Bcl-2 inhibitors: emerging drugs in cancer therapy

Dose-limiting toxicity to healthy tissues is among the major hurdles in anticancer treatment along with intrinsic or acquired multi-drug resistance. Development of small molecule inhibitors (SMI) specific for antiapoptotic Bcl-2 proteins is a novel approach in a way that these antagonists are aimed to interfere with specific protein-protein interactions unlike conventional chemo-/radiotherapies. SMIs of antiapoptotic Bcl-2 proteins are assumed to compete with proapoptotic Bcl-2s to occupy BH3 docking grooves on the surfaces of antiapoptotic family members. Instead of directly initiating cell death, these inhibitors are intended to decrease apoptotic threshold in tumor cells that were already primed to death. In this regard, antiapoptotic Bcl-2 protein SMIs have the advantage of lower normal tissue toxicity relative to conventional anticancer therapies that interfere with general mechanisms including DNA synthesis, mitosis and tyrosine kinase activity. Besides, Bcl-2 antagonists were shown to potentiate efficacies of established drugs in several hematological malignancies and solid tumors which render them promising candidates for combination anticancer therapy. Utilizing these SMIs in such a way may prove to decrease the patient drug load by diminishing the required chemo-/radiotherapy dose. This review summarizes and compares BH3 mimetics on the basis of specificity, mode of action and efficacy, as well as providing remarks on their therapeutical potential and routes of development in near future

Small inhibitor of Bcl-2, HA14-1, selectively enhanced the apoptotic effect of cisplatin by modulating Bcl-2 family members in MDA-MB-231 breast cancer cells

Inhibition or downregulation of Bcl-2 represents a new therapeutic approach to by-pass chemoresistance in cancer cells. Therefore, we explored the potential of this approach in breast cancer cells. Cisplatin and paclitaxel induced apoptosis in a dose-dependent manner in MCF-7 (drug-sensitive) and MDA-MB-231 (drug-insensitive) cells. Furthermore, when we transiently silenced Bcl-2, both cisplatin and paclitaxel induced apoptosis more than parental cells. Dose dependent induction of apoptosis by drugs was enhanced by the pre-treatment of these cells with HA14-1, a Bcl-2 inhibitor. Although the effect of cisplatin was significant on both cell lines, the effect of paclitaxel was much less potent only in MDA-MB-231 cells. To further understand the distinct role of drugs in MDA-MB-231 cells pretreated with HA14-1, caspases and Bcl-2 family proteins were studied. The apoptotic effect of cisplatin with or without HA14-1 pre-treatment is shown to be caspase-dependent. Among pro-apoptotic Bcl-2 proteins, Bax and Puma were found to be up-regulated whereas Bcl-2 and Bcl-x(L) were down-regulated when cells were pretreated with HA14-1 followed by paclitaxel or cisplatin. Enforced Bcl-2 expression in MDA-MB-231 cells abrogated the sensitizing effect of HA14-1 in cisplatin induced apoptosis. These results suggest that the potentiating effect of HA14-1 is drug and cell type specific and may not only depend on the inhibition of Bcl-2. Importantly, alteration of other pro-apoptotic or anti-apoptotic Bcl-2 family members may dictate the apoptotic response when HA14-1 is combined with chemotherapeutic drugs

Bcl-2 protein family: Implications in vascular apoptosis and atherosclerosis

Apoptosis has been recognized as a central component in the pathogenesis of atherosclerosis, in addition to the other human pathologies such as cancer and diabetes. The pathophysiology of atherosclerosis is complex, involving both apoptosis and proliferation at different phases of its progression. Oxidative modification of lipids and inflammation differentially regulate the apoptotic and proliferative responses of vascular cells during progression of the atherosclerotic lesion. Bcl-2 proteins act as the major regulators of extrinsic and intrinsic apoptosis signalling pathways and more recently it has become evident that they mediate the apoptotic response of vascular cells in response to oxidation and inflammation either in a provocative or an inhibitory mode of action. Here we address Bcl-2 proteins as major therapeutic targets for the treatment of atherosclerosis and underscore the need for the novel preventive and therapeutic interventions against atherosclerosis, which should be designed in the light of molecular mechanisms regulating apoptosis of vascular cells in atherosclerotic lesions

Hydrophobic pockets of SIRT1 and SIRT6.

<p>Complexes obtained by docking the inhibitor, Ex-527, to the close proximity of hydrophobic pocket of SIRT1 (A) and to the analogous hydrophobic pocket of SIRT6 (B), were used to simulate the permenance of the binding of the inhibitor to the hydrophobic cluster amino acids. Each amino acid was shown for clear positioning of the pockets. SIRT6 hydrophobic pocket amino acids (B) were predicted based on the corresponding amino acids of SIRT1 (A): V113, I183, I59, F62, V68 of SIRT6 were selected based on similarity to I347, I411, I270, F273, I279 of SIRT1. F297, a member of SIRT1 hydrophobic pocket shown in (A), does not have a corresponding hydrophobic residue in SIRT6 structure (B). (C)(D) Alanine and glycine mutations of SIRT1 hydrophobic pocket residues showed destabilizing characteristic (positive ΔΔG values) similar to the mutations of SIRT6, in part, validating the presence of a hydrophobic pocket in SIRT6 structure. FoldX was used to compute ΔΔG values to determine stability change. Protein structures obtained from PDB ID: 4I5I chain A and PDB ID: 3K35 chain A were used as SIRT1 and SIRT6, respectively.</p

Role of microRNA deregulation in breast cancer cell chemoresistance and stemness

Studies with breast cancer cells, showed that microRNAs (miRNAs) act as regulators of signaling pathways playing a key role in tumor progression and being targeted in chemotherapy. Deregulation of these pathways by altered miRNA expression or single nucleotide polymorphisms (SNPs) found in certain miRNA genes have been shown to lead tumor growth, metastasis, angiogenesis, and drug resistance. miRNAs have also been indicated to act on stem cell self-renewal and alter signal transduction in cancer stem-like cells (CSC), which are resistant to many conventional therapies and account for the inability of these therapies to cure cancers. By considering these findings, miRNAs are proposed as potential novel biomarkers as well as therapeutic targets in new anti-cancer strategies. In this review, the miRNAs found to be involved in breast cancer chemoresistance will be covered together with breast CSC and their contribution to chemotherapy resistance

The cofactor of SIRT6, NAD⁺ positively regulated nuclear SIRT6 accumulation and total AR expression under hyperosmotic stress.

<p>Control (C) indicates U937 cells treated with 5 mM glucose containing SFM for 16 hrs in (A) and (B). 100 mM N indicates U937 cells further treated with 100 mM NaCl (N) for 16 hrs in (A), (B) and (C). U937 cells were pretreated either with solvent (DMSO) or indicated concentrations of NAD⁺ or Ex-527 for 1 hr, followed by 16 hrs of 100 mM N treatment in (A), (B) and (C). (A)(C) The cofactor of SIRT6, NAD⁺, enhanced the nuclear accumulation of SIRT6 and total AR expression in dose-dependent manner under hyperosmotic stress. (B) A specific SIRT1 inhibitor and recently suggested SIRT6 inhibitor, Ex-527 did not altered nuclear SIRT6 expression under hyperosmotic stress, in part, justifying the data obtained in (A). Expressions were evaluated using immunoblotting in cytoplasmic and nuclear extracts in (A) & (B) and in total extracts in (C). Results obtained from this figure was based on the densitometry based statistical analyses, given in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161494#pone.0161494.s004" target="_blank">S4 Fig</a>.</p