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

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...

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Autores principales: Chow, Ariel KM, Cheng, Nathan SM, Lam, Colin SC, Ng, Lui, Wong, Sunny KM, Wan, Timothy MH, Man, Johnny HW, Cheung, Alvin HK, Yau, Thomas CC, Poon, Jensen TC, Law, Wai-Lun, Pang, Roberta WC
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481075/
https://www.ncbi.nlm.nih.gov/pubmed/25884645
http://dx.doi.org/10.1186/s12943-015-0352-y
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author Chow, Ariel KM
Cheng, Nathan SM
Lam, Colin SC
Ng, Lui
Wong, Sunny KM
Wan, Timothy MH
Man, Johnny HW
Cheung, Alvin HK
Yau, Thomas CC
Poon, Jensen TC
Law, Wai-Lun
Pang, Roberta WC
author_facet Chow, Ariel KM
Cheng, Nathan SM
Lam, Colin SC
Ng, Lui
Wong, Sunny KM
Wan, Timothy MH
Man, Johnny HW
Cheung, Alvin HK
Yau, Thomas CC
Poon, Jensen TC
Law, Wai-Lun
Pang, Roberta WC
author_sort Chow, Ariel KM
collection PubMed
description 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.
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spelling pubmed-44810752015-06-27 Preclinical analysis of the anti-tumor and anti-metastatic effects of Raf265 on colon cancer cells and CD26(+) cancer stem cells in colorectal carcinoma Chow, Ariel KM Cheng, Nathan SM Lam, Colin SC Ng, Lui Wong, Sunny KM Wan, Timothy MH Man, Johnny HW Cheung, Alvin HK Yau, Thomas CC Poon, Jensen TC Law, Wai-Lun Pang, Roberta WC Mol Cancer Research 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. BioMed Central 2015-04-11 /pmc/articles/PMC4481075/ /pubmed/25884645 http://dx.doi.org/10.1186/s12943-015-0352-y Text en © Chow et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
Chow, Ariel KM
Cheng, Nathan SM
Lam, Colin SC
Ng, Lui
Wong, Sunny KM
Wan, Timothy MH
Man, Johnny HW
Cheung, Alvin HK
Yau, Thomas CC
Poon, Jensen TC
Law, Wai-Lun
Pang, Roberta WC
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
title_full 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_fullStr 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_full_unstemmed 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_short 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_sort preclinical analysis of the anti-tumor and anti-metastatic effects of raf265 on colon cancer cells and cd26(+) cancer stem cells in colorectal carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4481075/
https://www.ncbi.nlm.nih.gov/pubmed/25884645
http://dx.doi.org/10.1186/s12943-015-0352-y
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