Mechanistic insight into a novel synthetic cantharidin analogue in a leukaemia model.
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.
Kok
Stanton Hon Lung
SH
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.
Chui
Chung Hin
CH
Lam
Wing Sze
WS
Chen
Jien
J
Lau
Fung Yi
FY
Wong
Raymond Siu Ming
RS
Cheng
Gregory Yin Ming
GY
Tang
Wing Ka
WK
Cheng
Chor Hing
CH
Tang
Johnny Cheuk On
JC
Chan
Albert Sun Chi
AS
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*
D000970:Antineoplastic Agents; C514252:CAN 032; D004791:Enzyme Inhibitors; D013844:Thiazoles; D002193:Cantharidin