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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
Title | Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma |
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Authors | |
Keywords | Raf/MEK/ERK signaling pathway Raf265 Metastasis Colorectal cancer Cancer stem cells |
Issue Date | 2015 |
Publisher | BioMed 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 Identifier | http://hdl.handle.net/10722/203161 |
ISSN | 2023 Impact Factor: 27.7 2023 SCImago Journal Rankings: 8.222 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Chow, AKM | - |
dc.contributor.author | Cheng, NSM | - |
dc.contributor.author | Lam, CSC | - |
dc.contributor.author | Ng, L | - |
dc.contributor.author | Wong, SKM | - |
dc.contributor.author | Wan, TMH | - |
dc.contributor.author | Man, JHW | - |
dc.contributor.author | Cheung, AHK | - |
dc.contributor.author | Yau, TCC | - |
dc.contributor.author | Poon, TCJ | - |
dc.contributor.author | Law, WL | - |
dc.contributor.author | Pang, RWC | - |
dc.date.accessioned | 2014-09-19T11:33:43Z | - |
dc.date.available | 2014-09-19T11:33:43Z | - |
dc.date.issued | 2015 | - |
dc.identifier.citation | Molecular Cancer, 2015, v. 14, article no. 80 | - |
dc.identifier.issn | 1476-4598 | - |
dc.identifier.uri | http://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.language | eng | - |
dc.publisher | BioMed Central Ltd. The Journal's web site is located at http://www.molecular-cancer.com | - |
dc.relation.ispartof | Molecular Cancer | - |
dc.rights | Molecular Cancer. Copyright © BioMed Central Ltd. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject | Raf/MEK/ERK signaling pathway | - |
dc.subject | Raf265 | - |
dc.subject | Metastasis | - |
dc.subject | Colorectal cancer | - |
dc.subject | Cancer stem cells | - |
dc.title | Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma | - |
dc.type | Article | - |
dc.identifier.email | Chow, AKM: chowakm@hku.hk | - |
dc.identifier.email | Cheng, NSM: nathanc@hku.hk | - |
dc.identifier.email | Lam, CSC: colin88@hku.hk | - |
dc.identifier.email | Ng, L: luing@hku.hk | - |
dc.identifier.email | Man, JHW: johnnyb@hku.hk | - |
dc.identifier.email | Yau, TCC: tyaucc@hku.hk | - |
dc.identifier.email | Poon, TCJ: tcjensen@hku.hk | - |
dc.identifier.email | Law, WL: lawwl@hkucc.hku.hk | - |
dc.identifier.email | Pang, RWC: robertap@hku.hk | - |
dc.identifier.authority | Yau, TCC=rp01466 | - |
dc.identifier.authority | Poon, TCJ=rp01603 | - |
dc.identifier.authority | Law, WL=rp00436 | - |
dc.identifier.authority | Pang, RWC=rp00274 | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.1186/s12943-015-0352-y | - |
dc.identifier.pmid | 25884645 | - |
dc.identifier.pmcid | PMC4481075 | - |
dc.identifier.scopus | eid_2-s2.0-84934271851 | - |
dc.identifier.hkuros | 254039 | - |
dc.identifier.volume | 14 | - |
dc.identifier.isi | WOS:000369749100001 | - |
dc.publisher.place | United Kingdom | - |
dc.identifier.issnl | 1476-4598 | - |