title: Sensitivity of apoptosis-resistant colon cancer cells to tanshinones is mediated by autophagic cell death and p53-independent cytotoxicity.
abstract: BACKGROUND
  Multidrug resistance (MDR) develops in nearly all patients with colon cancer. The reversal of MDR plays an important role in the success of colon cancer chemotherapy. One of the commonest mechanisms conferring MDR is the suppression of apoptosis in cancer cells.
  
  
  OBJECTIVE
  This study investigated the sensitivity of cryptotanshinone (CTS) and dihydrotanshinone (DTS), two lipophilic tanshinones from a traditional Chinese medicine Salvia miltiorrhiza, in apoptosis-resistant colon cancer cells.
  
  
  METHODS
  Cell viability was measured by MTT assay. Cell cycle distribution and apoptosis were determined by flow cytometry. Protein levels were analyzed by western blot analysis. The formation of acidic vesicular organelles was visualized by acridine orange staining.
  
  
  RESULTS
  Experimental results showed that multidrug-resistant colon cancer cells SW620 Ad300 were sensitive to both CTS and DTS in terms of cell death, but with less induction of apoptosis when compared with the parental cells SW620, suggesting that other types of cell death such as autophagy could occur. Indeed, the two tanshinones induced more LC3B-II accumulation in SW620 Ad300 cells with increased autophagic flux. More importantly, cell viability was increased after autophagy inhibition, indicating that autophagy induced by the two tanshinones was pro-cell death. Besides, the cytotoxic actions of the two tanshinones were p53-independent, which could be useful in inhibiting the growth of apoptosis-resistant cancer cells with p53 defects.
  
  
  CONCLUSIONS
  The current findings strongly indicate that both CTS and DTS could inhibit the growth of apoptosis-resistant colon cancer cells through induction of autophagic cell death and p53-independent cytotoxicity. They are promising candidates to be further developed as therapeutic agents in the adjuvant therapy for colon cancer, especially for the apoptosis-resistant cancer types.
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China. Electronic address: taohu1985@hotmail.com.
authors.forename: Tao
authors.initials: T
authors.lastname: Hu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, 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, 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, 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, Hong Kong, China.
authors.forename: Ruby L Y
authors.initials: RL
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Mingxing
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Anesthesia and Intensive Care, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.affiliation: School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Kenneth K W
authors.initials: KK
authors.lastname: To
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000473:pathology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D010616:Phenanthrenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D045784:Abietanes; D004365:Drugs, Chinese Herbal; D010616:Phenanthrenes; D016159:Tumor Suppressor Protein p53; C021751:tanshinone; C037886:cryptotanshinone
keywords: Apoptosis resistance; Autophagic cell death; Colon cancer; Cryptotanshinone; Dihydrotanshinone; p53-independent cytotoxicity