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Article

Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway

1
Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
2
Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
3
School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
4
Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333423, Taiwan
5
Genomics Research Center, Academia Sinica, Taipei 115201, Taiwan
6
Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
7
Department of Hematology and Oncology, Chang Gung Memorial Hospital, Linkou and Chang Gung University, Taoyuan 333423, Taiwan
8
Asclepiumm Taiwan Co., Ltd., New Taipei 25160, Taiwan
9
Institute of Biopharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Gautam Sethi
Biomedicines 2021, 9(8), 885; https://doi.org/10.3390/biomedicines9080885
Received: 18 June 2021 / Revised: 16 July 2021 / Accepted: 21 July 2021 / Published: 24 July 2021
Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and the cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the library of integrated network-based cellular signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy. View Full-Text
Keywords: cholangiocarcinoma; ALDH1A3; JAK2 inhibitor; STATs; ruxolitinib cholangiocarcinoma; ALDH1A3; JAK2 inhibitor; STATs; ruxolitinib
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MDPI and ACS Style

Chung, S.-Y.; Hung, Y.-P.; Pan, Y.-R.; Chang, Y.-C.; Wu, C.-E.; Hsu, D.S.-S.; Chang, P.M.-H.; Lu, M.-L.; Huang, C.-Y.F.; Su, Y.; Hsiao, M.; Yeh, C.-N.; Chen, M.-H. Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway. Biomedicines 2021, 9, 885. https://doi.org/10.3390/biomedicines9080885

AMA Style

Chung S-Y, Hung Y-P, Pan Y-R, Chang Y-C, Wu C-E, Hsu DS-S, Chang PM-H, Lu M-L, Huang C-YF, Su Y, Hsiao M, Yeh C-N, Chen M-H. Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway. Biomedicines. 2021; 9(8):885. https://doi.org/10.3390/biomedicines9080885

Chicago/Turabian Style

Chung, Shin-Yi, Yi-Ping Hung, Yi-Ru Pan, Yu-Chan Chang, Chiao-En Wu, Dennis S.-S. Hsu, Peter M.-H. Chang, Meng-Lun Lu, Chi-Ying F. Huang, Yeu Su, Michael Hsiao, Chun-Nan Yeh, and Ming-Huang Chen. 2021. "Ruxolitinib Combined with Gemcitabine against Cholangiocarcinoma Growth via the JAK2/STAT1/3/ALDH1A3 Pathway" Biomedicines 9, no. 8: 885. https://doi.org/10.3390/biomedicines9080885

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