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

Perri,Mariarita; Yap,Jeremy  L.; Fletcher,Steven; Cione,Erika; Kane,Maureen  A.

doi:10.3892/ol.2018.8258

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

Authors:
- Mariarita Perri
- Jeremy L. Yap
- Steven Fletcher
- Erika Cione
- Maureen A. Kane
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Affiliations: Department of Pharmacy, Health and Nutritional Sciences, Ed. Polifunzionale, University of Calabria, I‑87036 Arcavacata di Rende (Cs), Italy, Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201, USA
Published online on: March 14, 2018 https://doi.org/10.3892/ol.2018.8258
Pages: 7231-7236

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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 (xL)/myeloid cell leukemia sequence (Mcl)‑1 was demonstrated to be expressed at relatively high levels in clinically aggressive basal‑like cancers and inhibiting Bcl‑xL overexpression could potentially provoke cell death. A molecule able to target Bcl‑xL/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‑xL/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.

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