Related Experiment Video
Updated: Jun 11, 2025
Preclinical Assessment of the Bioactivity of the Anticancer Coumarin OT48 by Spheroids, Colony Formation Assays, and Zebrafish Xenografts
Published on: June 26, 2018
Silmitasertib in Combination With Cabozantinib Impairs Liver Cancer Cell Cycle Progression, Induces Apoptosis, and
Yuki Haga1, Ranjit Ray1,2, Ratna B Ray2,3
1Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.
Abstract:
The rising incidence of hepatocellular carcinoma (HCC) is a global problem. Several approved treatments, including immune therapy and multi-tyrosine kinase inhibitors, are used for treatment, although the results are not optimum. There is an unmet need to develop highly effective chemotherapies for HCC. Targeting multiple pathways to attack cancer cells is beneficial. Cabozantinib is an orally available bioactive multikinase inhibitor and has a modest effect on HCC treatment. Silmitasertib is an orally bioavailable, potent CK2 inhibitor with a direct role in DNA damage repair and is in clinical trials for other cancers. In this study, we planned to repurpose these existing drugs on HCC treatment. We observed a stronger antiproliferative effect of these two combined drugs on HCC cells generated from different etiologies as compared to the single treatment. Global RNA-seq analyses revealed a decrease in the expression of G2/M cell cycle transition genes in HCC cells following combination treatment, suggesting G2 phase cell arrest. We observed G2/M cell cycle phase arrest in HCC cells upon combination treatment compared to the single-treated or vehicle-treated control cells. The downregulation of CCNA2 and CDC25C following combination therapy further supported the observation. Subsequent analyses demonstrated that combination treatment inhibited 70 kDa ribosomal protein S6 kinase (p70S6K) phosphorylation, and increased Bim expression. Apoptosis of HCC cells were accompanied by increased poly (ADP-ribose) polymerase cleavage and caspase-9 activation. Next, we observed that a combination therapy significantly delayed the progression of HCC xenograft growth as compared to vehicle control. Together, our results suggested combining cabozantinib and silmitasertib would be a promising treatment option for HCC.
Insights
Combining cabozantinib and silmitasertib shows promise for hepatocellular carcinoma (HCC) treatment. This combination therapy effectively inhibits HCC cell proliferation and delays tumor growth by inducing cell cycle arrest and apoptosis.
Area of Science:
- Hepatocellular Carcinoma Research
- Cancer Therapeutics
- Molecular Oncology
Background:
- Hepatocellular carcinoma (HCC) incidence is rising globally, with current treatments offering suboptimal outcomes.
- Existing therapies like immunotherapy and multi-tyrosine kinase inhibitors necessitate the development of more effective treatments.
- There is a critical need for novel chemotherapies targeting multiple pathways for improved HCC management.
Purpose of the Study:
- To investigate the potential of repurposing cabozantinib and silmitasertib for HCC treatment.
- To evaluate the combined efficacy of cabozantinib and silmitasertib against HCC cells.
- To elucidate the molecular mechanisms underlying the combined therapeutic effect.
Main Methods:
- In vitro antiproliferative assays on HCC cells from various etiologies.
- Global RNA sequencing (RNA-seq) to analyze gene expression changes.
- Cell cycle analysis to detect G2/M phase arrest.
- Western blotting to assess protein phosphorylation and expression (p70S6K, Bim, PARP, Caspase-9).
- In vivo xenograft studies to evaluate tumor growth inhibition.
Main Results:
- The combination of cabozantinib and silmitasertib demonstrated a significantly stronger antiproliferative effect on HCC cells than single agents.
- Combination treatment induced G2/M cell cycle arrest, evidenced by decreased G2/M transition gene expression (CCNA2, CDC25C).
- Therapy inhibited p70S6K phosphorylation, increased Bim expression, and promoted apoptosis via PARP cleavage and caspase-9 activation.
- In vivo, the combination therapy significantly delayed HCC xenograft growth compared to controls.
Conclusions:
- Combining cabozantinib and silmitasertib is a promising therapeutic strategy for hepatocellular carcinoma.
- The combination induces cell cycle arrest and apoptosis, leading to significant tumor growth inhibition.
- Further clinical investigation of this drug combination for HCC is warranted.
More Related Videos
09:29Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
13:34A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Related Concept Videos
02:34Inhibition of Cdk Activity
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...