title: 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.
authors.affiliation: The American University in Cairo, New Cairo, 11835 Egypt.|Okinawa Institute of Science and Technology Graduate University, OIST, Okinawa, 904-0495 Japan.
authors.forename: Mohieldin M
authors.initials: MM
authors.lastname: Youssef
authors.affiliation: Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt.
authors.forename: Mai F
authors.initials: MF
authors.lastname: Tolba
authors.affiliation: The American University in Cairo, New Cairo, 11835 Egypt.
authors.forename: Noha N
authors.initials: NN
authors.lastname: Badawy
authors.affiliation: Okinawa Institute of Science and Technology Graduate University, OIST, Okinawa, 904-0495 Japan.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Liu
authors.affiliation: Immunology Department, Theodor-Bilharz Research Institute (TBRI), Giza, 12411 Egypt.
authors.forename: Eman
authors.initials: E
authors.lastname: El-Ahwany
authors.affiliation: Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt.
authors.forename: Amani E
authors.initials: AE
authors.lastname: Khalifa
authors.affiliation: The American University in Cairo, New Cairo, 11835 Egypt.
authors.forename: Suher
authors.initials: S
authors.lastname: Zada
authors.affiliation: Pharmacology and Toxicology Department, Faculty of Pharmacy, Ain-Shams University, Cairo, 11566 Egypt.
authors.forename: Ashraf B
authors.initials: AB
authors.lastname: Abdel-Naim
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D019833:Genistein / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D000077157:Sorafenib
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D019833:Genistein; C004541:biochanin A