Prostate cancer is the leading cause of cancer and the second leading cause of cancer-related deaths in men. Rho GTPases such as Rac, Cdc42, and RhoA are signaling proteins. They regulate cytoskeleton organization, cell cycle progression, cell survival, and migration directly contributing to tumor growth and progression. Cdc42 additionally plays a major role in the control of cell migration. Rho GTPases exist either as inactive, GDP-bound forms or active, GTP-bound forms that determine the cellular functions of Rho GTPases. The Rac1 signaling pathway also plays a significant role in cell survival involving v-akt murine thymoma viral oncogene homolog 1 (AKT) kinase. In addition, PAK1 is a further major downstream effector of Cdc42 and Rac1 in the control of programmed cell death. In this study, AZA1 is a potent dual inhibitor of Rac1 and Cdc42. AZA1 induces prostate cancer cells apoptosis. It also inhibits prostate cancer cells proliferation, migration, and invasion.
AZA1, a potent dual inhibitor of Rac1 and Cdc42, induces prostate cancer cells apoptosis and inhibits prostate cancer cells proliferation, migration, and invasion.
AZA1 blocks the proliferation of human prostate cancer cells 22Rv1 prostate cancer cells, it also reduces phosphorylation of PAK1, AKT, and BAD in EGF-stimulated 22Rv1 prostate cancer cells. Moreover, AZA1 blocks Rac1 and Cdc42-dependent cell cycle events in 22Rv1 prostate cancer cells. Furthermore, it blocks Rac1 and Cdc42-dependent migration of 22Rv1, DU 145, and PC-3 prostate cancer cells. AZA1 also affects cell motility and actin rearrangement in prostate cancer cells by suppressing Rac1 and Cdc42 activity via PAK1/2 phosphorylation. In addition, It is potent in suppressing human 22Rv1 xenograft growth in mice and improving survival.
In summary, AZA1 is a Rac1- and Cdc42-inhibiting agent. AZA1 inhibits Rac1 and Cdc42 in prostate cancer cells. Meanwhile, AZA1 suppresses cell proliferation and activation of PAK and AKT and signaling pathways. Additionally, AZA1 affects cytoskeletal dynamics and suppresses cancer cell migration. AZA1 also reduces tumor growth and prolonged survival in a human prostate cancer xenograft mouse model.
Reference:
Zins K, et al. PLoS One. 2013;8(9):e74924. Published 2013 Sep 11.