Regulation of Protein-Induced Apoptosis and Autophagy in Human Hepatocytes Treated with Metformin and Paclitaxel In
Norah Saeed Al-Zahrani1, Mazin Abdulaziz Zamzami2, Mohammed A Baghdadi3,4
1Department of Clinical Biochemistry, Collage of Medicine, King Khalid University, Abha 61421, Saudi Arabia.
Abstract:
Metformin and paclitaxel therapy offer promising outcomes in the treatment of liver cancer. Combining paclitaxel with metformin enhances treatment effectiveness and mitigates the adverse effects associated with paclitaxel alone. This study explored the anticancer properties of metformin and paclitaxel in HepG2 liver cancer cells, MCF-7 breast cancer cells, and HCT116 colon cancer cells. The results demonstrated that the combination of these agents exhibited a lower IC50 in the tested cell lines compared to paclitaxel monotherapy. Notably, treating the HepG2 cell line with this combination led to a reduction in the G0/G1 phase and an increase in the S and G2/M phases, ultimately triggering early apoptosis. To further investigate the interaction between the cellular proteins with paclitaxel and metformin, an in silico study was conducted using proteins chosen from a protein data bank (PDB). Among the proteins studied, AMPK-α, EGFRK, and FKBP12-mTOR exhibited the highest binding free energy, with values of -11.01, -10.59, and -15.63 kcal/mol, respectively, indicating strong inhibitory or enhancing effects on these proteins. When HepG2 cells were exposed to both paclitaxel and metformin, there was an upregulation in the gene expression of AMPK-α, a key regulator of the energy balance in cancer growth, as well as apoptotic markers such as p53 and caspase-3, along with autophagic markers including beclin1 and ATG4A. This combination therapy of metformin and paclitaxel exhibited significant potential as a treatment option for HepG2 liver cancer. In summary, the combination of metformin and paclitaxel not only enhances treatment efficacy but also reduces side effects. It induces cell cycle alterations and apoptosis and modulates key cellular proteins involved in cancer growth, making it a promising therapy for HepG2 liver cancer.
Insights
Combining metformin and paclitaxel shows promise for liver cancer treatment. This combination therapy enhances effectiveness, reduces side effects, and induces apoptosis in cancer cells.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Metformin and paclitaxel are established cancer therapies.
- Paclitaxel monotherapy can cause adverse effects.
- Combination therapy may improve efficacy and reduce toxicity.
Purpose of the Study:
- To investigate the combined anticancer effects of metformin and paclitaxel.
- To evaluate the impact on cell cycle, apoptosis, and gene expression in liver cancer cells.
- To explore protein interactions using in silico methods.
Main Methods:
- In vitro studies using HepG2, MCF-7, and HCT116 cancer cell lines.
- In silico molecular docking to assess protein-ligand binding.
- Gene expression analysis of key cancer-related proteins.
Main Results:
- The combination of metformin and paclitaxel demonstrated a lower IC50 compared to paclitaxel alone.
- Cell cycle analysis showed a reduction in G0/G1 phase and an increase in S and G2/M phases, leading to apoptosis in HepG2 cells.
- In silico studies revealed high binding affinities for AMPK-α, EGFRK, and FKBP12-mTOR.
- Upregulation of AMPK-α, p53, caspase-3, beclin1, and ATG4A gene expression was observed in HepG2 cells.
Conclusions:
- Metformin and paclitaxel combination therapy is a promising strategy for liver cancer.
- This combination enhances treatment efficacy and reduces adverse effects.
- The therapy induces cell cycle arrest, apoptosis, and modulates key cellular proteins.
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