The synthetic retinoid ST1926 attenuates prostate cancer growth and potentially targets prostate cancer stem-like cells
The synthetic retinoid ST1926 attenuates prostate cancer growth and potentially targets prostate cancer stem-like cells
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DOI：
10.1002/mc.23004
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发表时间：
2019-07-01
影响因子：
4.6
通讯作者：
Abou-Kheir, Wassim
中科院分区：
文献类型：
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作者：
Bahmad, Hisham F.;Samman, Houda;Abou-Kheir, Wassim
维甲酸是一种维生素A衍生物，可调节细胞增殖、凋亡和分化等关键生物学过程。由于天然维甲酸的毒性和肿瘤细胞的获得性耐药，其在癌症治疗中的使用受到限制。因此，人工合成的维甲酸被开发出来，例如非典型的金刚烷基维甲酸ST1926，它提供了更高的生物利用度和更低的毒性。我们评价了ST1926对人前列腺癌(Pca)细胞系DU145和PC3以及小鼠前列腺癌细胞系Pulum-AD和Plum-AI的体外和体内抗肿瘤特性及其作用机制。我们证明，ST1926显著减少了前列腺癌细胞的增殖，并诱导了细胞周期停滞、P53非依赖性的细胞凋亡和早期DNA损伤。它还减少了前列腺癌细胞的迁移和侵袭，并显着降低了前列腺球的体外形成能力，表明充分消除了高度雄激素耐药的癌症干细胞的自我更新能力。重要的是，ST1926在体内有效地抑制了前列腺癌的生长和进展。我们的结果突出了ST1926在前列腺癌治疗中的潜力，并为其临床开发提供了保证。
Retinoids are vitamin A derivatives that regulate crucial biological processes such as cellular proliferation, apoptosis, and differentiation. The use of natural retinoids in cancer therapy is limited due to their toxicity and the acquired resistance by cancer cells. Therefore, synthetic retinoids were developed, such as the atypical adamantyl retinoid ST1926 that provides enhanced bioavailability and reduced toxicity. We have assessed the in vitro and in vivo antitumor properties and mechanism of action of ST1926 in targeting cancer stem-like cells population of human prostate cancer (PCa) cell lines, DU145 and PC3, and mouse PCa cell lines, PLum-AD and PLum-AI. We demonstrated that ST1926 substantially reduced proliferation of PCa cells and induced cell cycle arrest, p53-independent apoptosis, and early DNA damage. It also decreased migration and invasion of PCa cells and significantly reduced prostate spheres formation ability in vitro denoting sufficient eradication of the self-renewal ability of the highly androgen-resistant cancer stem cells. Importantly, ST1926 potently inhibited PCa tumor growth and progression in vivo. Our results highlight the potential of ST1926 in PCa therapy and warrant its clinical development.