Issue 1, 2021

Effect of naringenin and its combination with cisplatin in cell death, proliferation and invasion of cervical cancer spheroids

Abstract

The main treatment alternative for cervical cancer is cisplatin chemotherapy. However, the resistance of tumor cells to cisplatin, in addition to side effects, limits its use. The flavonoid naringenin has shown cytotoxic effects on tumor cells and may be considered as a coadjuvant in the treatment of cervical cancer. In the present study, the effect of naringenin on cell viability, cytotoxicity, proliferation, apoptosis and invasion was evaluated in HeLa spheroid cultures. Naringenin impaired the cell viability as indicated by low ATP levels and caused concentration- and time-dependent cytotoxicity via the loss of cell membrane integrity. Furthermore, it did not activate caspases 3, 7, 8, and 9, suggesting that the cytotoxic effect was by necrotic cell death instead of apoptosis. Additionally, proliferation in the G0/G1 phase of the cell cycle was inhibited. Cell invasion also decreased as time progressed. Later, we determined if naringenin could improve the anti-tumor effect of cisplatin. The combination of naringenin with low concentrations of cisplatin improved the effect of the drug by significantly decreasing cell viability, potentiating the induction of cytotoxicity and decreasing the invasive capacity of the spheroids. Since these effects are regulated by some key proteins, molecular docking results indicated the interaction of naringenin with RIP3 and MLKL, cyclin B and with matrix metalloproteases 2 and 9. The results showed the anti-tumor effect of naringenin on the HeLa spheroids and improved effect of the cisplatin at low concentrations in combination with naringenin, placing flavonoids as a potential adjuvant in the therapy against cervical cancer.

Graphical abstract: Effect of naringenin and its combination with cisplatin in cell death, proliferation and invasion of cervical cancer spheroids

Supplementary files

Article information

Article type
Paper
Submitted
25 Aug 2020
Accepted
30 Nov 2020
First published
22 Dez 2020
This article is Open Access
Creative Commons BY-NC license

RSC Adv., 2021,11, 129-141

Effect of naringenin and its combination with cisplatin in cell death, proliferation and invasion of cervical cancer spheroids

O. P. Martínez-Rodríguez, A. González-Torres, L. M. Álvarez-Salas, H. Hernández-Sánchez, B. E. García-Pérez, M. D. R. Thompson-Bonilla and M. E. Jaramillo-Flores, RSC Adv., 2021, 11, 129 DOI: 10.1039/D0RA07309A

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