BH4 domain of Bcl-2 as a novel target for cancer therapy

Liu, Zhiqing; Wild, Christopher; Ding, Ye; Ye, Na; Chen, Haiying; Wold, Eric A.; Zhou, Jia

doi:10.1016/j.drudis.2015.11.008

Cited by 46 publications

(42 citation statements)

References 68 publications

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“…For example, a Bax-Bax dimer may induce apoptosis, whereas a Bcl-2-Bax dimer is more stable when compared with the former (16). As a consequence of increased Bcl-2 expression, the proportion of Bcl-2-Bax dimers will be increased relative to Bax-Bax dimers, resulting in a decrease in pro-apoptotic Bax-Bax activity (17). In the presence of Bcl-xS, formation of Bcl-xS-Bcl-2 dimer results in a decrease in Bcl-2-Bax dimer levels, which subsequently increases Bax-Bax levels, so as to induce apoptosis (18).…”

Section: Discussionmentioning

confidence: 99%

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

et al. 2017

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Abstract. The present study investigated whether poly(ADP-ribose) polymerase (PARP) has an effect on p53-regulated pancreatic cancer. The results of the present study demonstrated that the expression of PARP affects proliferation and apoptosis of pancreatic cancer cells. Olaparib was used to suppress the expression level of PARP-1 in PanC-1 cells. Decreased expression of PARP-1 suppressed cell proliferation and induced apoptosis of PanC-1 cells when compared with controls. Furthermore, decreased expression of PARP-1 resulted in decreased levels of pro-caspase-3 expression, increased caspase-3 activity, suppressed B-cell lymphoma 2 (Bcl-2) protein expression and increased p53 protein expression in PanC-1 cells. Subsequently, ataxia telangiectasia mutated (ATM) activity was inhibited alongside down-expression of PARP-1 resulting in significantly decreased cellular viability of PanC-1 cells, increased p53 protein expression, decreased expression of pro-caspase-3, increased caspase-3 activity and suppressed Bcl-2 protein expression, when compared with PARP-1 suppression alone. Overall, the in vitro data confirmed that down-expression of PARP-1 suppressed cell proliferation and induced apoptosis of pancreatic cancer via ATM-deficient p53 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

et al. 2017

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“…On the other hand, inducing apoptosis through interrupting BH4 functions may be a potential treatment to eliminate unwanted T cells. For example, malignant T cells in lymphocytic leukemia diseases may be eliminated by this strategy (320). …”

Section: Maintaining T Cell Survival For Therapeutic Purposementioning

confidence: 99%

“…For example, malignant T cells in lymphocytic leukemia diseases may be eliminated by this strategy. 315…”

Section: Bax and Bakmentioning

confidence: 99%

Dying to protect: cell death and the control of T‐cell homeostasis

Shanmuganad

Carroll

et al. 2017

Immunological Reviews

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Summary T cells play a critical role in immune responses as they specifically recognize peptide/MHC complexes with their T cell receptors (TCRs) and initiate adaptive immune responses. While T cells are critical for performing appropriate effector functions and maintaining immune memory, they also can cause autoimmunity or neoplasia if misdirected or dysregulated. Thus, T cells must be tightly regulated from their development onward. Maintenance of appropriate T cell homeostasis is essential to promote protective immunity and limit autoimmunity and neoplasia. This review will focus on the role of cell death in maintenance of T cell homeostasis and outline novel therapeutic strategies tailored to manipulate cell death to limit T cell survival (eg autoimmunity and transplantation) or enhance T cell survival (eg vaccination, immune-deficiency).

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“…There exist four BH domains (BH 1-4) of which the BH3 domain is responsible for activation and inactivation interactions of pro-apoptosis and antiapoptosis BCL2 family proteins. Since overexpression of BCL2 protein has implicated in several cancerous tumors [10], BH3 domain has been targeted for developing small molecule inhibitors of BCL2 protein (anti-apoptosis) to induced cell death in cancerous cells; inhibitors such as ABT-737, ABT-263, ABT-199, Disarib, etc. [8] have been developed with varying degree of success [5] [6].…”

Section: Introductionmentioning

confidence: 99%

“…[8] have been developed with varying degree of success [5] [6]. However, none has been approved for use; this is primarily due to the highly conserved nature of BH3 domains among the BCL2 family [10]; the search for small molecules inhibitors or antagonists of BCL2 protein has thus continued.…”

Section: Introductionmentioning

confidence: 99%

Virtual Screening and Elucidation of Putative Binding Mode for Small Molecule Antagonist of BCL2 BH4 Domain

Joel

Adigun

Ajibola

et al. 2020

Preprint

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Evading apoptosis is one of the hallmarks of cancer cells, therefore a lot of therapeutic strategies have been developed to induce cell death in these cells. BCL2 family protein governs the intrinsic pathway of cell death. The BCL2 family protein possess both pro and anti-apoptosis members. BCL2 protein, a pioneering member of the anti-apoptosis protein has been implicated in several cancerous cells; with dozens of small-molecule inhibitors developed to inhibit its activity. BCL2 family protein processes BH domains (1-4) for heterodimerization and homodimerization amidst it family members and targeting the BH4 domain is an established new strategy for cancer therapy; however, only BDA366 has been reported so far as a BH4 binding molecule. Using Computer-aided drug discovery techniques (Molecular docking, QM-polarized docking, Induced-fit docking, QM-MM optimization, and QM electronic descriptors) we screened M sample (∼ 99,000 compounds) of the SCUBIDOO database to find ligands that interacts with the BH4 domain of BCL2 protein with high affinity, we identified 11 putative BH4 specific small molecules with binding affinity ranging from ∼ −84kcal/mol to −64kcal/mol with a putative binding hypothesis with BH4 amino acid residues: ASP10, ARG12, GLU13, MET16, LYS17, and HIS20

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BH4 domain of Bcl-2 as a novel target for cancer therapy

Cited by 46 publications

References 68 publications

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

Down‑expression of poly(ADP‑ribose) polymerase in p53‑regulated pancreatic cancer cells

Dying to protect: cell death and the control of T‐cell homeostasis

Virtual Screening and Elucidation of Putative Binding Mode for Small Molecule Antagonist of BCL2 BH4 Domain

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