title: Altholactone induces apoptotic cell death in human colorectal cancer cells.
abstract: Resistance of colorectal cancer (CRC) to the available chemotherapy reveals the demand for identification of new anticancer agents. We evaluated the antitumour potential of altholactone, a naturally occurring bioactive compound isolated from Goniothalamus spp. (Annonaceae) hooks, against CRC cells. Antitumour activity of altholactone was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and the propidium iodide method. Apoptosis mediators involved were assessed using biochemical inhibitors and Western blotting analysis. Results revealed that altholactone induced varying degrees of apoptosis in CRC cells but not in normal fibroblasts. Dissection of the altholactone-induced apoptotic signalling pathway revealed that altholactone activated caspase-dependent and -independent apoptotic pathways. Activation of caspase-4 appeared to be the initiating event in the caspase-dependent apoptotic pathway. Pre-treatment of CRC cells with the antioxidant N-acetylcysteine (NAC) significantly inhibited activation of caspase-4 and altholactone-induced apoptosis. These results indicate that altholactone induces selective cytotoxicity against colon carcinoma cells and warrants further clinical evaluation.
authors: Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan. nizarm@just.edu.jo
authors: Nizar M
authors: NM
authors: Mhaidat
authors: Kalid K
authors: KK
authors: Abdul-Razzak
authors: Ahmad S
authors: AS
authors: Alkofahi
authors: Aseera M
authors: AM
authors: Alsarhan
authors: Ahmad N
authors: AN
authors: Aldaher
authors: Rick F
authors: RF
authors: Thorne
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D061945:Caspase Inhibitors; D053471:Caspases, Initiator / Q000378:metabolism; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000473:pathology; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D005347:Fibroblasts / Q000187:drug effects; D005663:Furans / Q000494:pharmacology*; D054335:Goniothalamus / Q000737:chemistry; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D018384:Oxidative Stress; D011419:Propidium / Q000737:chemistry; D011753:Pyrones / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013778:Tetrazolium Salts / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D061945:Caspase Inhibitors; D005663:Furans; D011753:Pyrones; D017382:Reactive Oxygen Species; D013778:Tetrazolium Salts; D013844:Thiazoles; C459359:altholactone; D011419:Propidium; C093516:CASP4 protein, human; D053471:Caspases, Initiator; C022616:thiazolyl blue; D000111:Acetylcysteine