteasomal degraded mechanism [23]. In the same way, not only in a known lung cancer cell line, but we also proved that the absence of Mcl-1 after RT treatment in primary lung cancer cell lines derived from patients (Figure 3a,b) could trigger the apoptotic pathway, which led to the death of cancer cells (Figure 1f,g).…”

Section: Discussionsupporting

confidence: 62%

“…Recent evidence has suggested that the ability to evade apoptosis, survival during metastasis, and resistance to therapy are likely to be dependent on the expression and function of the pro-survival Bcl-2 proteins [8]. Consequently, it is not unexpected that the amplification and overexpression of pro-survival Bcl-2 proteins, such as Bcl-2 and Mcl-1, are found in many cancer types (e.g., non-small-cell lung cancer, breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer) [9][10][11]. Bcl-2 family members, like Bcl-2 and Mcl-1, have been shown to dominate negative regulation for apoptosis control and to be responsible for chemotherapeutic resistance [12].…”

Section: Introductionmentioning

confidence: 99%

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Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Petsri

Yokoya

Tungsukruthai

et al. 2020

Cancers

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Myeloid cell leukemia 1 (Mcl-1) and B-cell lymphoma 2 (Bcl-2) proteins are promising targets for cancer therapy. Here, we investigated the structure–activity relationships (SARs) and performed molecular docking analysis of renieramycin T (RT) and its analogues and identified the critical functional groups of Mcl-1 targeting. RT have a potent anti-cancer activity against several lung cancer cells and drug-resistant primary cancer cells. RT mediated apoptosis through Mcl-1 suppression and it also reduced the level of Bcl-2 in primary cells. For SAR study, five analogues of RT were synthesized and tested for their anti-cancer and Mcl-1- and Bcl-2-targeting effects. Only two of them (TM-(–)-18 and TM-(–)-4a) exerted anti-cancer activities with the loss of Mcl-1 and partly reduced Bcl-2, while the other analogues had no such effects. Specific cyanide and benzene ring parts of RT’s structure were identified to be critical for its Mcl-1-targeting activity. Computational molecular docking indicated that RT, TM-(–)-18, and TM-(–)-4a bound to Mcl-1 with high affinity, whereas TM-(–)-45, a compound with a benzene ring but no cyanide for comparison, showed the lowest binding affinity. As Mcl-1 helps cancer cells evading apoptosis, these data encourage further development of RT compounds as well as the design of novel drugs for treating Mcl-1-driven cancers.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Petsri

Yokoya

Tungsukruthai

et al. 2020

Cancers

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“…Using RT-qPCR, the authors of the current study revealed that MYB may improve cell proliferation by enhancing cell cycle progression through CCND1 upregulation and p21 downregulation. Additionally, MYB may decrease apoptosis by upregulating MCL1 expression, which encodes proteins belonging to the Bcl-2 family (34).…”

Section: Discussionmentioning

confidence: 99%

“…Significant changes were identified in five of the 22 genes (data not shown). The expression of CCND1 and MCL1, which are associated with cell proliferation (33,34), was upregulated following MYB overexpression, whereas p21 expression was downregulated (Fig. 5A).…”

Section: Myb Promotes Sacc Lung Metastasis In Vivomentioning

confidence: 99%

MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma

Zhao

Yang

et al. 2019

Int J Oncol

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The incidence of recurrent t(6;9) translocation of the MYB proto-oncogene to NFIB (the gene that encodes nuclear factor 1 B-type) in adenoid cystic carcinoma (ACC) tumour tissues is high. However, MYB [the gene that encodes transcriptional activator Myb (MYB)] overexpression is more common, indicating that MYB serves a key role in ACC. The current study aimed to investigate the role of MYB in salivary (S)ACC growth and metastasis. A total of 50 fresh-frozen SACC tissues and 41 fresh-frozen normal submandibular gland (SMG) tissues were collected to measure MYB mRNA expression, and to analyse the associations between MYB and epithelial-mesenchymal transition (EMT) markers. Compared with normal SMG tissue, SACC tissues demonstrated significantly increased MYB expression, with a high expression rate of 90%. Interestingly, MYB tended to be negatively correlated with CDH1 [the gene that encodes cadherin-1 (E-cadherin)] and positively correlated with VIM (the gene that encodes vimentin), suggesting that MYB is associated with SACC metastasis. To explore the role of MYB in SACC, the authors stably overexpressed and knocked down MYB in SACC cells. The authors of the current study demonstrated that MYB overexpression promoted SACC cell proliferation, migration and invasion, whereas its knockdown inhibited these activities. Additionally, when MYB was overexpressed, CDH1 expression was downregulated, and CDH2 (the gene that encodes cadherin-2), VIM and ACTA2 (the gene that encodes actin, aortic smooth muscle) expression was upregulated. Then, the effect of MYB on lung tumour metastasis was investigated in vivo in non-obese diabetic/severe combined immunodeficiency mice. MYB overexpressing and control cells were injected into the mice through the tail vein. The results revealed that MYB promoted SACC lung metastasis. Collectively, these results demonstrated that MYB is aberrantly overexpressed in SACC tissues, and promotes SACC cell proliferation and metastasis, indicating that MYB may be a novel therapeutic target for SACC.

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“…AT-101 has been administered in combination with ABT-737 representing the first small molecule with anti MCL-1 activity investigated in clinical trials [109]. Additionally, a number of MCL-1 targeting compounds (MIK665, S64315, AMG176, AZD5991) have entered phase I clinical trials as a single agent for lymphoma, myeloma and hematologic malignancies [116].…”

Section: Treatment Approaches Targeting the Anti-apoptotic Bcl-2 Famimentioning

confidence: 99%

Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer

Krishnan

Golden

Woodward

et al. 2020

Cancers

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The Rab GTPase family of proteins are mediators of membrane trafficking, conferring identity to the cell membranes. Recently, Rab and Rab-associated factors have been recognized as major regulators of the intracellular positioning and activity of signaling pathways regulating cell growth, survival and programmed cell death or apoptosis. Membrane trafficking mediated by Rab proteins is controlled by intracellular localization of Rab proteins, Rab-membrane interactions and GTP-activation processes. Aberrant expression of Rab proteins has been reported in multiple cancers such as lung, brain and breast malignancies. Mutations in Rab-coding genes and/or post-translational modifications in their protein products disrupt the cellular vesicle trafficking network modulating tumorigenic potential, cellular migration and metastatic behavior. Conversely, Rabs also act as tumor suppressive factors inducing apoptosis and inhibiting angiogenesis. Deconstructing the signaling mechanisms modulated by Rab proteins during apoptosis could unveil underlying molecular mechanisms that may be exploited therapeutically to selectively target malignant cells.

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MCL-1 inhibition in cancer treatment

Cited by 125 publications

References 91 publications

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

Structure–Activity Relationships and Molecular Docking Analysis of Mcl-1 Targeting Renieramycin T Analogues in Patient-derived Lung Cancer Cells

MYB promotes the growth and metastasis of salivary adenoid cystic carcinoma

Rab GTPases: Emerging Oncogenes and Tumor Suppressive Regulators for the Editing of Survival Pathways in Cancer

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