title: Platycodin D, a metabolite of Platycodin grandiflorum, inhibits highly metastatic MDA-MB-231 breast cancer growth in vitro and in vivo by targeting the MDM2 oncogene.
abstract: The objective of the present study was to explore the in vitro and in vivo anticancer effects of Platycodin D (PD), derived from Platycodin grandiflorum, on highly metastatic MDA-MB-231 breast cancer cells. Using the MTT assay, we found that PD inhibited MDA-MB-231 cell growth in a concentration-dependent manner, with an IC50 value of 7.77±1.86 µM. Further studies showed that PD had anti-proliferative effects and induced cell cycle arrest in the G0/G1 phase. To explore the detailed mechanism(s) by which PD suppressed MDA-MB-231 cell growth, western blot analyses were used to detect the expression levels of proteins related to cell proliferation and survival. The data showed that PD decreased the expression of proteins related to the G0/G1 phases, downregulated the protein expression of MDM2, MDMX, and mutant p53, and increased the expression levels of p21 and p27 in vitro. We verified the effects of PD on the expression of MDM2, MDMX, mutant p53, p21 and p27 using a pcDNA3-Flag-MDM2 plasmid and MDM2 siRNA transfection, and found that PD inhibited MDA-MB-231 cell viability by targeting MDM2 and mutant p53. Compared with the corresponding parental cells, the cells with siRNA-MDM2 transfection had a greater decrease in cell viability and proliferation, while those with pcDNA3-MDM2 plasmid transfection did not show any increase in the effects of PD. We also established a MDA-MB-231 xenograft model in BALB/c nude mice, and found that PD significantly inhibited the growth of MDA-MB-231 xenograft tumors in these mice. The expression levels of various proteins in the tumor tissue exhibited changes similar to those observed in vitro. These findings indicate that PD exerted in vitro and in vivo anticancer effects against MDA-MB-231 breast cancer cells, that PD is a potential MDM2/MDMX inhibitor, and that the anticancer effects of PD were likely associated with its inhibition of these proteins. Our observations help to identify a mechanism by which PD functions as an anti-breast cancer agent.
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Zong-Liang
authors.initials: ZL
authors.lastname: Lu
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Hai-Lan
authors.initials: HL
authors.lastname: Sun
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Nutrition, Daping Hospital and Research Institute of Surgery, Third Military Medical University, Chongqing 400042, P.R. China.
authors.forename: Hong-Xia
authors.initials: HX
authors.lastname: Xu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009857:Oncogenes / Q000187:drug effects*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D012503:Saponins / Q000378:metabolism* / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D012503:Saponins; D014315:Triterpenes; D016159:Tumor Suppressor Protein p53; C008936:platycodin; C108953:platycodin D; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2