title: Mechanistic insight into a novel synthetic cantharidin analogue in a leukaemia model.
abstract: Cantharidin isolated from Mylabris caraganae and other insects is used traditionally as an anti-cancer drug especially on hepatoma and leukaemia. Previously, we demonstrated that the novel synthetic cantharidin analogue CAN 032 possessed apoptotic activity on two human hepatoma cell lines Hep3B hepatocellular carcinoma and SK-Hep-1 liver adenocarcinoma. However, its underlying mechanistic action on cancer cells remained unclear. Herein, we furthered our work by making use of KG1a acute myelogenous leukaemia (AML) and K562 chronic myelogenous leukaemia (CML) as experimental models. As anticipated, both leukaemia cell lines were sensitive to the cytotoxic action of CAN 032. The activity of CAN 032 was both dose- and time-course-dependent. CAN 032 readily inhibited the colony formation potential of both leukaemia cell lines. KG1a AML treated with CAN032 decreased G1 phase cell population, mitochondrial membrane potential collapse, caspase 3 activation and hence DNA fragmentation. Pre-incubation of leukaemia cells with the general caspase inhibitor Z-VAD-FMK could partially reversed the apoptotic action of CAN 032. This result suggested that the caspase- dependent pathway is necessary for the apoptotic action of CAN 032. CAN 032 provides a new direction for novel drug discovery in experimental cancer therapy.
authors.affiliation: Cancer Drug Research and Development Centre, Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, P.R. China.
authors.forename: Stanton Hon Lung
authors.initials: SH
authors.lastname: Kok
authors.forename: Chung Hin
authors.initials: CH
authors.lastname: Chui
authors.forename: Wing Sze
authors.initials: WS
authors.lastname: Lam
authors.forename: Jien
authors.initials: J
authors.lastname: Chen
authors.forename: Fung Yi
authors.initials: FY
authors.lastname: Lau
authors.forename: Raymond Siu Ming
authors.initials: RS
authors.lastname: Wong
authors.forename: Gregory Yin Ming
authors.initials: GY
authors.lastname: Cheng
authors.forename: Wing Ka
authors.initials: WK
authors.lastname: Tang
authors.forename: Chor Hing
authors.initials: CH
authors.lastname: Cheng
authors.forename: Johnny Cheuk On
authors.initials: JC
authors.lastname: Tang
authors.forename: Albert Sun Chi
authors.initials: AS
authors.lastname: Chan
mesh_terms: D000328:Adult; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002193:Cantharidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor / Q000187:drug effects*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D007313:Insecta; D007951:Leukemia, Myeloid; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C514252:CAN 032; D004791:Enzyme Inhibitors; D013844:Thiazoles; D002193:Cantharidin