Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents

Wan, Yicong; Dai, Ningning; Tang, Zilong; Fang, Hao

doi:10.1016/j.ejmech.2018.01.076

Cited by 71 publications

(45 citation statements)

References 70 publications

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“…In addition, MCL-1 overexpression induced resistance to Bcl-2 inhibitors and some widely applied anticancer therapies, including paclitaxel, vincristine, and gemcitabine. Studies also demonstrated that silencing Mcl-1 could restore the sensitivity of drug-resistant cells 41,42 . It was highly expressed in MM cells as one of the major survival factors of MM cells and was involved in the process of tumor resistance, but the specific mechanism of its drug resistance is not clear.…”

Section: Discussionmentioning

confidence: 96%

LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p

et al. 2019

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Radiotherapy, chemotherapy, autologous/allogeneic stem cell transplantation, and targeted drug therapy are currently available therapeutic options for multiple myeloma (MM), but the clinical outcome remains unsatisfactory owing to frequent occurrence of drug resistance. Anti apoptosis is one of the main mechanisms to mediate drug resistance. Studies have shown that MCL-1 plays a key role in the growth of cancer cells “escaping” drug attacks, but the underlying mechanism remains unclear. Our previous study demonstrated that lncRNA H19 was highly expressed in the serum of MM patients. Bioinformatics predicts that miR-29b-3p is the downstream target gene, and MCL-1 is the downstream target protein of miR-29b-3p. Therefore, we speculated that MCL-1 may be involved in the occurrence of drug resistance through epigenetics. On the basis of these previous findings, the present study was intended to explore the biological function of H19, interactions between the downstream target genes, and the effect of H19 on BTZ resistance of myeloma cells. In addition, in vivo experiments we have also confirmed that H19 promoted tumor growth and may develop resistance to bortezomib partly. It was found that H19 reduced cell sensitivity to the chemotherapeutic drug BTZ by working as a miRNA sponge to inhibit the expression of miR-29b-3p, enhance MCL-1 transcriptional translation and inhibit apoptosis. These findings may help gain insights into the molecular mechanism of acquired BTZ resistance and develop new drug targets for the clinical treatment of MM.

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Section: Discussionmentioning

confidence: 96%

LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p

et al. 2019

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“…Apoptosis evasion is an important hallmark of cancers 64 and limits the efficacy of CDDP. 6,7 Although Mcl-1 has received much attention due to its unique role in mediating apoptosis and chemoresistance, 11,65,66 Pt IV complexes targeting Mcl-1, and further targeting RAD51 and BRCA2 have not been reported so far. This study provides uncommon examples of the design of such complexes; also, it gives some new insight into the cytostatic mechanism of such complexes and broadens the way to designing Pt complexes for overcoming CDDP resistance.…”

Section: Discussionmentioning

confidence: 99%

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

et al. 2020

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“…To our knowledge, direct STAT3 inhibitors of clinical grade are not yet available [102]. The development of potent small-molecule inhibitors specific for Mcl-1 have been reported in the literature [103] and, currently, six phase 1 clinical trials are underway for hematological malignancies, among other cancers [104]. Additionally, the ability of NGAL-R antibodies to promote CLL cell death might provide a new experimental tool for apoptosis-based therapeutic strategies in CLL.…”

Section: Discussionmentioning

confidence: 99%

Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia

Bauvois

Pramil

Jondreville

et al. 2020

Cancers

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The resistance to apoptosis of chronic lymphocytic leukemia (CLL) cells partly results from the deregulated production of survival signals from leukemic cells. Despite the development of new therapies in CLL, drug resistance and disease relapse still occur. Recently, neutrophil gelatinase-associated lipocalin (NGAL), a secreted glycoprotein, has been suggested to have a critical role in the biology of tumors. Thus, we investigated the relevance of NGAL in CLL pathogenesis, analyzed the expression of its cellular receptor (NGAL-R) on malignant B cells and tested whether CLL cells are resistant to apoptosis through an autocrine process involving NGAL and NGAL-R. We observed that NGAL concentrations were elevated in the serum of CLL patients at diagnosis. After treatment (and regardless of the therapeutic regimen), serum NGAL levels normalized in CLL patients in remission but not in relapsed patients. In parallel, NGAL and NGAL-R were upregulated in leukemic cells from untreated CLL patients when compared to normal peripheral blood mononuclear cells (PBMCs), and returned to basal levels in PBMCs from patients in remission. Cultured CLL cells released endogenous NGAL. Anti-NGAL-R antibodies enhanced NGAL-R+ leukemia cell death. Conversely, recombinant NGAL protected NGAL-R+ CLL cells against apoptosis by activating a STAT3/Mcl-1 signaling pathway. Our results suggest that NGAL and NGAL-R, overexpressed in untreated CLL, participate in the deregulation of the apoptotic machinery in CLL cells, and may be potential therapeutic clues for CLL treatment.

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Small-molecule Mcl-1 inhibitors: Emerging anti-tumor agents

Cited by 71 publications

References 70 publications

LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p

LncRNA H19 overexpression induces bortezomib resistance in multiple myeloma by targeting MCL-1 via miR-29b-3p

Interfering in apoptosis and DNA repair of cancer cells to conquer cisplatin resistance by platinum(iv) prodrugs

Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia

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