Anti-tumor effect of hedgehog signaling inhibitor, vismodegib, on castration-resistant prostate cancer

Aya Ishii; Katsumi Shigemura; Koichi Kitagawa; Shian Ying Sung; Kuan Chou Chen; Chiang Yi-Te; Ming Che Liu; Masato Fujisawa

doi:10.21873/anticanres.14514

Anti-tumor effect of hedgehog signaling inhibitor, vismodegib, on castration-resistant prostate cancer

Aya Ishii, Katsumi Shigemura, Koichi Kitagawa, Shian Ying Sung, Kuan Chou Chen, Chiang Yi-Te, Ming Che Liu, Masato Fujisawa

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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.

Original language	English
Pages (from-to)	5107-5114
Number of pages	8
Journal	Anticancer Research
Volume	40
Issue number	9
DOIs	https://doi.org/10.21873/anticanres.14514
Publication status	Published - Sept 1 2020

Keywords

Castration-resistant prostate cancer
Epithelial-mesenchymal transition
Hedgehog signaling
Sonic hedgehog
Vismodegib
Immunohistochemistry
Hedgehog Proteins/metabolism
Humans
Immunophenotyping
Male
Anilides/pharmacology
Signal Transduction/drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents/pharmacology
Animals
Cell Line, Tumor
Epithelial-Mesenchymal Transition/drug effects
Mice
Cell Proliferation/drug effects
Prostatic Neoplasms, Castration-Resistant/drug therapy
Disease Models, Animal
Pyridines/pharmacology

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.21873/anticanres.14514

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title = "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.",

keywords = "Castration-resistant prostate cancer, Epithelial-mesenchymal transition, Hedgehog signaling, Sonic hedgehog, Vismodegib, Immunohistochemistry, Hedgehog Proteins/metabolism, Humans, Immunophenotyping, Male, Anilides/pharmacology, Signal Transduction/drug effects, Xenograft Model Antitumor Assays, Antineoplastic Agents/pharmacology, Animals, Cell Line, Tumor, Epithelial-Mesenchymal Transition/drug effects, Mice, Cell Proliferation/drug effects, Prostatic Neoplasms, Castration-Resistant/drug therapy, Disease Models, Animal, Pyridines/pharmacology",

author = "Aya Ishii and Katsumi Shigemura and Koichi Kitagawa and Sung, {Shian Ying} and Chen, {Kuan Chou} and Chiang Yi-Te and Liu, {Ming Che} and Masato Fujisawa",

year = "2020",

month = sep,

day = "1",

doi = "10.21873/anticanres.14514",

language = "English",

volume = "40",

pages = "5107--5114",

journal = "Anticancer Research",

issn = "0250-7005",

publisher = "International Institute of Anticancer Research",

number = "9",

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TY - JOUR

T1 - Anti-tumor effect of hedgehog signaling inhibitor, vismodegib, on castration-resistant prostate cancer

AU - Ishii, Aya

AU - Shigemura, Katsumi

AU - Kitagawa, Koichi

AU - Sung, Shian Ying

AU - Chen, Kuan Chou

AU - Yi-Te, Chiang

AU - Liu, Ming Che

AU - Fujisawa, Masato

PY - 2020/9/1

Y1 - 2020/9/1

N2 - 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.

AB - 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.

KW - Castration-resistant prostate cancer

KW - Epithelial-mesenchymal transition

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KW - Sonic hedgehog

KW - Vismodegib

KW - Immunohistochemistry

KW - Hedgehog Proteins/metabolism

KW - Humans

KW - Immunophenotyping

KW - Male

KW - Anilides/pharmacology

KW - Signal Transduction/drug effects

KW - Xenograft Model Antitumor Assays

KW - Antineoplastic Agents/pharmacology

KW - Animals

KW - Cell Line, Tumor

KW - Epithelial-Mesenchymal Transition/drug effects

KW - Mice

KW - Cell Proliferation/drug effects

KW - Prostatic Neoplasms, Castration-Resistant/drug therapy

KW - Disease Models, Animal

KW - Pyridines/pharmacology

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U2 - 10.21873/anticanres.14514

DO - 10.21873/anticanres.14514

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SN - 0250-7005

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SP - 5107

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JO - Anticancer Research

JF - Anticancer Research

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Anti-tumor effect of hedgehog signaling inhibitor, vismodegib, on castration-resistant prostate cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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