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Article: Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma

TitlePreclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma
Authors
KeywordsRaf/MEK/ERK signaling pathway
Raf265
Metastasis
Colorectal cancer
Cancer stem cells
Issue Date2015
PublisherBioMed Central Ltd. The Journal's web site is located at http://www.molecular-cancer.com
Citation
Molecular Cancer, 2015, v. 14, article no. 80 How to Cite?
Abstract© 2015 Chow et al.Background: In colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26+ cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26+ CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26+ CSCs in CRC patients. Methods: HT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26+ CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model. Results: Raf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26+ cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated. Conclusions: This preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.
Persistent Identifierhttp://hdl.handle.net/10722/203161
ISSN
2015 Impact Factor: 5.888
2015 SCImago Journal Rankings: 2.337
PubMed Central ID

 

DC FieldValueLanguage
dc.contributor.authorChow, AKM-
dc.contributor.authorCheng, NSM-
dc.contributor.authorLam, CSC-
dc.contributor.authorNg, L-
dc.contributor.authorWong, SKM-
dc.contributor.authorWan, TMH-
dc.contributor.authorMan, JHW-
dc.contributor.authorCheung, AHK-
dc.contributor.authorYau, TCC-
dc.contributor.authorPoon, TCJ-
dc.contributor.authorLaw, WL-
dc.contributor.authorPang, RWC-
dc.date.accessioned2014-09-19T11:33:43Z-
dc.date.available2014-09-19T11:33:43Z-
dc.date.issued2015-
dc.identifier.citationMolecular Cancer, 2015, v. 14, article no. 80-
dc.identifier.issn1476-4598-
dc.identifier.urihttp://hdl.handle.net/10722/203161-
dc.description.abstract© 2015 Chow et al.Background: In colorectal carcinoma (CRC), activation of the Raf/MEK/ERK signaling pathway is commonly observed. In addition, the commonly used 5FU-based chemotherapy in patients with metastatic CRC was found to enrich a subpopulation of CD26+ cancer stem cells (CSCs). As activation of the Raf/MEK/ERK signaling pathway was also found in the CD26+ CSCs and therefore, we hypothesized that an ATP-competitive pan-Raf inhibitor, Raf265, is effective in eliminating the cancer cells and the CD26+ CSCs in CRC patients. Methods: HT29 and HCT116 cells were treated with various concentrations of Raf265 to study the anti-proliferative and apoptotic effects of Raf265. Anti-tumor effect was also demonstrated using a xenograft model. Cells were also treated with Raf265 in combination with 5FU to demonstrate the anti-migratory and invasive effects by targeting on the CD26+ CSCs and the anti-metastatic effect of the combined treatment was shown in an orthotopic CRC model. Results: Raf265 was found to be highly effective in inhibiting cell proliferation and tumor growth through the inhibition of the RAF/MEK/ERK signaling pathway. In addition, anti-migratory and invasive effect was found with Raf265 treatment in combination with 5FU by targeting on the CD26+ cells. Finally, the anti-tumor and anti-metastatic effect of Raf265 in combination with 5FU was also demonstrated. Conclusions: This preclinical study demonstrates the anti-tumor and anti-metastatic activity of Raf265 in CRC, providing the basis for exploiting its potential use and combination therapy with 5FU in the clinical treatment of CRC.-
dc.languageeng-
dc.publisherBioMed Central Ltd. The Journal's web site is located at http://www.molecular-cancer.com-
dc.relation.ispartofMolecular Cancer-
dc.rightsMolecular Cancer. Copyright © BioMed Central Ltd.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectRaf/MEK/ERK signaling pathway-
dc.subjectRaf265-
dc.subjectMetastasis-
dc.subjectColorectal cancer-
dc.subjectCancer stem cells-
dc.titlePreclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma-
dc.typeArticle-
dc.identifier.emailChow, AKM: chowakm@hku.hk-
dc.identifier.emailCheng, NSM: nathanc@hku.hk-
dc.identifier.emailLam, CSC: colin88@hku.hk-
dc.identifier.emailNg, L: luing@hku.hk-
dc.identifier.emailMan, JHW: johnnyb@hku.hk-
dc.identifier.emailYau, TCC: tyaucc@hku.hk-
dc.identifier.emailPoon, TCJ: tcjensen@hku.hk-
dc.identifier.emailLaw, WL: lawwl@hkucc.hku.hk-
dc.identifier.emailPang, RWC: robertap@hku.hk-
dc.identifier.authorityYau, TCC=rp01466-
dc.identifier.authorityPoon, TCJ=rp01603-
dc.identifier.authorityLaw, WL=rp00436-
dc.identifier.authorityPang, RWC=rp00274-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1186/s12943-015-0352-y-
dc.identifier.pmid25884645-
dc.identifier.pmcidPMC4481075-
dc.identifier.scopuseid_2-s2.0-84932097797-
dc.identifier.hkuros254039-
dc.identifier.volume14-
dc.publisher.placeUnited Kingdom-

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