title: Dihydrotanshinone I induced apoptosis and autophagy through caspase dependent pathway in colon cancer.
abstract: BACKGROUND
  Dihydrotanshinone I (DHTS) was previously reported to exhibit the most potent anti-cancer activity among several tanshinones in colon cancer cells. Its cytotoxic action was reactive oxygen species (ROS) dependent but p53 independent.
  
  
  OBJECTIVE
  To further study the anti-cancer activity of DHTS and its molecular mechanisms of action in colon cancer both in vitro and in vivo.
  
  
  METHODS
  Caspase activity was detected by fluorescence assay. Apoptosis was detected by flow cytometry and TUNEL assay. Protein levels were analyzed by western blotting. Knockdown of target gene was achieved by siRNA transfection. Formation of LC3B puncta and activation of caspase-3 were detected by confocal fluorescence microscope. In vivo anti-colon cancer activity of DHTS was observed in xenograft tumors in NOD/SCID mice.
  
  
  RESULTS
  Anti-colon cancer activity of DHTS by inducing apoptosis and autophagy was observed both in vitro and in vivo. Mitochondria mediated caspase dependent pathway was essential in DHTS-induced cytotoxicity. The apoptosis induced by DHTS was suppressed by knockdown of apoptosis inducing factor (AIF), inhibition of caspase-3/9 but was increased after knockdown of caspase-2. Meantime, knockdown of caspase-2, pretreatment with Z-VAD-fmk or NAC (N-Acety-L-Cysteine) efficiently inhibited the autophagy induced by DHTS. A crosstalk between cytochrome c and AIF was also reported.
  
  
  CONCLUSIONS
  DHTS-induced caspase and ROS dependent apoptosis and autophagy were mediated by mitochondria in colon cancer. DHTS could be a promising leading compound for the development of anti-tumor agent or be developed as an adjuvant drug for colon cancer therapy.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China. Electronic address: wanglinster@gmail.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China.
authors.forename: Ruby Lok-Yi
authors.initials: RL
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, NT, Hong Kong, China.
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
authors.affiliation: Department of Anaesthesia and Intensive Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D001343:Autophagy; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D045784:Abietanes; D017382:Reactive Oxygen Species; C021751:tanshinone; D020169:Caspases
keywords: Apoptosis; Autophagy; Caspase; Colon cancer; Dihydrotanshinone I; Dihydrotanshinone I (PubChem CID: 11425923); Mitochondria