Therapeutic potential of Bcl-xl/Mcl-1 synthetic inhibitor JY-1-106 and retinoids for human triple-negative breast cancer treatment

Abstract

Abstract. Overexpression of anti-apoptotic proteins belonging to the B cell lymphoma (Bcl)-2 family is observed in numerous cancer types and has been postulated to promote cancer cell survival and chemotherapy resistance. Bcl-extra large (x L) /myeloid cell leukemia sequence (Mcl)-1 was demonstrated to be expressed at relatively high levels in clinically aggressive basal-like cancers and inhibiting Bcl-x L overexpression could potentially provoke cell death. A molecule able to target Bcl-x L /Mcl-1, JY-1-106, is herein under investigation. It is also known that vitamin A-derived compounds exhibit antitumor activity in a variety of in vitro experimental models, promoting their effects via nuclear receptor isoforms including retinoic acid receptors (RARs). Pre-clinical observation highlighted that triple negative (estrogen receptor/progesterone receptor/human epidermal growth factor receptor)-breast cancer cells displayed resistance to retinoids due to the RARγ high expression profile. The present study used the triple-negative human breast cancer cell line, MDA-MB-231, to analyze the effects of the Bcl-x L /Mcl-1 synthetic inhibitor, JY-1-106, alone or in combination with retinoids on cell viability. The results revealed a synergistic effect in reducing cell viability primarily by using JY-1-106 with the selective RARγ antagonist SR11253, which induces massive autophagy and necrosis. Furthermore, the results highlighted that JY-1-106 alone is able to positively influence the gene expression profile of p53 and RARα, providing a therapeutic advantage in human triple-negative breast cancer treatment. IntroductionThe B-cell lymphoma/leukemia-2 (Bcl-2) family proteins are central regulators of cell death having both anti-and pro-apoptotic biochemical action. In humans, six anti-apoptotic members of this family have been identified, Bcl-2, Bcl-x L , Bcl-B, Bcl-W, Bfl-1, and Mcl-1, further divided into three groups on the basis of their Bcl-2 homology, in which the BH3 domain explicate the main role in the anti-apoptotic signaling (1).Bcl-2 and the anti-apoptotic proteins Mcl-1 and Bcl-x L were found to be co-expressed at relatively high levels in a substantial proportion of heterogeneous breast tumors, including clinically aggressive basal-like cancers (2-5). The anti-apoptotic Bcl-2 proteins neutralize the cell-killing function of the pro-apoptotic family members engaging their BH3 domains. Therefore, small-molecule designed to target BH3 domain such as the mimetic showed therapeutic potential for treating cancer (6-8). Although, ABT-263 evidenced promising results for solid tumor such as small lung cancer cells and other non-hematological malignancies, the clinical trial was early stopped due to its severe side effect (7). Finally, only ABT-199 was recently approved (April 2016) by US-FDA as Venetoclax for the pharmacological treatment of Chronic Lymphocytic Leukemia (8). Currently, the activity of Bcl-2 family inhibitors is the subject of interest in an intense area of research concerning therapeutic agents against...

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