Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin‐induced eIF4E activation

Tan, Jun; Ye, Jingfen; Song, Meijun; Zhou, Mi; Hu, Yaoren

doi:10.1002/jbt.22007

Cited by 14 publications

(11 citation statements)

References 25 publications

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“…These data could be in part explained with the well-known immune-modulating activity of RBV, independently from the dosage, which may improve immune surveillance, while both boosting Th1 response and switching from Th2 to a Th1 CD4 pattern too [27]. Moreover, some kind of protective activity of RBV against HCC, when associated with Doxorubicin, most likely implicating the immune-surveillance, has also been recently demonstrated [28].…”

Section: Discussionmentioning

confidence: 99%

“…Early HCC occurrence appears to be associated with an advanced CTP stage, male gender, higher liver stiffness value and diabetes. However, interestingly, it is also more often correlated to SOF based therapy without Ribavirin, in CTP A, whereas the use of this latter antiviral seems exert a protective effect on HCC onset, as some literature also suggests [27, 28].…”

Section: Discussionmentioning

confidence: 99%

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Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study

et al. 2019

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Background An unexpected increased HCC recurrence and occurrence rate among HCV patients treated with direct acting antivirals combination has been reported. Aim of the study was the evaluation of early HCC occurrence rate and its risk factors in a HCV infected population, treated with direct-acting-antivirals. Methods According to the Italian ministerial guidelines for direct-acting-antivirals treatment, 1022 consecutive HCV patients treated with direct-acting-antivirals were enrolled. Patients either with active HCC at imaging or history of previous treated HCC, HBV or HIV co-infection, or liver transplant recipients were excluded. The SVR, defined as the persistent absence of detectable serum HCV-RNA 12 weeks after the end of treatment (SVR12), was assessed for all enrolled patients. Abdominal ultrasound was performed before starting antiviral therapy, and repeated every 6 months. HCC was diagnosed according to the international guidelines. Patients showing either nodular patterns suggestive of HCC or with uncertain dynamic vascular behaviour were excluded from a further follow-up. Results Nine hundred and eighty-five patients completed the 48 weeks follow-up after the end of treatment. A Sofosbuvir-based regimen was administered in the 74.9% of patients, among whom, the 71.6% underwent a simultaneous Ribavirin administration. A sustained virological response at 12 weeks off treatment was documented in 966 patients (98.2%). During the post treatment follow-up HCC was detected in 35 patients, with a cumulative incidence rate of the 3.55%. At multivariate analysis, four variables resulted independently associated with HCC development, both in a cirrhosis based and a class B Child based model, respectively: cirrhosis/class B Child, therapeutic schedule including Sofosbuvir without Ribavirin, liver stiffness values, male gender and presence of diabetes. A multivariate analysis performed on Child A cirrhotic patients, showed that Sofosbuvir based therapeutic treatment without Ribavirin had a HCC occurrence 5.7 higher than Ribavirin-based schedules with or without Sofosbuvir (p < 0.0001, OR: 5.686, 95% CI 2.455–13.169). Conclusions Our data suggest that early HCC occurrence appears more frequently related to Sofosbuvir-based therapy without Ribavirin which, indeed, seems to play a protective role on HCC onset. Therefore, a careful follow-up should be mandatory, especially in those regimens including Sofosbuvir without Ribavirin.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study

et al. 2019

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“…Aberrant activation of a variety of signaling pathways including AKT/mTOR has been implied in the development of HCC and predicts shorter survival of patients (Whittaker et al, ). It is well established that the inhibition of one canonical signaling by chemotherapeutic will activate another compensatory pathway in cancerous cells, which contributes to the resistance to chemotherapeutics (Chen et al, ; Tan et al, ). As a multi‐kinase inhibitor (TKI) targeting Raf/MAPK/ERK signaling pathway, sorafenib has been found to have crosstalk with AKT/mTOR signaling.…”

Section: Discussionmentioning

confidence: 99%

Retracted: Physcion Synergistically Enhances the Cytotoxicity of Sorafenib in Hepatocellular Carcinoma

Pan

Wang

Zhang

2019

The Anatomical Record

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Hepatocellular carcinoma (HCC) is a common human malignancy. Physcion is a naturally occurring anthraquinone derivative found in plant and marine sources. Our previous studies have indicated that physcion could suppress tumor growth and induce apoptosis in HCC. This study was aimed to investigate the effect of a combination of physcion and sorafenib on HCC. Our findings indicated that physcion could significantly augment the antiproliferative and proapoptotic activities of sorafenib in vitro and in vivo. Mechanistically, the synergistic effect correlates with physcion‐induced suppression of Notch3/AKT signaling. This preclinical evidence highlights the potential application of physcion in the treatment of HCC. Anat Rec, 302:2171–2177, 2019. © 2019 American Association for Anatomy

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“…For instance, AKT1 de-phosphorylation, which results from down-regulation of the direct EIF4E target transcript NBN , also was reported after ribavirin treatment in a glioblastoma cell line (72), breast cancer cell lines (53), hepatocellular carcinoma (73), oral squamous cell carcinoma (74), Ph+ ALL and CML (56) and in AML in patients (15). Additionally, we find decreases in MYC levels with ribavirin treatment in infant ALL and RS4:11 cells, and ribavirin caused MYC levels to decrease in primary AML cells (41), a diffuse large B-cell lymphoma cell line (19), colon and cervical cancer (75) and hepatocellular carcinoma (73). The decreased MYC is of interest because of protean roles of MYC in up-regulating EIF4E (76, 77) and ribosome biogenesis ( e.g.…”

Section: Discussionmentioning

confidence: 86%

Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia

et al. 2018

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The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A -rearranged ( KMT2A -R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A -R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A - AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A- R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A -R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.

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Ribavirin augments doxorubicin's efficacy in human hepatocellular carcinoma through inhibiting doxorubicin‐induced eIF4E activation

Abstract: Activation of eukaryotic translation initiation factor 4E (eIF4E) is a cellular survival mechanism in response to chemotherapy in cancers. In this work, we demonstrate that targeting eIF4E by rib-

Cited by 14 publications

References 25 publications

Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study

Incidence and risk factors of early HCC occurrence in HCV patients treated with direct acting antivirals: a prospective multicentre study

Retracted: Physcion Synergistically Enhances the Cytotoxicity of Sorafenib in Hepatocellular Carcinoma

Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia

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