title: ML-7 amplifies the quinocetone-induced cell death through akt and MAPK-mediated apoptosis on HepG2 cell line.
abstract: The study aims at evaluating the combination of the quinocetone and the ML-7 in preclinical hepatocellular carcinoma models. To this end, the effect of quinocetone and ML-7 on apoptosis induction and signaling pathways was analyzed on HepG2 cell lines. Here, we report that ML-7, in a nontoxic concentration, sensitized the HepG2 cells to quinocetone-induced cytotoxicity. Also, ML-7 profoundly enhances quinocetone-induced apoptosis in HepG2 cell line. Mechanistic investigations revealed that ML-7 and quinocetone act in concert to trigger the cleavage of caspase-8 as well as Bax/Bcl-2 ratio up-regulation and subsequent cleavage of Bid, capsases-9 and -3. Importantly, ML-7 weakened the quinocetone-induced Akt pathway activation, but strengthened the phosphorylation of p-38, ERK and JNK. Further treatment of Akt activator and p-38 inhibitor almost completely abolished the ML-7/quinocetone-induced apoptosis. In contrast, the ERK and JNK inhibitor aggravated the ML-7/quinocetone-induced apoptosis, indicating that the synergism critically depended on p-38 phosphorylation and HepG2 cells provoke Akt, ERK and JNK signaling pathways to against apoptosis. In conclusion, the rational combination of quinocetone and ML-7 presents a promising approach to trigger apoptosis in hepatocellular carcinoma, which warrants further investigation.
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Shen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Sijun
authors.initials: S
authors.lastname: Deng
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Chongshan
authors.initials: C
authors.lastname: Dai
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Shusheng
authors.initials: S
authors.lastname: Tang
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Xiayun
authors.initials: X
authors.lastname: Yang
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Daowen
authors.initials: D
authors.lastname: Li
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Kena
authors.initials: K
authors.lastname: Zhao
authors.affiliation: a Department of Pharmacology and Toxicology , College of Veterinary Medicine, China Agricultural University , Haidian , Beijing , PR China.
authors.forename: Xilong
authors.initials: X
authors.lastname: Xiao
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001381:Azepines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D002470:Cell Survival / Q000187:drug effects*; D004359:Drug Therapy, Combination; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D009281:Naphthalenes / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011810:Quinoxalines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*
chemical_list: D001381:Azepines; D009281:Naphthalenes; D011810:Quinoxalines; C502851:quinocetone; C070571:ML 7; D051057:Proto-Oncogene Proteins c-akt; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Akt; HepG2; MAPK; ML-7; apoptosis; quinocetone