Anti-tumor Effect of Hedgehog Signaling Inhibitor, Vismodegib, on Castration-resistant Prostate Cancer.

Abstract

BACKGROUND/AIM:

Epithelial-mesenchymal transition (EMT) via Sonic Hedgehog (Shh) signaling may be one of the mechanisms of progression of castration-resistant prostate cancer (CRPC). In this study, we investigated the possible therapeutic effect of vismodegib, a new Shh inhibitor, in a mouse CRPC model.

MATERIALS AND METHODS:

We determined cell proliferation, apoptosis and the expression of EMT-related genes for three prostate cancer cell lines; androgen-dependent LNCaP and independent C4-2B and PC-3 in the presence of vismodegib in vitro. Fifty mg/kg of vismodegib were orally administered into mice bearing C4-2B and PC-3 tumors, respectively every other week for 3 weeks.

RESULTS:

Vismodegib significantly inhibited cell proliferation and induced cell apoptosis in all cell lines in vitro (p<0.05). Vismodegib significantly inhibited EMT in CRPC cells and tumor growth in C4-2B-bearing mice compared to controls in vivo (p<0.05). Higher expression of caspase-3 and lower expression of vimentin in PC-3 and C4-2B tumors were induced by vismodegib in immunohistochemical analysis.

CONCLUSION:

Vismodegib inhibited cell proliferation via apoptosis and also suppressed EMT, showing anti-tumor effects in mice. Further mechanistic studies are needed to investigate the feasibility of vismodegib for CRPC treatment.

• Authors: Aya Ishii, Katsumi Shigemura, Koichi Kitagawa, Shian-Ying Sung, Kuan-Chou Chen, Chiang Yi-Te, Ming-Che Liu, Masato Fujisawa
• Journal: Anticancer research (Anticancer Res) Vol. 40 Issue 9 Pg. 5107-5114 (Sep 2020) ISSN: 1791-7530 [Electronic] Greece
• PMID: 32878799 (Publication Type: Journal Article)
• Copyright: Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Chemical References

• Anilides
• Antineoplastic Agents
• Hedgehog Proteins
• HhAntag691
• Pyridines

Topics

• Anilides (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Epithelial-Mesenchymal Transition (drug effects)
• Hedgehog Proteins (metabolism)
• Humans
• Immunohistochemistry
• Immunophenotyping
• Male
• Mice
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Pyridines (pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays