Antitumor activities of the synthetic retinoid ST1926 in two-dimensional and three-dimensional human breast cancer models

Abstract

Despite recent advances in chemotherapy, aggressive and metastatic breast cancers remain refractory to targeted therapy and the development of novel drugs is urgently needed. Retinoids are crucial regulators of cellular proliferation, differentiation, and cell death, and have shown potent chemotherapeutic and chemopreventive properties. The major drawback of the use of all-trans retinoic acid (ATRA) in cancer therapy is disease relapse. Therefore, synthetic retinoids, specifically ST1926, have emerged as potent anticancer agents. Given the importance of the microenvironment in modulating the response of cancer cells to chemotherapeutic drugs, we investigated the antitumor activities of ST1926 in two-dimensional (2D) and different three-dimensional (3D) human breast cancer models and compared them with ATRA. We have shown that in 2D cell culture models, ATRA-resistant MCF-7 and MDA-MB-231 cells were sensitive to ST1926 at submicromolar concentrations that spared the 'normal-like' breast epithelial cells. ST1926 induced apoptosis and S-phase arrest, caused DNA damage, and downregulated the Wnt/β-catenin pathway in breast cancer cells in 2D and 3D cell culture models. ST1926-mediated growth inhibition was independent of the retinoid receptor-signaling pathway. Long-term treatments with low submicromolar ST1926 concentrations reduced the anchorage-independent growth and decreased the sphere-forming ability of breast cancer progenitor cells in the sphere formation assay. Furthermore, ST1926 potently induced cell death of breast cancer cells under 3D conditions and spared the lumen-forming ability of normal-like breast epithelial cells. In tested 3D models, ATRA had minimal effects on the growth of breast cancer cells compared with ST1926. In summary, our results highlight the therapeutic potential of ST1926 in breast cancer and warrant its further clinical development.

The synthetic retinoid ST1926 attenuates prostate cancer growth and potentially targets prostate cancer stem‐like cells

“…Treatment with ST1926 for 24 hours induced an S phase increase by 39% and 18% in DU145 and PC3, respectively ( P = 0.16 for DU145; P = 0.295 for PC3), and by 64% and 34% at 48 hours in DU145 and PC3 cells, respectively ( P = 0.325 for DU145; P = 0.193 for PC3). These results are in agreement with previous reports demonstrating that ST1926 treatment induces the S phase arrest among different solid and hematological malignant cells …”

“…However, cancer cells can develop resistance to the natural retinoids, which prompted the development of new synthetic retinoids with a more specific and less toxic mechanism of actions than the natural ones . One of the promising synthetic retinoids with antineoplastic activities, increased bioavailability, and reduced toxicity is the adamantyl retinoid ST1926 …”

“…Although the exact mechanism of action of synthetic retinoids is not fully understood, their antiproliferative and proapoptotic effects are attributed to their ability to induce both receptor‐dependent and ‐independent mechanisms. Promising synthetic retinoids with antineoplastic activities include N‐(4‐hydroxyphenyl) retinamide (4HPR), 6‐[3‐(1‐adamantyl)‐4‐hydroxyphenyl]‐2‐naphthalene carboxylic acid (CD437), and ST1926; an analog of CD437 …”

“…Orally administered ST1926, has potent antitumor effects on both solid tumors and hematological malignancies . We investigated ST1926 mode of action in PCa in vitro and in vivo models and assessed its effect in targeting an enriched population of PCa stem‐like/progenitor cells.…”

“…Promising synthetic retinoids with antineoplastic activities include N-(4-hydroxyphenyl) retinamide (4HPR), 12 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), 13 and ST1926; an analog of CD437. [14][15][16][17][18][19][20] Orally administered ST1926, has potent antitumor effects on both solid tumors and hematological malignancies. [14][15][16][17][18]21,22 We investigated ST1926 mode of action in PCa in vitro and in vivo models and assessed its effect in targeting an enriched population of PLum-AI (androgen-independent) PCa cells, that were established in our laboratory, 4 were cultured in PrEGM medium (Lonza) with supplements.…”