diptoindonesin-g and Prostatic-Neoplasms--Castration-Resistant

The androgen receptor (AR) signaling pathway has been well demonstrated to play a crucial role in the development, progression, and drug resistance of prostate cancer. Although the current anti-androgen therapy could significantly benefit prostate cancer patients initially, the efficacy of the single drug usually lasts for a relatively short period, as drug resistance quickly emerges.. We have performed an unbiased bioinformatics analysis using the RNA-seq results in 22Rv1 cells to identify the cell response toward Dip G treatment. The RNA-seq results were validated by qRT-PCR. Protein levels were detected by western blot or staining. Cell viability was measured by Aquabluer and colony formation assay.. Here, we identified that Diptoindonesin G (Dip G), a natural extracted compound, could promote the proteasome degradation of AR and polo-like kinase 1 (PLK1) through modulating the activation of CHIP E3 ligase. Administration of Dip G has shown a profound efficiency in the suppression of AR and PLK1, not only in androgen-dependent LNCaP cells but also in castration-resistant and enzalutamide-resistant cells in a CHIP-dependent manner. Through co-targeting the AR signaling, Dip G robustly improved the efficacy of HSP90 inhibitors and enzalutamide in both human prostate cancer cells and in vivo xenograft mouse model.. Our results revealed that Dip G-mediated AR degradation would be a promising and valuable therapeutic strategy in the clinic.

Topics: Androgen Antagonists; Animals; Benzofurans; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Male; Mice; Nitriles; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; Xenograft Model Antitumor Assays