title: Novel phyto-derivative BRM270 inhibits hepatocellular carcinoma cells proliferation by inducing G2/M phase cell cycle arrest and apoptosis in xenograft mice model.
abstract: Hepatocellular carcinoma (HCC) is a major threat to human health worldwide and development of novel antineoplastic drug is demanding task. BRM270 is a proprietary combination of traditional medicinal herbs, has been shown to be effective against a wide range of stem-like cancer initiating cells (SLCICs). However, the underlying mechanism and antitumor efficacy of BRM270 in human hepatocellular carcinoma (HCC) cells have not been well elucidated till date. Here we studied the tumoricidal effect of BRM270 on human-CD133+expressing stem-like HepG-2 and SNU-398 cells. Gene expression profiling by qPCR and specific cellular protein expressions was measured using immunocytochemistry/western blot analysis. In vivo efficacy of BRM270 has been elucidated in the SLCICs induced xenograft model. In addition, 2DG-(2-Deoxy-d-Glucose) optical-probe guided tumor monitoring was performed to delineate the size and extent of metastasized tumor. Significant (P<0.05) induction of Annexin-V positive cell population and dose-dependent upregulation of caspase-3 confirmed apoptotic cell death by pre/late apoptosis. In addition, bright field and fluorescence microscopy of treated cells revealed apoptotic morphology and DNA fragmentation in Hoechst33342 staining. Levels of c-Myc, Bcl-2 and c-Jun as invasive potential apoptotic marker were detected using qPCR/Western blot. Moreover, BRM270 significantly (P<0.05) increased survival rate that observed by Kaplan-Meier log rank test. In conclusion, these results indicate that BRM270 can effectively inhibit proliferation and induce apoptosis in hepatoma cells by down-regulating CyclinD1/Bcl2 mediated c-Jun apoptotic pathway.
authors.affiliation: Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology and Advance Next Generation Convergence Technology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar Mongre
authors.affiliation: Division of Veterinary Medicine, Faculty of Veterinary Science & Animal Husbandry, Sher-e-Kashmir University of Agricultural Sciences & Technology, R.S. Pura, Jammu, India.
authors.forename: Neelesh
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Veterinary and Animal Husbandry Extension Education, Guru Angad Dev I Veterinary and Animal Sciences University, Ludhiana 141004, India.
authors.forename: Simrinder
authors.initials: S
authors.lastname: Singh Sodhi
authors.affiliation: Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology and Advance Next Generation Convergence Technology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.
authors.forename: Mrinmoy
authors.initials: M
authors.lastname: Ghosh
authors.affiliation: Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology and Advance Next Generation Convergence Technology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar Singh
authors.affiliation: Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology and Advance Next Generation Convergence Technology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.
authors.forename: Nameun
authors.initials: N
authors.lastname: Kim
authors.affiliation: BRM Institute, Seoul, Republic of Korea.
authors.forename: Yang Ho
authors.initials: YH
authors.lastname: Park
authors.affiliation: BRM Institute, Seoul, Republic of Korea.
authors.forename: Young Gyu
authors.initials: YG
authors.lastname: Shin
authors.affiliation: CHA Cancer Institute, CHA University, Seoul, Republic of Korea.
authors.forename: Sung Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology and Advance Next Generation Convergence Technology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Jiao Jiao
authors.affiliation: Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology and Advance Next Generation Convergence Technology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea.
authors.forename: Do Luong
authors.initials: DL
authors.lastname: Huynh
authors.affiliation: Laboratory of Animal Genetic Engineering and Stem Cell Biology, Department of Animal Biotechnology and Advance Next Generation Convergence Technology, Faculty of Biotechnology, Jeju National University, Jeju, Republic of Korea. Electronic address: dkjeong@jejunu.ac.kr.
authors.forename: Dong Kee
authors.initials: DK
authors.lastname: Jeong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics; D053148:Caspase 3 / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D056945:Hep G2 Cells; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D051028:bcl-2-Associated X Protein / Q000235:genetics
chemical_list: D004365:Drugs, Chinese Herbal; C587679:Jiedu Xiaozheng Yin; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053148:Caspase 3
keywords: 2DG; Apoptosis; BRM270; Naturaceutics; Stem like cancer initiating cells