Effects of selective inhibitors of the isoprenoid biosynthetic pathway on androgen‐dependent and independent prostate cancer cells (842.6)

Abstract

The isoprenoid biosynthetic pathway (IBP) provides substrates, such as geranylgeranyl diphosphate (GGDP), which are used to post‐translationally modify proteins that are key regulators of malignant cell properties such as proliferation, migration, and invasion. Clinically relevant IBP inhibitors, including statins and nitrogenous bisphosphonates, affect these malignant cell properties. However, they broadly deplete all mevalonate derivatives, thus affecting farnesylated proteins and cholesterol. XZ‐1‐269 and XZ‐4‐37 were developed as selective inhibitors of GGDP synthase to reduce protein GGation. In the androgen‐dependent prostate cancer (PCa) cell line LNCaP and the highly metastatic androgen‐independent PCa cell line PC3, lovastatin and XZ‐1‐269 more potently reduce protein GGation and cell viability than digeranyl bisphosphonate, XZ‐4‐37, and zoledronate. In the androgen‐independent PCa cell line 22Rv1, all compounds are less potent in reducing protein GGation and cell viability than in LNCaP and PC3 cells. Our findings detail novel compounds for selectively reducing protein GGation in three prostate cancer cell lines. Further work defining the isoprenoid proteins involved in advancing PCa will identify new targets for therapeutic intervention.Grant Funding Source: Supported by NIH Pharmacological Sciences Training Grant T32 GM067795