A Rac1/Cdc42 GTPase-specific small molecule inhibitor suppresses growth of primary human prostate cancer xenografts and prolongs survival in mice

PLoS One. 2013 Sep 11;8(9):e74924. doi: 10.1371/journal.pone.0074924. eCollection 2013.

Abstract

Deregulated Rho GTPases Rac1 and Cdc42 have been discovered in various tumors, including prostate and Rac protein expression significantly increases in prostate cancer. The Rac and Cdc42 pathways promote the uncontrolled proliferation, invasion and metastatic properties of human cancer cells. We synthesized the novel compound AZA1 based on structural information of the known Rac1 inhibitor NSC23766. In the current study we investigated the effects of inhibition of these pathways by AZA1 on prostate tumorigenicity by performing preclinical studies using a xenograft mouse model of prostate cancer. In androgen-independent prostate cancer cells, AZA1 inhibited both Rac1 and Cdc42 but not RhoA GTPase activity in a dose-dependent manner and blocked cellular migration and proliferation. Cyclin D1 expression significantly decreased following Rac1/Cdc42 inhibition in prostate cancer cells. AZA1 treatment also down-regulated PAK and AKT activity in prostate cancer cells, associated with induction of the pro-apoptotic function of BAD by suppression of serine-112 phosphorylation. Daily systemic administration of AZA1 for 2 weeks reduced growth of human 22Rv1 prostate tumor xenografts in mice and improved the survival of tumor-bearing animals significantly. These data suggest a role of AZA1 in blocking Rac1/Cdc42-dependent cell cycle progression, cancer cell migration and increase of cancer cell apoptosis involving down-regulation of the AKT and PAK signaling pathway in prostate cancer cells. We therefore propose that a small-molecule inhibitor therapy targeting Rac1/Cdc42 Rho GTPase signaling pathways may be used as a novel treatment for patients with advanced prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Aminoquinolines / chemistry
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Cytoskeleton / metabolism
  • Dose-Response Relationship, Drug
  • GTPase-Activating Proteins / antagonists & inhibitors*
  • GTPase-Activating Proteins / metabolism
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Male
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Phosphoproteins / antagonists & inhibitors*
  • Phosphoproteins / metabolism
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / metabolism*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Xenograft Model Antitumor Assays
  • rac1 GTP-Binding Protein / antagonists & inhibitors*
  • rac1 GTP-Binding Protein / metabolism

Substances

  • ARHGAP31 protein, human
  • Actins
  • Aminoquinolines
  • Antineoplastic Agents
  • GTPase-Activating Proteins
  • Indoles
  • N2,N4-bis(2-methyl-1H-indol-5-yl)pyrimidine-2,4-diamine
  • NSC 23766
  • Phosphoproteins
  • Pyrimidines
  • RAC1 protein, human
  • rac1 GTP-Binding Protein

Grants and funding

PRIZE project number: Z080347; Austria Wirtschaftsservice Ges.m.b.H (aws). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.