Dasabuvir suppresses esophageal squamous cell carcinoma growth in vitro and in vivo through targeting ROCK1

Esophageal squamous cell carcinoma (ESCC) is an upper gastrointestinal cancer with high morbidity and mortality. New strategies are urgently needed to prolong patients' survival. Through screening FDA-approved drugs, we found dasabuvir, a drug approved for hepatitis C virus (HCV) treatment, suppressed ESCC proliferation. Dasabuvir could inhibit the growth of ESCC cells in a time and dose-dependent manner and arrested cell cycle at the G0/G1 phase. The antitumor activity was further validated in vivo using patient-derived xenograft tumor models. In terms of mechanism, we unveil that dasabuvir is a Rho-associated protein kinase 1 (ROCK1) inhibitor. Dasabuvir can bind to ROCK1 and suppress its kinase activity, thus downregulating the phosphorylation of ERK1/2 by ROCK1 and the expression of cyclin-dependent kinase 4 (CDK4) and cyclin D1. These results provide evidence that dasabuvir suppresses ESCC growth in vivo and in vitro through blocking ROCK1/ERK signaling pathway.

 

Comments：

The fact that dasabuvir is already an FDA-approved drug for treating hepatitis C virus (HCV) could be an advantage in terms of facilitating the clinical development of this drug for ESCC treatment. Repurposing existing drugs for new indications can save time and resources compared to developing a completely new drug.

The finding that dasabuvir acts as a Rho-associated protein kinase 1 (ROCK1) inhibitor is also interesting. ROCK1 is involved in various cellular processes, including cell proliferation, migration, and invasion. Inhibition of ROCK1 could potentially slow down tumor growth and metastasis in ESCC.

It's encouraging to hear that the antitumor activity of dasabuvir was validated in vivo using patient-derived xenograft tumor models. These models can provide more relevant information on drug efficacy and toxicity compared to traditional cell line-based models.

Overall, the results you have described provide a basis for further investigation of dasabuvir as a potential therapy for ESCC. Future studies could focus on optimizing the dosing and delivery of dasabuvir, as well as investigating its safety and efficacy in clinical trials.

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S5402	Dasabuvir (ABT-333)	Dasabuvir (ABT-333) is a non-nucleoside inhibitor of NS5B viral RNA-dependent RNA polymerase that inhibits recombinant NS5B polymerases derived from HCV genotype 1a and 1b clinical isolates with IC50 values between 2.2 and 10.7 nM. It is at least 7,000-fold selective for the inhibition of HCV genotype 1 polymerases over human/mammalian polymerases.

Related Targets

HCV Protease