Novel combination of sorafenib and biochanin-A synergistically enhances the anti-proliferative and pro-apoptotic effects on hepatocellular carcinoma cells

Abstract

Sorafenib (SOR) is the first-line treatment for hepatocellular carcinoma (HCC). However, its use is hindered by the recently expressed safety concerns. One approach for reducing SOR toxicity is to use lower doses in combination with other less toxic agents. Biochanin-A (Bio-A), a promising isoflavone, showed selective toxicity to liver cancer cells. We postulated that combining SOR and Bio-A could be synergistically toxic towards HCC cells. We further evaluated the underlying mechanism. Cytotoxicity assay was performed to determine the IC50 of Bio-A and SOR in HepG2, SNU-449 and Huh-7 cells. Then, combination index in HepG2 was evaluated using Calcusyn showing that the concurrent treatment with lower concentrations of SOR and Bio-A synergistically inhibited cell growth. Our combination induced significant arrest in pre-G and G0/G1 cell cycle phases and decrease in cyclin D1 protein level. Concomitantly, SOR/Bio-A reduced Bcl-2/Bax ratio. Furthermore, this co-treatment significantly increased caspase-3 & -9 apoptotic markers, while decreased anti-apoptotic and proliferative markers; survivin and Ki-67, respectively. Active caspase-3 in HepG2, SNU-449 and Huh-7 confirmed our synergism hypothesis. This study introduces a novel combination, where Bio-A synergistically enhanced the anti-proliferative and apoptotic effects of SOR in HCC cells, which could serve as a potential effective regimen for treatment.

Neurochemical and Behavior Deficits in Rats with Iron and Rotenone Co-treatment: Role of Redox Imbalance and Neuroprotection by Biochanin A

“…Moreover, biochanin A may improve lipid profile as a peroxisome proliferator-activated receptor gamma (PPARγ) agonist and provide beneficial effects on metabolic syndrome such as hyperglycaemia (Wang et al, 2014 ; Park et al, 2016 ). It has been reported that biochanin A may be useful in the prevention and treatment of breast cancer, prostate cancer and hepatocellular carcinoma (Sun et al, 1998 ; Khan et al, 2011 ; Chen J. et al, 2015 ; Youssef et al, 2016 ). In addition, biochanin A was shown to exert neuroprotective effect in neurodegenerative diseases via inhibiting microglia activation or attenuating L-glutamate cytotoxicity (Chen et al, 2007 ; Tan et al, 2013 ; Wang J. et al, 2016 ).…”

CISNE: An accurate description of dose-effect and synergism in combination therapies

“…We have made the new implementation freely available through the use of our new program CISNE (Code for the Identification of Synergism Numerically Efficient) 27 . Therefore, our new method keeps the generality of a theory that has been widely validated and applied to a variety of biological systems 28 , but, at the same time, it represents an improvement on the implementation of that theory. This is because it allows to determine accurately possible synergistic effects in biological systems within a wide range of characteristic parameters where the previous methods failed.…”

In vitro and in vivo evaluation of novel NGR-modified liposomes containing brucine

“…21 On the 8th day, the kunming mice were randomly assigned to four groups (12 animals per group): group 1 was administered a 5% glucose injection, group 2 was administered free brucine, group 3 was administered brucine liposomes and group 4 was administered NGR-brucine liposomes. The brucine formulations were all injected via the tail vein on days 8, 10, 12 and 14, at a dose of 15 mg/kg.…”