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A Dimeric sesquiterpenoid from a Malaysian Meiogyne as a new inhibitor of Bcl-xL/BakBH3 domain peptide interaction

Litaudon M, Bousserouel H, Awang K, Nosjean O, Martin MT, Dau ME, et al.

J Nat Prod, 2009 Mar 27;72(3):480-3.
PMID: 19161318 DOI: 10.1021/np8006292

In an effort to find potent inhibitors of the antiapoptotic protein Bcl-xL, a systematic in vitro evaluation was undertaken on 1470 Malaysian plant extracts. The ethyl acetate extract obtained from the bark of Meiogyne cylindrocarpa was selected for its interaction with the Bcl-xL/Bak association. Bioassay-guided purification of this species led to the isolation of two new dimeric sesquiterpenoids (1 and 2) possessing an unprecedented substituted cis-decalin carbon skeleton. Meiogynin A (1) showed the strongest activity with a K(i) of 10.8 +/- 3.1 microM.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors*
Suppression of BCL-2 synergizes cisplatin sensitivity in nasopharyngeal carcinoma cells

Low SY, Tan BS, Choo HL, Tiong KH, Khoo AS, Leong CO

Cancer Lett, 2012 Jan 28;314(2):166-75.
PMID: 22033244 DOI: 10.1016/j.canlet.2011.09.025

The efficacy of cisplatin for treating nasopharyngeal carcinoma (NPC) is limited by the dose-related toxicities and the development of resistance to cisplatin. Recent studies have shown that B cell lymphoma-2 (BCL-2) is overexpressed and confers chemoresistance in NPC. Thus, targeted therapy against BCL-2 may enhance the antitumour effects of chemotherapy by sensitizing the tumor cells to undergo apoptosis. This study evaluated the combined effects of BCL-2 inhibition and cisplatin in NPC cells. Our results demonstrate that inhibition of BCL-2 by small-hairpin RNA (shRNA) or the BCL-2 inhibitor YC137, synergizes cisplatin sensitivity in NPC cells that overexpress BCL-2. We also show that YC137 enhance cisplatin-induced apoptosis in HK1 and CNE1 cells through suppression of BCL-2 protein expression, induction of mitochondrial depolarization and activation of caspase 9 and caspase 3/7. These findings suggest that the combination of BCL-2 inhibition and cisplatin represents a promising strategy for treating NPC.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors*
Fulltext In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells

Leong SW, Chia SL, Abas F, Yusoff K

Molecules, 2020 Aug 26;25(17).
PMID: 32858795 DOI: 10.3390/molecules25173877

In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure-activity relationship study suggested that the insertions of tetrahydro-4H-thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC50 values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4H-thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors*
Fulltext Targeting the B-cell lymphoma 2 anti-apoptotic proteins for cervical cancer treatment

Abdul Rahman SF, Xiang Lian BS, Mohana-Kumaran N

Future Oncol, 2020 Oct;16(28):2235-2249.
PMID: 32715755 DOI: 10.2217/fon-2020-0389

The B-cell lymphoma 2 (BCL-2) anti-apoptotic proteins have become attractive therapeutic targets especially with the development of BH3-mimetics which selectively target these proteins. However, it is important to note that expression levels of the anti-apoptotic proteins and their relevance in inhibiting apoptosis varies between different cell lineages. This addiction to certain anti-apoptotic proteins for survival, can be determined with various techniques and targeted effectively with selective BH3-mimetics. Studies have highlighted that anti-apoptotic proteins BCL-XL and MCL-1 are crucial for cervical cancer cell survival. Co-targeting BCL-XL and MCL-1 with selective BH3-mimetics yielded promising results in cervical cancer cell lines. In this review, we focus on the expression levels of the anti-apoptotic proteins in cervical cancer tissues and how to possibly target them with BH3-mimetics.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors*
Fulltext Synergistic anti-proliferative effects of combination of ABT-263 and MCL-1 selective inhibitor A-1210477 on cervical cancer cell lines

Lian BSX, Yek AEH, Shuvas H, Abdul Rahman SF, Muniandy K, Mohana-Kumaran N

BMC Res Notes, 2018 Mar 27;11(1):197.
PMID: 29580266 DOI: 10.1186/s13104-018-3302-0

OBJECTIVE: There are number of studies which report that BCL-2 anti-apoptotic proteins (e.g. BCL-2, BCL-XL, and MCL-1) are highly expressed in cervical cancer tissues compared to the normal cervical epithelia. Despite these reports, targeting these proteins for cervical cancer treatment has not been explored extensively. BH3-mimetics that inhibit specific BCL-2 anti-apoptotic proteins may hold encouraging treatment outcomes for cervical cancer management. Hence, the aim of this pilot study is to investigate the sensitivity of cervical cancer cell lines to combination of two BH3-mimetics namely ABT-263 which selectively inhibits BCL-2, BCL-XL and BCL-w and A-1210477, a selective MCL-1 inhibitor.
RESULTS: We report that combination of A-1210477 and ABT-263 exhibited synergistic effects on all cervical cancer cell lines tested. Drug sensitization studies revealed that A-1210477 sensitised the cervical cancer cell lines SiHa and CaSki to ABT-263 by 11- and fivefold, respectively. Sensitization also occurred in the opposite direction whereby ABT-263 sensitised SiHa and CaSki to A-1210477 by eightfold. This report shows that combination of ABT-263 and A-1210477 could be a potential treatment strategy for cervical cancer. Extensive drug mechanistic studies and drug sensitivity studies in physiological models are necessary to unleash the prospect of this combination for cervical cancer therapy.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
Fulltext The Chemopreventive Effect of Tanacetum Polycephalum Against LA7-Induced Breast Cancer in Rats and the Apoptotic Effect of a Cytotoxic Sesquiterpene Lactone in MCF7 Cells: A Bioassay-Guided Approach

Karimian H, Fadaeinasab M, Moghadamtousi SZ, Hajrezaei M, Zahedifard M, Razavi M, et al.

Cell Physiol Biochem, 2015;36(3):988-1003.
PMID: 26087920 DOI: 10.1159/000430273

BACKGROUND: Tanacetum polycephalum L. Schultz-Bip is a member of the Asteraceae family. This study evaluated the chemopreventive effect of a T. polycephalum hexane extract (TPHE) using in in vivo and in vitro models.
METHODS AND RESULTS: Five groups of rats: normal control, cancer control, TPHE low dose, TPHE high dose and positive control (tamoxifen) were used for the in vivo study. Histopathological examination showed that TPHE significantly suppressed the carcinogenic effect of LA7 tumour cells. The tumour sections from TPHE-treated rats demonstrated significantly reduced expression of Ki67 and PCNA compared to the cancer control group. Using a bioassay-guided approach, the cytotoxic compound of TPHE was identified as a tricyclic sesquiterpene lactone, namely, 8β- hydroxyl- 4β, 15- dihydrozaluzanin C (HDZC). Signs of early and late apoptosis were observed in MCF7 cells treated with HDZC and were attributed to the mitochondrial intrinsic pathway based on the up-regulation of Bax and the down-regulation of Bcl-2. HDZC induced cell cycle arrest in MCF7 cells and increased the expression of p21 and p27 at the mRNA and protein levels.
CONCLUSION: This results of this study substantiate the anticancer effect of TPHE and highlight the involvement of HDZC as one of the contributing compounds that act by initiating mitochondrial-mediated apoptosis.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors
Molecular docking studies of bioactive compounds from Annona muricata Linn as potential inhibitors for Bcl-2, Bcl-w and Mcl-1 antiapoptotic proteins

Mohamad Rosdi MN, Mohd Arif S, Abu Bakar MH, Razali SA, Mohamed Zulkifli R, Ya'akob H

Apoptosis, 2018 01;23(1):27-40.
PMID: 29204721 DOI: 10.1007/s10495-017-1434-7

Annona muricata Linn or usually identified as soursop is a potential anticancer plant that has been widely reported to contain valuable chemopreventive agents known as annonaceous acetogenins. The antiproliferative and anticancer activities of this tropical and subtropical plant have been demonstrated in cell culture and animal studies. A. muricata L. exerts inhibition against numerous types of cancer cells, involving multiple mechanism of actions such as apoptosis, a programmed cell death that are mainly regulated by Bcl-2 family of proteins. Nonetheless, the binding mode and the molecular interactions of the plant's bioactive constituents have not yet been unveiled for most of these mechanisms. In the current study, we aim to elucidate the binding interaction of ten bioactive phytochemicals of A. muricata L. to three Bcl-2 family of antiapoptotic proteins viz. Bcl-2, Bcl-w and Mcl-1 using an in silico molecular docking analysis software, Autodock 4.2. The stability of the complex with highest affinity was evaluated using MD simulation. We compared the docking analysis of these substances with pre-clinical Bcl-2 inhibitor namely obatoclax. The study identified the potential chemopreventive agent among the bioactive compounds. We also characterized the important interacting residues of protein targets which involve in the binding interaction. Results displayed that anonaine, a benzylisoquinoline alkaloid, showed a high affinity towards the Bcl-2, thus indicating that this compound is a potent inhibitor of the Bcl-2 antiapoptotic family of proteins.

Matched MeSH terms: Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors*