Abstract:
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.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Chen Y,Chen HN,Wang K,Zhang L,Huang Z,Liu J,Zhang Z,Luo M,Lei Y,Peng Y,Zhou ZG,Wei Y,Huang Cdoi
10.1016/j.jhep.2018.09.022subject
Has Abstractpub_date
2019-01-01 00:00:00pages
66-77issue
1eissn
0168-8278issn
1600-0641pii
S0168-8278(18)32441-3journal_volume
70pub_type
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abstract:BACKGROUND:Hepatopulmonary syndrome (HPS) has been defined as a clinical triad, including chronic liver disease, gas exchange defects (increased alveolar-arterial PO2 difference irrespective of the presence of arterial hypoxemia), and widespread intrapulmonary vascular dilatations. We determined the incidence and the c...
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journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
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pub_type: 杂志文章
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pub_type: 杂志文章
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更新日期:2009-11-01 00:00:00
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pub_type: 杂志文章
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更新日期:2013-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2009-07-01 00:00:00
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pub_type: 杂志文章
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