المؤلفون: Zong-Guang Zhou, Jiayang Liu, Yan Chen, Hai-Ning Chen, Canhua Huang, Maochao Luo, Zhe Zhang, Kui Wang, Zhao Huang, Yong Peng, Yunlong Lei, Lu Zhang, Yuquan Wei

المصدر: Journal of Hepatology. 70:66-77

مصطلحات موضوعية: 0301 basic medicine, Sorafenib, Programmed cell death, Carcinoma, Hepatocellular, Cell, Down-Regulation, Apoptosis, PINK1, Parkin, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, Mitophagy, Humans, Medicine, Hepatology, business.industry, Liver Neoplasms, digestive system diseases, Ketoconazole, 030104 developmental biology, medicine.anatomical_structure, Cyclooxygenase 2, Hepatocytes, Commentary, Cancer research, Cytochrome P-450 CYP3A Inhibitors, 030211 gastroenterology & hepatology, business, medicine.drug

الوصف: Background & Aims Hepatocellular carcinoma (HCC) is a common cancer worldwide and remains a major clinical challenge. Ketoconazole, a traditional antifungal agent, has attracted considerable attention as a therapeutic option for cancer treatment. However, its mechanism of action is still not clearly defined. We aimed to evaluate the effect of ketoconazole on HCC and investigate the underlying mechanisms. Methods We examined the antitumor effect of ketoconazole on HCC cells, cell line-derived xenografts, and a patient-derived xenograft (PDX) model. Ketoconazole-induced mitophagy was quantified by immunofluorescence, immunoblotting and transmission electron microscopy analysis. We used mitophagy inhibitors to study the role of mitophagy on HCC cell death induced by ketoconazole. The role of cyclooxygenase-2 (COX-2 [encoded by PTGS2]) on ketoconazole-induced mitophagy was evaluated using gain- and loss-of-function methods. The synergistic effect of ketoconazole with sorafenib on HCC was measured in vivo and in vitro. Results Ketoconazole stimulated apoptosis in HCC cells by triggering mitophagy in vitro and in vivo. Mechanistically, ketoconazole downregulated COX-2, which led to PINK1 accumulation and subsequent mitochondrial translocation of Parkin (PRKN), and thereby promoted mitophagy-mediated mitochondrial dysfunction. Inhibiting mitophagy alleviated ketoconazole-induced mitochondrial dysfunction and apoptosis, supporting a causal role for mitophagy in the antitumor effect of ketoconazole. In the HCC PDX model, ketoconazole demonstrated a marked antitumor effect characterized by COX-2 downregulation, mitophagy activation, and apoptosis induction. Moreover, ketoconazole acted synergistically with sorafenib to suppress HCC xenograft growth in vivo. Conclusion Our results demonstrate a novel link between ketoconazole and mitophagy machinery, providing preclinical proof of concept for the use of ketoconazole in HCC treatment. Lay summary Hepatocellular carcinoma (HCC) is a common malignancy worldwide and remains a major clinical challenge. Our study reveals that ketoconazole, a broad-spectrum antifungal agent, activates PINK1/Parkin-mediated mitophagy by downregulating COX-2, consequently resulting in the acceleration of apoptosis and thereby inhibiting the growth of HCC. Furthermore, ketoconazole acts synergistically with sorafenib in the suppression of HCC growth in vitro and in vivo.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2579853cc92f345746b9b2056156c52aTest
https://doi.org/10.1016/j.jhep.2018.09.022Test

المؤلفون: Hai-Ning Chen, Li-Bin Huang, Ting-Han Yang

المصدر: Gastroenterology. 161:732-733

مصطلحات موضوعية: Hepatology, Tumor budding, business.industry, Colorectal cancer, Gastroenterology, Cancer research, Medicine, Lymph node metastasis, business, medicine.disease

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::90b0a2f5ba1144839bf6e23a46cf7620Test
https://doi.org/10.1053/j.gastro.2020.12.053Test

المؤلفون: Canhua Huang, Xingyue Yang, Hai-Ning Chen, Maochao Luo, Edouard C. Nice

المصدر: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1876:188623

مصطلحات موضوعية: Cancer Research, Colorectal cancer, Drug resistance, Epigenesis, Genetic, Histones, Genetics, Humans, Medicine, Epigenetics, neoplasms, Gene, biology, business.industry, DNA Methylation, medicine.disease, Non-coding RNA, digestive system diseases, Histone, Oncology, Drug Resistance, Neoplasm, DNA methylation, Cancer research, biology.protein, Colorectal Neoplasms, business, Epigenetic therapy, Signal Transduction

الوصف: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Despite significant progress that has been made in therapies against CRC over the past decades, drug resistance is still a major limitation in CRC treatment. Numerous investigations have unequivocally shown that epigenetic regulation plays an important role in CRC drug resistance because of the high rate of epigenetic alterations in multiple genes during cancer development or drug treatment. Furthermore, the reversibility of epigenetic alterations provides novel therapeutic strategies to overcome drug resistance using small molecules, which can target non-coding RNAs or reverse histone modification and DNA methylation. In this review, we discuss epigenetic regulation in CRC drug resistance and the possible role of preventing or reversing CRC drug resistance using epigenetic therapy in CRC treatment.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::921db992c5d63154f9e181f7ab2f0bb5Test
https://doi.org/10.1016/j.bbcan.2021.188623Test

المؤلفون: Bo Zhang, Zhi-Xin Chen, Yuan Yin, Hong-Xin Yang, Hai-Ning Chen

المصدر: Annals of Oncology. 24:iv73

مصطلحات موضوعية: Oncology, GiST, business.industry, Mutation (genetic algorithm), Cancer research, Medicine, Hematology, PDGFRA, business, Platelet-Derived Growth Factor alpha Receptor, Protein expression

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::60a80db2d2192b3cca7bedb2d62257b2Test
https://doi.org/10.1093/annonc/mdt203.132Test

المؤلفون: Bo Zhang, Hong-Xin Yang, Zhi-Xin Chen, Hai-Ning Chen

المصدر: Annals of Oncology. 24:iv46

مصطلحات موضوعية: Oncology, medicine.medical_specialty, business.industry, Internal medicine, medicine, Cancer research, Hematology, Stromal tumor, business, Stromal Neoplasm

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_________::caa2917a71f058b63eb085e105761a43Test
https://doi.org/10.1093/annonc/mdt203.31Test