title: Apoptotic activity of a novel synthetic cantharidin analogue on hepatoma cell lines.
abstract: Cantharidin isolated from Mylabris caraganae and other insects is used traditionally as an anti-cancer drug. However, its toxicity on the renal system and suppression effect on bone marrow limits its clinical usage. Recently, we have synthesized two cantharidin analogues, CAN 029 (compound 2) and CAN 030 (compound 3). Although both showed an apoptotic induction ability on cancer cells, they were still relatively toxic towards non-malignant haematological disordered bone marrow. Based on the principle structure of cantharidin, we have further chemically synthesized another analogue, CAN 032. The cytotoxic activity of this analogue was screened on both Hep3B hepatocellular carcinoma and SK-Hep-1 liver adenocarcinoma cell lines by [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] (MTS) assay. Morphological changes of hepatoma cell lines were recorded under an inverted microscope. The possible tolerance of these analogues was further investigated using non-malignant haematological bone marrow primary culture. CAN 032 showed a significant cytotoxic response on both hepatoma cell lines in which the potencies were comparable to that of cantharidin. Further screening on the bone marrow tolerance revealed that compound CAN 032 showed a relatively less toxic effect. Phase contrast microscopy demonstrated that cell shrinkage, rounding, loss of adherent property and loss of colony-formation ability were induced. The dose-dependence of the response of CAN 032 on Hep3B was further assayed by DNA fragmentation gel electrophoresis. The G1 peak of Hep3B cells was reduced. Chemically synthesized CAN 032 may provide an improved therapeutic advantage over traditional cantharidin.
authors.affiliation: Cancer Drug and Development Centre, 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: Gregory Yin Ming
authors.initials: GY
authors.lastname: Cheng
authors.forename: Raymond Siu Ming
authors.initials: RS
authors.lastname: Wong
authors.forename: Paul Po San
authors.initials: PP
authors.lastname: Lai
authors.forename: Thomas Wai Tong
authors.initials: TW
authors.lastname: Leung
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; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D002193:Cantharidin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D048429:Cell Size / Q000187:drug effects; D053938:DNA Fragmentation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008858:Microscopy, Phase-Contrast; D015394:Molecular Structure; D013844:Thiazoles / Q000138:chemical synthesis / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; C514252:CAN 032; D013844:Thiazoles; D002193:Cantharidin