title: Apoptogenic activity of a synthetic cantharimide in leukaemia: implication on its structural activity relationship.
abstract: Cantharidin isolated from Mylabris caraganae and other insects has been used as an anti-cancer drug in China for many years. However, its toxicity on the renal system and suppression effect on bone marrow limits its usage clinically. A synthetic analogue of cantharidin (CAN 037) has been shown to have cytotoxic effect on the SK-Hep 1 hepatoma cell line but its underlying working principle remains undefined. Here we further report the action of CAN 037 on an acute myelogenous leukaemia (AML) cell line, KG1a. [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay was used to demonstrate the cytotoxicity of CAN 037 on KG1a cells. Morphological changes of CAN 037-treated leukaemia cells were recorded under an inverted microscope. Possible activation of caspase 3, 8 and 9 from KG1a cells was also investigated. KG1a AML cells were sensitive to CAN 037. Morphological changes including cell shrinkage and loss of colony formation ability were observed. Caspase 3, 8 and 9 activity was elevated, whereas pre-incubating the KG1a cells with the generic caspase inhibitor z-VAD-fmk could only partially reverse the CAN 037-induced cell death. In addition to the SK-Hep-1 hepatoma cell line, CAN 037 is also effective in inducing the death of KG1a AML cells in vitro. Apoptosis is involved in the action of CAN 037 including the activation of the caspase family. Caspase-dependent cell death pathway may be necessary but not essential in CAN 037-induced apoptosis of KG1a cells. Further consideration of the structural activity relationship of CAN 037 may provide opportunities to improve its therapeutic value.
authors.affiliation: State Key Laboratory of Chinese Medicine and Molecular Pharmacology, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, PR 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: Raymund 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: Ivy Tuang Ngo
authors.initials: IT
authors.lastname: Teo
authors.forename: Filly
authors.initials: F
authors.lastname: Cheung
authors.forename: Chor Hing
authors.initials: CH
authors.lastname: Cheng
authors.forename: Albert Sun Chi
authors.initials: AS
authors.lastname: Chan
authors.forename: Johnny Cheuk On
authors.initials: JC
authors.lastname: Tang
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects*; D002193:Cantharidin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000633:toxicity*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003601:Cytotoxicity Tests, Immunologic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D013329:Structure-Activity Relationship
chemical_list: D020169:Caspases; D002193:Cantharidin