title: A novel synthetic C-1 analogue of 7-deoxypancratistatin induces apoptosis in p53 positive and negative human colorectal cancer cells by targeting the mitochondria: enhancement of activity by tamoxifen.
abstract: The natural compound pancratistatin (PST), isolated from the Hymenocallis littoralis plant, specifically induces apoptosis in many cancer cell lines. Unlike many other chemotherapeutics, PST is not genotoxic and has minimal adverse effects on non-cancerous cells. However, its availability for preclinical and clinical work is limited due to its low availability in its natural source and difficulties in its chemical synthesis. Several synthetic analogues of 7-deoxypancratistatin with different modifications at C-1 were synthesized and screened for apoptosis inducing activity in human colorectal cancer (CRC) cells. We found that a C-1 acetoxymethyl derivative of 7-deoxypancratistatin, JC-TH-acetate-4 (JCTH-4), was effective in inducing apoptosis in both p53 positive (HCT 116) and p53 negative (HT-29) human CRC cell lines, demonstrating similar efficacy to that of natural PST. JCTH-4 was able to decrease mitochondrial membrane potential (MMP), increase levels of reactive oxygen species in isolated mitochondria, cause release of the apoptogenic factor cytochrome c (Cyto c) from isolated mitochondria, and induce autophagy in HCT 116 and HT-29 cells. Interestingly, when JCTH-4 was administered with tamoxifen (TAM), there was an enhanced effect in apoptosis induction, reactive oxygen species (ROS) production and Cyto c release by isolated mitochondria, and autophagic induction by CRC cells. Minimal toxicity was exhibited by a normal human fetal fibroblast (NFF) and a normal colon fibroblast (CCD-18Co) cell line. Hence, JCTH-4 is a novel compound capable of selectively inducing apoptosis and autophagy in CRC cells alone and in combination with TAM and may serve as a safer and more effective alternative to current cancer therapies.
authors.affiliation: Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, ON, N9B 3P4, Canada.
authors.forename: Dennis
authors.initials: D
authors.lastname: Ma
authors.forename: Phillip
authors.initials: P
authors.lastname: Tremblay
authors.forename: Kevinjeet
authors.initials: K
authors.lastname: Mahngar
authors.forename: Pardis
authors.initials: P
authors.lastname: Akbari-Asl
authors.forename: Jonathan
authors.initials: J
authors.lastname: Collins
authors.forename: Tomas
authors.initials: T
authors.lastname: Hudlicky
authors.forename: James
authors.initials: J
authors.lastname: McNulty
authors.forename: Siyaram
authors.initials: S
authors.lastname: Pandey
mesh_terms: D047151:Amaryllidaceae Alkaloids / Q000494:pharmacology*; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C418326:7-deoxypancratistatin; D047151:Amaryllidaceae Alkaloids; D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007546:Isoquinolines; C574667:JCTH-4; D017382:Reactive Oxygen Species; D020845:Selective Estrogen Receptor Modulators; D016159:Tumor Suppressor Protein p53; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D013629:Tamoxifen; D020169:Caspases