B Cell Lymphoma-2 (BCL-2) Homology Domain 3 (BH3) Mimetics Demonstrate Differential Activities Dependent upon the Functional Repertoire of Pro- and Anti-apoptotic BCL-2 Family Proteins

Renault, Thibaud T.; Elkholi, Rana; Bharti, Archana; Chipuk, Jerry E.

doi:10.1074/jbc.m114.569632

Cited by 29 publications

(21 citation statements)

References 43 publications

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“…However, levels of this protein do not correlate with in vivo response of pediatric ALL xenografts [82 ]. Using liposomes and recombinant proteins, Renault et al have found that not only anti-apoptotic proteins but also proapoptotic members of the family contribute to determining the response to specific BH3-mimetics [83]. Clearly, these results indicate that predicting the sensitivity of BH3-mimetics will probably require more complex systems that include several players of the mitochondrial pathway.…”

Section: Discussionmentioning

confidence: 95%

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

Vela

Marzo

2015

Current Opinion in Pharmacology

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Section: Discussionmentioning

confidence: 95%

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

Vela

Marzo

2015

Current Opinion in Pharmacology

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“…18 Therefore, dual-target inhibitor, such as TW-37, has the specific potential application. 19 Both CDDP and 5-Fu decrease protein level of Bcl-2 and Mcl-1 in NPC cells. This result is comparable with several kinds of cancer.…”

Section: Discussionmentioning

confidence: 92%

Small molecule inhibitor TW-37 is tolerable and synergistic with chemotherapy in nasopharyngeal carcinoma

Huang

Yang

et al. 2017

Cell Cycle

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Chemotherapy is a crucial adjuvant therapy of advanced nasopharyngeal carcinoma (NPC). However, enhancing sensitivity and tolerance of chemotherapeutics in NPC treatment have been challenging. Both Bcl-2 and Mcl-1, 2 pro-survival proteins of Bcl-2 family, play essential roles on the chemotherapy tolerance of numerous cancers. In the present study, we explored the influences of TW-37, a small molecule inhibitor of Bcl-2 and Mcl-1, on the efficiency of chemotherapy for NPC. Oncomine cancer database shows that NPC tissues have higher expression of Bcl-2 and Mcl-1 than those of normal nasopharyngeal epithelial (NPE) tissues. And our results reveal that chemotherapeutics, Cisplatin (CDDP) and 5-Fluoracil (5-FU), result in the greater decrease of protein level of Bcl-2 and Mcl-1 in NPC cells than those in NPE cells. TW-37 does not have significant impact on the chemotherapeutics-treated NPE cell viability at a dosage that efficiently reduces chemotherapeutics-treated NPC cell viability. Moreover, impacts of TW-37 on the cell viability of chemotherapeutics-treated NPC cells are dependent on the expression of Bcl-2 and Mcl-1 in NPC cells. Further explorations suggest that TW-37 prominently promotes apoptosis in NPC cells under chemotherapeutics treatments but not in NPE cells. Meanwhile, TW-37 also remarkably reduces colony formation ability of chemotherapeutics-treated NPC cells. Importantly, in vivo models, TW-37 observably increases chemosensitivity of NPC tumors but has not markedly influence on the normal tissues in mice. In conclusion, our results point to TW-37 as a promising ancillary drug for the chemotherapy of NPC.

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“…The second model suggests that mitochondrial apoptogenic factors can be released through the pores in the OMM formed by the pro-apoptotic Bcl-2 family members that do not affect m . Key members of the anti-apoptotic (Bcl-2, Bcl-x L , and Bcl-w) and proapoptotic (Bax, Bak, Bad, Bim and Bid) Bcl-2 family of proteins are major players in the OMM permeabilisation and apoptotic susceptibility in this model of cytosolic release of apoptogenic mediators [59].…”

Section: Caspase-dependent and -Independent Programmed Cell Deathmentioning

confidence: 99%

Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer

Tomasetti¹,

Santarelli²,

Alleva³

et al. 2015

CMC

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Tumours exhibit higher basal levels of reactive oxygen species (ROS) and altered redox environment compared to normal cells. Excessive level of ROS can be toxic to these cells, thus they become more vulnerable to damage by further ROS insults induced by pharmacological agents. However, the upregulation of antioxidant capacity in adaptation to intrinsic oxidative stress in cancer cells can confer drug resistance. Therefore, abrogation of such drug-resistant mechanisms by redox modulation could have significant therapeutic implications. Many redox-modulating agents have been developed. The redox-active system epitomised by ascorbate-driven quinone redox cycling, and the group of redox-silent vitamin E analogues represented by α-tocopheryl succinate have been shown to induce selective cancer cell death in different types of cancer. These compounds synergistically act by destabilising organelles like mitochondria, unleashing their apoptogenic potential, which results in efficient death of malignant cells and suppression of tumour growth. Consistent with this notion, clinical trials that aim to examine the therapeutic performance of novel redox-modulating drugs in cancer patients are currently under way.

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B Cell Lymphoma-2 (BCL-2) Homology Domain 3 (BH3) Mimetics Demonstrate Differential Activities Dependent upon the Functional Repertoire of Pro- and Anti-apoptotic BCL-2 Family Proteins

Cited by 29 publications

References 43 publications

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside

Small molecule inhibitor TW-37 is tolerable and synergistic with chemotherapy in nasopharyngeal carcinoma

Redox-active and Redox-silent Compounds: Synergistic Therapeutics in Cancer

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