title: α-Tomatine-mediated anti-cancer activity in vitro and in vivo through cell cycle- and caspase-independent pathways.
abstract: α-Tomatine, a tomato glycoalkaloid, has been reported to possess antibiotic properties against human pathogens. However, the mechanism of its action against leukemia remains unclear. In this study, the therapeutic potential of α-tomatine against leukemic cells was evaluated in vitro and in vivo. Cell viability experiments showed that α-tomatine had significant cytotoxic effects on the human leukemia cancer cell lines HL60 and K562, and the cells were found to be in the Annexin V-positive/propidium iodide-negative phase of cell death. In addition, α-tomatine induced both HL60 and K562 cell apoptosis in a cell cycle- and caspase-independent manner. α-Tomatine exposure led to a loss of the mitochrondrial membrane potential, and this finding was consistent with that observed on activation of the Bak and Mcl-1 short form (Mcl-1s) proteins. Exposure to α-tomatine also triggered the release of the apoptosis-inducing factor (AIF) from the mitochondria into the nucleus and down-regulated survivin expression. Furthermore, α-tomatine significantly inhibited HL60 xenograft tumor growth without causing loss of body weight in severe combined immunodeficiency (SCID) mice. Immunohistochemical test showed that the reduced tumor growth in the α-tomatine-treated mice was a result of increased apoptosis, which was associated with increased translocation of AIF in the nucleus and decreased survivin expression ex vivo. These results suggest that α-tomatine may be a candidate for leukemia treatment.
authors.affiliation: Phamacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Min-Wu
authors.initials: MW
authors.lastname: Chao
authors.forename: Chun-Han
authors.initials: CH
authors.lastname: Chen
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chang
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Shiow-Lin
authors.initials: SL
authors.lastname: Pan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D020014:K562 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D014053:Tomatine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051033:Apoptosis Inducing Factor; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; C484751:alpha-tomatine; D014053:Tomatine; D020169:Caspases