Synergistic effect of fisetin combined with sorafenib in human cervical cancer HeLa cells through activation of death receptor-5 mediated caspase-8/caspase-3 and the mitochondria-dependent apoptotic pathway.

Abstract

Combining antitumor agents with bioactive compounds is a potential strategy for improving the effect of chemotherapy on cancer cells. The goal of this study was to elucidate the antitumor effect of the flavonoid, fisetin, combined with the multikinase inhibitor, sorafenib, against human cervical cancer cells in vitro and in vivo. The combination of fisetin and sorafenib synergistically induced apoptosis in HeLa cells, which is accompanied by a marked increase in loss of mitochondrial membrane potential. Apoptosis induction was achieved by caspase-3 and caspase-8 activation which increased the ratio of Bax/Bcl-2 and caused the subsequent cleavage of PARP level while disrupting the mitochondrial membrane potential in HeLa cells. Decreased Bax/Bcl-2 ratio level and mitochondrial membrane potential were also observed in siDR5-treated HeLa cells. In addition, in vivo studies revealed that the combined fisetin and sorafenib treatment was clearly superior to sorafenib treatment alone using a HeLa xenograft model. Our study showed that the combination of fisetin and sorafenib exerted better synergistic effects in vitro and in vivo than either agent used alone against human cervical cancer, and this synergism was based on apoptotic potential through a mitochondrial- and DR5-dependent caspase-8/caspase-3 signaling pathway. This combined fisetin and sorafenib treatment represents a novel therapeutic strategy for further clinical developments in advanced cervical cancer.

• Authors: Ming-Te Lin, Chia-Liang Lin, Tzu-Yu Lin, Chun-Wen Cheng, Shun-Fa Yang, Chu-Liang Lin, Chih-Chien Wu, Yi-Hsien Hsieh, Jen-Pi Tsai
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 37 Issue 5 Pg. 6987-96 (May 2016) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 26662956 (Publication Type: Journal Article)

Chemical References

• Flavonoids
• Flavonols
• Phenylurea Compounds
• Receptors, TNF-Related Apoptosis-Inducing Ligand
• Niacinamide
• Sorafenib
• Caspase 3
• Caspase 8
• fisetin

Topics

• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Caspase 8 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Disease Models, Animal
• Drug Synergism
• Female
• Flavonoids (pharmacology)
• Flavonols
• HeLa Cells
• Humans
• Membrane Potential, Mitochondrial (drug effects)
• Mitochondria (drug effects, metabolism)
• Niacinamide (analogs & derivatives, pharmacology)
• Phenylurea Compounds (pharmacology)
• Receptors, TNF-Related Apoptosis-Inducing Ligand (agonists)
• Signal Transduction (drug effects)
• Sorafenib
• Tumor Burden (drug effects)
• Uterine Cervical Neoplasms (genetics, metabolism, pathology)
• Xenograft Model Antitumor Assays