Anti-cancer activity and cellular uptake of 7,3′,4′- and 7,8,4′-trihydroxyisoflavone in HepG2 cells under hypoxic conditions

Abstract

Transarterial chemoembolisation (TACE) is used for unresectable hepatocellular carcinoma (HCC) treatment, but TACE-induced hypoxia leads to poor prognosis. The anti-cancer effects of soybean isoflavones daidzein derivatives 7,3′,4′-trihydroxyisoflavone (734THIF) and 7,8,4′-trihydroxyisoflavone (784THIF) were evaluated under hypoxic microenvironments. Molecular docking of these isomers with cyclooxygenase-2 (COX-2) and vascular endothelial growth factor receptor 2 (VEGFR2) was assessed. About 40 μM of 734THIF and 784THIF have the best effect on inhibiting the proliferation of HepG2 cells under hypoxic conditions. At a concentration of 40 μM, 784THIF significantly inhibits COX-2 expression in pre-hypoxia conditions compared to 734THIF, with an inhibition rate of 67.73%. Additionally, 40 μM 784THIF downregulates the expression of hypoxic, inflammatory, and metastatic-related proteins, regulates oxidative stress, and inhibits the expression of anti-apoptotic proteins. The uptake by HepG2 confirmed higher 784THIF level and slower degradation characteristics under post- or pre-hypoxic conditions. In conclusion, our results showed that 784THIF had better anti-cancer effects and cellular uptake than 734THIF.

Graphical Abstract

Keywords:

• Cellular uptake
• hepatocellular carcinoma
• hypoxia
• 734′-trihydroxyisoflavone
• 784′-trihydroxyisoflavone

Acknowledgements

The authors thank Professor Chih-Hua Tseng who provided 7,3′,4′-trihydroxyisoflavone and 7,8,4′-trihydroxyisoflavone..

Author contribution

Wen-Sheng Tzeng: Conceptualisation and Writing - Original Draft. Wei-Lin Teng: Methodology, Validation, Investigation, and Writing - Original Draft. Pao-Hsien Huang: Validation and Investigation. Feng-Lin Yen: Conceptualisation, Project administration, Writing- Reviewing and Editing. Yow-Ling Shiue: Conceptualisation. All authors provided the final approval of the version to be published and all authors agree to be accountable for all aspects of the work.

Disclosure statement

The authors report there are no competing interests to declare.

Data availability statement

The data that support the findings of this study are available from the corresponding author on reasonable request. Some data may not be made available because of privacy or ethical restrictions.

Additional information

Funding

This research was supported by the research project of Pingtung Christian Hospital (NO. PS109007).