Cargando…

Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity

BACKGROUND: Abnormalities of tubulin polymerization and microtubule assembly are often seen in cancer, which make them very suitable targets for the development of therapeutic approach against rapidly dividing and aggressive cancer cells. CYT997 is a novel microtubule-disrupting agent with anticance...

Descripción completa

Detalles Bibliográficos
Autores principales: Teng, Yong, Cai, Yafei, Pi, Wenhu, Gao, Lixia, Shay, Chloe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469135/
https://www.ncbi.nlm.nih.gov/pubmed/28606127
http://dx.doi.org/10.1186/s13045-017-0485-0
_version_ 1783243530446045184
author Teng, Yong
Cai, Yafei
Pi, Wenhu
Gao, Lixia
Shay, Chloe
author_facet Teng, Yong
Cai, Yafei
Pi, Wenhu
Gao, Lixia
Shay, Chloe
author_sort Teng, Yong
collection PubMed
description BACKGROUND: Abnormalities of tubulin polymerization and microtubule assembly are often seen in cancer, which make them very suitable targets for the development of therapeutic approach against rapidly dividing and aggressive cancer cells. CYT997 is a novel microtubule-disrupting agent with anticancer activity in multiple cancer types including prostate cancer. However, the molecular mechanisms of action of CYT997 in prostate cancer have not been well characterized. METHODS: Src knockdown cells were achieved by lentiviral-mediated interference. The drug effects on cell proliferation were measured by MTS. The drug effects on cell viability and death were determined by Cell Titer-Glo® Luminescent cell viability kit and flow cytometry with Zombie Aqua™ staining. The drug effects on apoptosis were assessed by Cell Death Detection Elisa kit and Western blot with a cleaved PARP antibody. The drug effects on cell invasion were examined by Matrigel-coated Boyden chambers. Oxidative stress was detected by DCFH-DA staining and electrochemical biosensor. Mouse models generated by subcutaneous or intracardiac injection were used to investigate the in vivo drug efficacy in tumor growth and metastasis. RESULTS: CYT997 effectively inhibited proliferation, survival, and invasion of prostate cancer cells via blocking multiple oncogenic signaling cascades but not the Src pathway. Inhibition of Src expression by small hairpin RNA or inactivation of Src by dasatinib increased the CYT997-induced cytotoxicity of in vitro. Moreover, the combination of dasatinib and CYT997 exhibited a superior inhibitory effect on tumor growth and metastasis compared with either of the drugs alone. CONCLUSION: Our findings demonstrate that blockage of Src augments the anticancer effect of CYT997 on prostate cancer and suggest that co-treatment of dasatinib and CYT997 may represent an effective therapeutic regimen for limiting prostate cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-017-0485-0) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-5469135
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-54691352017-06-14 Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity Teng, Yong Cai, Yafei Pi, Wenhu Gao, Lixia Shay, Chloe J Hematol Oncol Research BACKGROUND: Abnormalities of tubulin polymerization and microtubule assembly are often seen in cancer, which make them very suitable targets for the development of therapeutic approach against rapidly dividing and aggressive cancer cells. CYT997 is a novel microtubule-disrupting agent with anticancer activity in multiple cancer types including prostate cancer. However, the molecular mechanisms of action of CYT997 in prostate cancer have not been well characterized. METHODS: Src knockdown cells were achieved by lentiviral-mediated interference. The drug effects on cell proliferation were measured by MTS. The drug effects on cell viability and death were determined by Cell Titer-Glo® Luminescent cell viability kit and flow cytometry with Zombie Aqua™ staining. The drug effects on apoptosis were assessed by Cell Death Detection Elisa kit and Western blot with a cleaved PARP antibody. The drug effects on cell invasion were examined by Matrigel-coated Boyden chambers. Oxidative stress was detected by DCFH-DA staining and electrochemical biosensor. Mouse models generated by subcutaneous or intracardiac injection were used to investigate the in vivo drug efficacy in tumor growth and metastasis. RESULTS: CYT997 effectively inhibited proliferation, survival, and invasion of prostate cancer cells via blocking multiple oncogenic signaling cascades but not the Src pathway. Inhibition of Src expression by small hairpin RNA or inactivation of Src by dasatinib increased the CYT997-induced cytotoxicity of in vitro. Moreover, the combination of dasatinib and CYT997 exhibited a superior inhibitory effect on tumor growth and metastasis compared with either of the drugs alone. CONCLUSION: Our findings demonstrate that blockage of Src augments the anticancer effect of CYT997 on prostate cancer and suggest that co-treatment of dasatinib and CYT997 may represent an effective therapeutic regimen for limiting prostate cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13045-017-0485-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-06-12 /pmc/articles/PMC5469135/ /pubmed/28606127 http://dx.doi.org/10.1186/s13045-017-0485-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Teng, Yong
Cai, Yafei
Pi, Wenhu
Gao, Lixia
Shay, Chloe
Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
title Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
title_full Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
title_fullStr Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
title_full_unstemmed Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
title_short Augmentation of the anticancer activity of CYT997 in human prostate cancer by inhibiting Src activity
title_sort augmentation of the anticancer activity of cyt997 in human prostate cancer by inhibiting src activity
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469135/
https://www.ncbi.nlm.nih.gov/pubmed/28606127
http://dx.doi.org/10.1186/s13045-017-0485-0
work_keys_str_mv AT tengyong augmentationoftheanticanceractivityofcyt997inhumanprostatecancerbyinhibitingsrcactivity
AT caiyafei augmentationoftheanticanceractivityofcyt997inhumanprostatecancerbyinhibitingsrcactivity
AT piwenhu augmentationoftheanticanceractivityofcyt997inhumanprostatecancerbyinhibitingsrcactivity
AT gaolixia augmentationoftheanticanceractivityofcyt997inhumanprostatecancerbyinhibitingsrcactivity
AT shaychloe augmentationoftheanticanceractivityofcyt997inhumanprostatecancerbyinhibitingsrcactivity