Apigenin enhances sorafenib anti-tumour efficacy in hepatocellular carcinoma
Deepti Singh1, Mohammad Afsar Khan1, Dhruv Mishra2
1Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India.
Background:
The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore.
Methods:
We used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 μM) and Sorafenib (1-10 μM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done.
Results:
The results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4.
Conclusions:
In conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.
Insights
Apigenin enhances sorafenib's effectiveness against liver cancer. This combination therapy shows improved tumor reduction and cell death, offering a promising approach for hepatocellular carcinoma (HCC) treatment.
Area of Science:
- Hepatocellular Carcinoma Research
- Pharmacology
- Natural Product Chemistry
Background:
- The limitations of single-drug therapies, including resistance and side effects, necessitate combination approaches.
- Sorafenib, an FDA-approved drug for liver cancer, has significant limitations.
- Apigenin, a plant-derived flavone, presents a potential agent to enhance sorafenib efficacy and reduce toxicity.
Purpose of the Study:
- To investigate the potential of Apigenin as an adjunct therapy to Sorafenib for liver cancer.
- To evaluate the combined therapeutic efficacy and underlying mechanisms of Apigenin and Sorafenib.
- To assess the impact of Apigenin on Sorafenib's bioavailability and toxicity profile.
Main Methods:
- In silico molecular docking, in vitro cell culture (HepG2, Huh7), and in vivo animal models (DEN-induced tumors) were employed.
- Apigenin and Sorafenib treatments were administered alone and in combination.
- Bioavailability, tumor growth, cytotoxicity, apoptosis, cell cycle arrest, and molecular marker expression (qRT-PCR, immunohistochemistry) were analyzed.
Main Results:
- Apigenin demonstrated good bioavailability and synergistic binding affinity with key cancer-related proteins (p53, NANOG, ß-Catenin, c-MYC, TLR4).
- Combined treatment significantly improved therapeutic efficacy compared to monotherapy, including enhanced cytotoxicity, apoptosis induction, and cell cycle arrest.
- The combination therapy led to substantial tumor growth reduction and modulated the expression of specific tumor markers, including increased p53 and decreased cancer stem cell markers.
Conclusions:
- Apigenin can significantly enhance the therapeutic efficacy of Sorafenib in treating liver cancer.
- The combination of Apigenin and Sorafenib represents a promising therapeutic strategy for hepatocellular carcinoma (HCC).
- Further research is warranted to elucidate the detailed mechanistic insights of this combined approach.
