Cargando…

In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines

BACKGROUND: Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and b...

Descripción completa

Detalles Bibliográficos
Autores principales: Dokduang, Hasaya, Jamnongkarn, Wassana, Promraksa, Bundit, Suksawat, Manida, Padthaisong, Sureerat, Thanee, Malinee, Phetcharaburanin, Jutarop, Namwat, Nisana, Sangkhamanon, Sakkarn, Titapun, Attapol, Khuntikeo, Narong, Klanrit, Poramate, Loilome, Watcharin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296552/
https://www.ncbi.nlm.nih.gov/pubmed/32606601
http://dx.doi.org/10.2147/DDDT.S250061
_version_ 1783546865268031488
author Dokduang, Hasaya
Jamnongkarn, Wassana
Promraksa, Bundit
Suksawat, Manida
Padthaisong, Sureerat
Thanee, Malinee
Phetcharaburanin, Jutarop
Namwat, Nisana
Sangkhamanon, Sakkarn
Titapun, Attapol
Khuntikeo, Narong
Klanrit, Poramate
Loilome, Watcharin
author_facet Dokduang, Hasaya
Jamnongkarn, Wassana
Promraksa, Bundit
Suksawat, Manida
Padthaisong, Sureerat
Thanee, Malinee
Phetcharaburanin, Jutarop
Namwat, Nisana
Sangkhamanon, Sakkarn
Titapun, Attapol
Khuntikeo, Narong
Klanrit, Poramate
Loilome, Watcharin
author_sort Dokduang, Hasaya
collection PubMed
description BACKGROUND: Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models. MATERIALS AND METHODS: HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model. RESULTS: Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response. CONCLUSION: Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended.
format Online
Article
Text
id pubmed-7296552
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Dove
record_format MEDLINE/PubMed
spelling pubmed-72965522020-06-29 In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines Dokduang, Hasaya Jamnongkarn, Wassana Promraksa, Bundit Suksawat, Manida Padthaisong, Sureerat Thanee, Malinee Phetcharaburanin, Jutarop Namwat, Nisana Sangkhamanon, Sakkarn Titapun, Attapol Khuntikeo, Narong Klanrit, Poramate Loilome, Watcharin Drug Des Devel Ther Original Research BACKGROUND: Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models. MATERIALS AND METHODS: HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model. RESULTS: Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response. CONCLUSION: Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended. Dove 2020-06-11 /pmc/articles/PMC7296552/ /pubmed/32606601 http://dx.doi.org/10.2147/DDDT.S250061 Text en © 2020 Dokduang et al. http://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
spellingShingle Original Research
Dokduang, Hasaya
Jamnongkarn, Wassana
Promraksa, Bundit
Suksawat, Manida
Padthaisong, Sureerat
Thanee, Malinee
Phetcharaburanin, Jutarop
Namwat, Nisana
Sangkhamanon, Sakkarn
Titapun, Attapol
Khuntikeo, Narong
Klanrit, Poramate
Loilome, Watcharin
In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines
title In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines
title_full In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines
title_fullStr In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines
title_full_unstemmed In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines
title_short In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines
title_sort in vitro and in vivo anti-tumor effects of pan-her inhibitor varlitinib on cholangiocarcinoma cell lines
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7296552/
https://www.ncbi.nlm.nih.gov/pubmed/32606601
http://dx.doi.org/10.2147/DDDT.S250061
work_keys_str_mv AT dokduanghasaya invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT jamnongkarnwassana invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT promraksabundit invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT suksawatmanida invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT padthaisongsureerat invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT thaneemalinee invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT phetcharaburaninjutarop invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT namwatnisana invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT sangkhamanonsakkarn invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT titapunattapol invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT khuntikeonarong invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT klanritporamate invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines
AT loilomewatcharin invitroandinvivoantitumoreffectsofpanherinhibitorvarlitiniboncholangiocarcinomacelllines