Life sciences · 2022
Necroptosis modulation by cisplatin and sunitinib in hepatocellular carcinoma cell line.
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El-Demiry Sarah M, El-Yamany Mohamed, El-Gendy Saad M, Salem H A, Saber Mona M
Аннотация
UNLABELLED: Aim Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Systemic chemotherapy such as cisplatin and multi-targeted receptor tyrosine kinase inhibitors, including sunitinib, has marginal activity and frequent toxicity. Recently, necroptosis has been investigated as a potential target in treating cancer. Our aim is to evaluate the influence of cisplatin-sunitinib combination on HepG2 cells regarding their cytotoxicity and implicated intracellular pathways.
MATERIALS AND METHODS: The half-maximal inhibitory concentration (IC50) values of cisplatin, sunitinib, and their combination were determined by Sulforhodamine-B assay. Bcl-2 and Bax protein levels were assayed using western blot. ELISA technique was used to measure pRIPK3/RIPK3, pERK/ERK, caspase-9, caspase-8, malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase (GPx).
KEY FINDINGS: Cisplatin-sunitinib combination exhibited a superior cytotoxic effect on HepG2 cells. Low concentrations of 4 μg/ml cisplatin and 2.8 μg/ml sunitinib showed significant Bcl-2 down-regulation and Bax up-regulation. The combined treatment also lowered pRIPK3/RIPK3 by 74% (p < 0.05) compared to the control. Significant increase in pERK/ERK by 3.9 folds over the normal control was also demonstrated. Moreover, combined treatment produced a significant 4 and 4.6 folds increase in caspase-9 and -8 levels. An increase in MDA level by 1.3 folds, a decrease in the intracellular GSH level by 63%, and an increase in GPx level by 1.17 folds were demonstrated.
SIGNIFICANCE: Sunitinib modulated cisplatin effect on cytotoxicity, oxidative stress, apoptosis, necroptosis and MAPK pathways. Sunitinib enhanced cisplatin-induced apoptosis and increased oxidative stress, but decreased necroptosis. Combined cisplatin and sunitinib might be promising for treating advanced HCC.
MATERIALS AND METHODS: The half-maximal inhibitory concentration (IC50) values of cisplatin, sunitinib, and their combination were determined by Sulforhodamine-B assay. Bcl-2 and Bax protein levels were assayed using western blot. ELISA technique was used to measure pRIPK3/RIPK3, pERK/ERK, caspase-9, caspase-8, malondialdehyde (MDA), glutathione (GSH), and glutathione peroxidase (GPx).
KEY FINDINGS: Cisplatin-sunitinib combination exhibited a superior cytotoxic effect on HepG2 cells. Low concentrations of 4 μg/ml cisplatin and 2.8 μg/ml sunitinib showed significant Bcl-2 down-regulation and Bax up-regulation. The combined treatment also lowered pRIPK3/RIPK3 by 74% (p < 0.05) compared to the control. Significant increase in pERK/ERK by 3.9 folds over the normal control was also demonstrated. Moreover, combined treatment produced a significant 4 and 4.6 folds increase in caspase-9 and -8 levels. An increase in MDA level by 1.3 folds, a decrease in the intracellular GSH level by 63%, and an increase in GPx level by 1.17 folds were demonstrated.
SIGNIFICANCE: Sunitinib modulated cisplatin effect on cytotoxicity, oxidative stress, apoptosis, necroptosis and MAPK pathways. Sunitinib enhanced cisplatin-induced apoptosis and increased oxidative stress, but decreased necroptosis. Combined cisplatin and sunitinib might be promising for treating advanced HCC.