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Interaction studies to evaluate 2- carboxyphenolate analogues as inhibitor of anti-apoptotic protein Bcl-2.

ABSTRACT: Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, pro-apoptotic proteins bind anti-apoptotic proteins, thus allowing apoptosis to go forward. An excess of anti-apoptotic proteins can prevent apoptosis. Designed molecules that imitate the roles of pro-apoptotic proteins can promote the death of cancer cells. In this work we have applied an insilico approach to study the binding of 2-carboxyphenolate analogues as potent inhibitors of anti-apoptotic protein Bcl-2. Molecular docking study was performed in order to find specific binding mode using AutoDock. From the docking results it was observed that zinc 2- carboxyphenolate showed strong inhibition with Bcl-2 with docking energy of -4.6 kcal/mol. The effects of the Zinc 2- hydroxybenzoate on apoptosis in HT-1080 cell lines were also analysed, which shows strong evidence for their apoptotic mode of action using flow cytometric analysis of Annexin-V. Our study gave valuable insights on inhibitor specificity of anti-apoptotic proteins and might be considered as potent chemopreventive agents.

SUBMITTER: Al-Karaawi MA

PROVIDER: S-EPMC3705619 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Interaction studies to evaluate 2- carboxyphenolate analogues as inhibitor of anti-apoptotic protein Bcl-2.

Al-Karaawi Mohammed A MA

Bioinformation 20130525 9

Apoptosis is a cellular process that leads to the death of damaged cells. Its malfunction can cause cancer and poor response to conventional chemotherapy. After being activated by cellular stress signals, pro-apoptotic proteins bind anti-apoptotic proteins, thus allowing apoptosis to go forward. An excess of anti-apoptotic proteins can prevent apoptosis. Designed molecules that imitate the roles of pro-apoptotic proteins can promote the death of cancer cells. In this work we have applied an insi ...[more]

PMID: 23847403

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Project description:BackgroundNew therapeutic targets are needed to improve the outcomes for gastric cancer (GC) patients with advanced disease. Evasion of programmed cell death (apoptosis) is a hallmark of cancer cells and direct induction of apoptosis by targeting the pro-survival BCL2 family proteins represents a promising therapeutic strategy for cancer treatment. Therefore, understanding the molecular mechanisms underpinning cancer cell survival could provide a molecular basis for potential therapeutic interventions.MethodHere we explored the role of BCL2L1 and the encoded anti-apoptotic BCL-XL in GC. Using Droplet Digital PCR (ddPCR) technology to investigate the DNA amplification of BCL2L1 in GC samples and GC cell lines, the sensitivity of GC cell lines to selective BCL-XL inhibitors A1155463 and A1331852, pan-inhibitor ABT-263, and VHL-based PROTAC-BCL-XL was analyzed using (CellTiter-Glo) CTG assay in vitro. Western Blot (WB) was used to detect the protein expression of BCL2 family members in GC cell lines and the manner in which PROTAC-BCL-XL kills GC cells. Co-immunoprecipitation (Co-IP) was used to investigate the mechanism of A1331852 and ABT-263 kills GC cell lines. DDPCR, WB, and real-time PCR (RTPCR) were used to investigate the correlation between DNA, RNA, protein levels, and drug activity.ResultsThe functional assay showed that a subset of GC cell lines relies on BCL-XL for survival. In gastric cancer cell lines, BCL-XL inhibitors A1155463 and A1331852 are more sensitive than the pan BCL2 family inhibitor ABT-263, indicating that ABT-263 is not an optimal inhibitor of BCL-XL. VHL-based PROTAC-BCL-XL DT2216 appears to be active in GC cells. DT2216 induces apoptosis of gastric cancer cells in a time- and dose-dependent manner through the proteasome pathway. Statistical analysis showed that the BCL-XL protein level predicts the response of GC cells to BCL-XL targeting therapy and BCL2L1 gene CNVs do not reliably predict BCL-XL expression.ConclusionWe identified BCL-XL as a promising therapeutic target in a subset of GC cases with high levels of BCL-XL protein expression. Functionally, we demonstrated that both selective BCL-XL inhibitors and VHL-based PROTAC BCL-XL can potently kill GC cells that are reliant on BCL-XL for survival. However, we found that BCL2L1 copy number variations (CNVs) cannot reliably predict BCL-XL expression, but the BCL-XL protein level serves as a useful biomarker for predicting the sensitivity of GC cells to BCL-XL-targeting compounds. Taken together, our study pinpointed BCL-XL as potential druggable target for specific subsets of GC.

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Interaction studies to evaluate 2- carboxyphenolate analogues as inhibitor of anti-apoptotic protein Bcl-2.

Publications

Interaction studies to evaluate 2- carboxyphenolate analogues as inhibitor of anti-apoptotic protein Bcl-2.

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