In vitro assessment of renal toxicity and inflammatory events of two protein phosphatase inhibitors cantharidin and nor-cantharidin.
In China, cantharidin has been reported to be active against various human cancers, but with severe side effects such as nephrotoxicity. In order to reduce this toxicity, its demethylated analogue nor-cantharidin has been synthesized and used in cancer therapy, but with only few data regarding safety assessment. The aim of this study was to compare the in vitro effects of cantharidin and nor-cantharidin on renal toxicity and on inflammatory events associated with tumoural process where protein phosphatases could be involved (energy status, prostanoid production, glutathione and nitrite contents) on RAW 264.7 and LLC-PK1 cells. In macrophages, both cantharidin and nor-cantharidin decreased cell viability, in a concentration- and time-dependent manner. However, IC50 was lower with cantharidin than with nor-cantharidin. These two drugs significantly decreased the ATP level after 24 hr incubation. However, ATP decreased much more with cantharidin (up to 4 times) than with nor-cantharidin. When control macrophages were activated with lipopolysaccharide+interferon-gamma for 24 hr a significant increase in nitrite content and in prostanoids were observed. Addition of either drug decreased nitrite generation and prostanoids, however these decreases were greater with cantharidin than with nor-cantharidin. In LLC-PK1 cells, incubated with either cantharidin or nor-cantharidin, our results show significant differences between the two drugs, similar to those observed in peritoneal macrophages, except for GSH content with opposite variations in both cells. We provide a better understanding of the various mechanisms of cantharidin side effects, allowing an easier comparison with nor-cantharidin which could be an attractive therapeutic potential in cancer chemotherapy in western countries.
Massicot
France
F
Laboratory of Toxicology, Faculty of Pharmaceutical and Biological Sciences, University René Descartes-Paris 5, 75270 Paris Cedex 06, France. france.massicot@univ-paris5.fr
Dutertre-Catella
Hélène
H
Pham-Huy
Chuong
C
Liu
Xu-Hui
XH
Duc
Huynh Thien
HT
Warnet
Jean-Michel
JM
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000633:toxicity*; D002193:Cantharidin / Q000633:toxicity*; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011464:Epoprostenol / Q000096:biosynthesis; D005978:Glutathione / Q000378:metabolism; D007249:Inflammation / Q000473:pathology; D007509:Irritants / Q000633:toxicity*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000473:pathology*; D018374:LLC-PK1 Cells; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D009569:Nitric Oxide / Q000096:biosynthesis; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors*; D011453:Prostaglandins / Q000096:biosynthesis; D013552:Swine; D013929:Thromboxane B2 / Q000096:biosynthesis
D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; D007509:Irritants; D008070:Lipopolysaccharides; D011453:Prostaglandins; D009569:Nitric Oxide; D013929:Thromboxane B2; C069741:norcantharidin; D000255:Adenosine Triphosphate; D011464:Epoprostenol; D010749:Phosphoprotein Phosphatases; D005978:Glutathione; D002193:Cantharidin