title: Selective killing of cancer cells by beta -lapachone: direct checkpoint activation as a strategy against cancer.
abstract: Most chemotherapeutic drugs kill cancer cells by indirectly activating checkpoint-mediated apoptosis after creating nonselective damage to DNA or microtubules, which accounts for their toxicity toward normal cells. We seek to target cancer cells by directly activating checkpoint regulators without creating such damage. Here, we show that beta-lapachone selectively induces apoptosis in cancer cells without causing the death of nontransformed cells in culture. This unusual selectivity against cancer cells is preceded by activation of S-phase checkpoint and selective induction of E2F1, a regulator of checkpoint-mediated apoptosis. This study suggests direct checkpoint activation as a strategy against cancer.
authors.affiliation: Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
authors.forename: Youzhi
authors.initials: Y
authors.lastname: Li
authors.forename: Xiangao
authors.initials: X
authors.lastname: Sun
authors.forename: J Thomas
authors.initials: JT
authors.lastname: LaMont
authors.forename: Arthur B
authors.initials: AB
authors.lastname: Pardee
authors.forename: Chiang J
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D016923:Cell Death; D002455:Cell Division; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004396:Coloring Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005434:Flow Cytometry; D006801:Humans; D008954:Models, Biological; D009285:Naphthoquinones / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy*; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D009285:Naphthoquinones; D016160:Retinoblastoma Protein; D013778:Tetrazolium Salts; D013844:Thiazoles; D014157:Transcription Factors; C014638:beta-lapachone; C022616:thiazolyl blue