Investigating the antineoplastic effects of the synthetic retinoid ST1926 and its underlying molecular mechanism on prostate cancer -

Abstract

Prostate cancer, the most common non-cutaneous cancer among men worldwide, remains the second leading cause of death among male cancer patients. Despite its curability with castration, radiation and hormonal therapy, some patients develop metastatic disease and die. Initially, prostate cancer cell growth depends on androgens and androgen receptor (AR) signaling, however it often becomes androgen-independent, a state called castration-resistant prostate cancer (CRPC). This later form of prostate cancer is lethal and metastasizes to secondary distant organs. The limited therapeutic options, in addition to acquired-resistance to existing and new anti-androgen and anti-AR drugs, have paved the way for a new generation of treatments for CRPC. Retinoids are vitamin A derivatives and synthetic analogs, which regulate crucial biological processes such as cellular proliferation, apoptosis, and differentiation. Therefore, retinoids have been used successfully in the treatment and prevention of solid and liquid tumors. However, the use of natural retinoids as anti-cancer agents is restricted by their toxicity and acquired resistance. As a result, synthetic retinoids were developed with reduced toxicity and increased specificity, namely the atypical adamantyl retinoid ST1926 which has increased bioavailability and reduced toxicity.We were interested in testing the anti-tumor properties and mechanism of action of ST1926 in prostate cancer using well-characterized human prostate cancer lines, namely DU145 and PC3. We have shown, using 2D conventional models, a significant reduction in cell viability and inhibition of proliferation in both cell lines upon treatment with pharmacologically achievable micromolar (μM) concentrations of ST1926. ST1926-induced cell death was through apoptosis, as it was evident by the accumulation of treated cells in the pre-G1 region of the cell cycle, TUNEL positivity, and PARP cleavage. Moreover, 1 μM ST1926 induced a major upregulation in the expression levels of the sensit