Epirubicin directly promotes hepatitis B virus (HBV) replication in stable HBV-expressing cell lines: A novel mechanism of HBV reactivation following anticancer chemotherapy

Abstract

Abstract. Chronic hepatitis B virus (HBV) infection is a worldwide problem and HBV reactivation following anticancer chemotherapy has become an emerging clinical challenge. However, the mechanisms of HBV reactivation following chemotherapy remain unclear. Epirubicin is an anthracycline drug used in chemotherapy to treat numerous types of malignancy, including breast cancer, acute leukemia, malignant lymphoma, lung cancer, ovarian cancer and stomach cancer. Epirubicin acts by intercalating DNA strands and inhibiting DNA and RNA synthesis. In this study, it was demonstrated that epirubicin directly upregulated the levels of in vitro HBV replication in a concentration-dependent manner. Exposure to epirubicin for 24 h induced >11-and 6-fold increases in the levels of intracellular and secreted HBV DNA, respectively. In concordance with the elevated levels of HBV DNA, the expression levels of HBV pregenomic RNA, intracellular HBV surface and HBV core antigens, and secreted HBV e antigen were significantly increased by treatment with 0.5 µM epirubicin. Notably, epirubicin promoted cellular excretion of HBV nucleocapsids, which are closely associated with the pathological effects of HBV, including acute liver failure. In conclusion, epirubicin exhibited a direct stimulatory effect on HBV replication and this may be a novel mechanism of HBV reactivation following cytotoxic anticancer chemotherapy.

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014

“…Reactivation of HBV could be either spontaneous or due to intensive chemotherapy or immunosuppressive therapy [10,11], immune restoration after highly active antiretroviral therapy for HIV [12,13], treatment-related [14], or reactivation of the occult HBV infection by rituximab (anti-CD20)-based chemotherapy [15][16][17]. Similarly, reactivation of Hepatitis C virus infection has also been reported, especially after immune suppressive therapy [18,19].…”

“…Acute hepatic insults of infectious etiology included reactivation of Hepatitis B virus (HBV) as the leading cause of ACLF in the Asian region [10][11][12][13][14][15][16][17][18][19]. Reactivation of HBV could be either spontaneous or due to intensive chemotherapy or immunosuppressive therapy [10,11], immune restoration after highly active antiretroviral therapy for HIV [12,13], treatment-related [14], or reactivation of the occult HBV infection by rituximab (anti-CD20)-based chemotherapy [15][16][17].…”

C6 ceramide sensitizes the anti-hepatocellular carcinoma (HCC) activity by AZD-8055, a novel mTORC1/2 dual inhibitor

“…This procedure was based on selective DNA denaturation in apoptotic cells by formamide and detection of the denatured DNA by monoclonal antibody to singlestranded DNA. The detailed procedure was described in other studies [29,30].…”

Reactivation of Hepatitis B Virus and Its Prevention in Patients with Rheumatic Diseases Receiving Immunosuppressive Therapy

“…Glucocorticoid directly increases viral replication via binding to glucocorticoid responsive element in HBV genome. Anthracyline derivatives (doxorubicin, epirubicin et al) also directly promote replication of HBV [16,17]. In addition, some studies showed that TNF-α promoted HBV clearance and decrease of HBV transcription [18].…”