Chromosomal instability and cytotoxicity induced by ribavirin: comparative analysis in cell lines with different drug-metabolizing profiles

Abstract

Ribavirin is an important component of the treatment for hepatitis C virus (HCV) infection and, in combination with the new direct-acting antiviral (DAA) agents, comprises the major current therapeutic regimens. This study evaluated the cytotoxicity and chromosomal instability induced by ribavirin using the in vitro cytokinesis-block micronucleus cytome (CBMN-Cyt) assay in two cell lines with different expression levels of drug-metabolizing enzymes: human hepatocellular carcinoma cells (HepG2) and Chinese hamster ovary (CHO-K1) cells. HepG2 cells were treated with nine concentrations (from 15.3 μg/ml to 3.9 mg/ml) and CHO-K1 cells were exposed to eight concentrations (from 15.3 μg/ml to 1.9 mg/ml) of ribavirin for 24 h. Ribavirin inhibited cell proliferation in both cell lines, but at different concentrations: 3.9 mg/ml in HepG2 and 244.2 μg/ml in CHO-K1 cells. No significant differences were observed regarding aspects of cell death in HepG2 and CHO-K1 cells, reflecting the absence of cytotoxic effects associated to ribavirin. Ribavirin did not increase the frequency of nucleoplasmic bridges (NPBs) and nuclear bud (NBUD). However, when compared to the negative control, a significant increase in micronuclei (MNi) frequency was observed in both cell lines. However, chromosomal instability was induced by higher concentrations of ribavirin in HepG2 cells (from 61.1 to 976.8 μg/ml), compared with CHO-K1 cells (15.3 and 30.5 μg/ml). These results demonstrate the potential of ribavirin to promote chromosomal instability, and suggest that cells with different expressions of drug-metabolizing enzymes show different susceptibility to ribavirin effects.

Evaluation of the genetic toxicity of sofosbuvir and simeprevir with and without ribavirin in a human-derived liver cell line

“…It is possible that these results were caused by RBV. In vitro genotoxicity studies using cultured human lymphocytes (Joksić et al 2000(Joksić et al , 2006, CHO-K1 (Chinese hamster ovary), and HepG2 cells (Librelotto et al 2019) also demonstrated that different RBV concentrations inhibit cell proliferation. It has been proposed that the cytotoxic effect of RBV is due to induction of cell death and suppression of cell division and proliferation (D'Souza & Narayana 2002).…”

“…Two independent experiments, in duplicate, were performed. Data about treatment of HepG2 cells with RBV alone were previously published by our research group (Librelotto et al 2019).…”

“…Several studies have demonstrated a favorable clinical safety profile of SOF-based treatment regimens (Liu et al 2014, Beck et al 2016, Calleja et al 2017, Crespo et al 2017, Flisiak et al 2017b, Yang & Choi 2017; however, few studies have investigated its genotoxic profile (FDA 2013a, EMA 2016. The genotoxic effects of RBV have already been demonstrated in cell culture studies (Joksić et al 2000, Librelotto et al 2019), but there are few studies evaluating the genotoxic effects of DAAs, which are often used in combination.…”

SMC1 promotes proliferation and inhibits apoptosis through the NF‑κB signaling pathway in colorectal cancer

“…Genomic instability has various causes, of which chromosomal instability (CIN) and microsatellite instability have received the most focus (6). In CRC, CIN is the most common form of genomic instability, which occurs in nearly 80–85% of patients with CRC (7). Current research in the field is focused on elucidating the molecular basis of CIN, including the possible roles of defects in the spindle checkpoint and other regulators of mitosis.…”

Peptidomimetic Oligomers Targeting Membrane Phosphatidylserine Exhibit Broad Antiviral Activity

“…However, viral polymerases exhibit low replication fidelity, enabling them to overcome antiviral treatment modalities through rapid generation of resistance mutations . Resistance to antivirals has been widely observed for human immunodeficiency virus (HIV), hepatitis B virus, influenza virus, and many other RNA viruses, emphasizing the challenge for developing novel, long-lasting treatments. , In addition, host cell dependence is a requirement for virus replication, yet targeting host factors can result in cytotoxicity and severe side effects in patients . The recent COVID-19 pandemic highlights the aforementioned challenges of designing therapies against viruses, especially considering the prospect of preparing for the next virus outbreak of unknown origin.…”