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-(4,5dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4sulfophenyl)-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.

Molecular biology of cantharidin in cancer cells

“…The ability of Bcl-2 to protect against cantharidin-induced apoptosis seen in this study indicates that DNA damage-triggered mitochondrial pathway is involved. Mitochondrial dysfunction and activation of caspases involved in the intrinsic (mitochondrial) pathway of apoptosis have also been detected in other cell types after cantharidin or norcantharidin treatment [69,70,76-83]. A role of the Fas/CD95 extrinsic pathway of apoptosis has been reported [84], but not confirmed by other authors [85].…”

The effect of cantharidins on leukemic stem cells

“…In future studies we will examine the pharmacokinetic profile and tissue penetration of C and NC, since these are the most common causes of in vivo drug failure after primary in vitro success. Further chemical modifications and formulations of cantharidin are desirable, since molecules may be developed with reduced toxicity and retention of antitumor and target efficacy as previously demonstrated 31, 71–74. Since norcantharidin is described to reduce multidrug resistance39 and to enhance radiosensitivity,75 combinations with agents with known efficacy in AML are also warranted.…”

Crystal Structures of (3R,3aR,4S,7R,7aS)-3-(Allyloxy)hexahydro-4,7-epoxyisobenzofuran-1(3H)-one and (3S,3aR,4S,7R,7aS)-3-((E)-But-2-en-1-yloxy)hexahydro-4,7-epoxyisobenzofuran-1(3H)-one: Confirmation of NMR Predicted Stereocentre Geometry

“…Over the past decade we and others have expended considerable effort in the development of a better understanding of the key structural features that are required for both protein phosphatase inhibition and the anti-cancer effects of these analogues [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. In the course of one such study we re-discovered, Novo-6 (3) (Fig.…”