In vitro Assessment of Renal Toxicity and Inflammatory Events of Two Protein Phosphatase Inhibitors Cantharidin and Nor‐Cantharidin*
- 24 January 2005
- journal article
- Published by Wiley in Basic & Clinical Pharmacology & Toxicology
- Vol. 96 (1), 26-32
- https://doi.org/10.1111/j.1742-7843.2005.pto960104.x
Abstract
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‐γ 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.This publication has 57 references indexed in Scilit:
- Macrophage colony‐stimulating factor‐dependent macrophage proliferation is mediated through a calcineurin‐independent but immunophilin‐dependent mechanism that mediates the activation of external regulated kinasesEuropean Journal of Immunology, 2003
- Induction of apoptosis by norcantharidin in human colorectal carcinoma cell lines: involvement of the CD95 receptor/ligandZeitschrift für Krebsforschung und Klinische Onkologie, 2002
- Involvement of ERK and Protein Tyrosine Phosphatase Signaling Pathways in EGCG-Induced Cyclooxygenase-2 Expression in Raw 264.7 CellsBiochemical and Biophysical Research Communications, 2001
- Protein Tyrosine Phosphatase φ Regulates Paxillin Tyrosine Phosphorylation and Mediates Colony-Stimulating Factor 1-Induced Morphological Changes in MacrophagesMolecular and Cellular Biology, 2001
- Anhydride modified cantharidin analogues: synthesis, inhibition of protein phosphatases 1 and 2A and anticancer activityBioorganic & Medicinal Chemistry Letters, 2000
- Effects of norcantharidin, a protein phosphatase type-2A inhibitor, on the growth of normal and malignant haemopoietic cellsEuropean Journal of Cancer, 1995
- Cantharidin, another natural toxin that inhibits the activity of serine/threonine protein phosphatases types 1 and 2AFEBS Letters, 1993
- Antitumor Imide Derivatives of 7-Oxabicyclo[2.2.1]heptane-2,3-dimethyl-2,3-dicarboxylic AcidJournal of Pharmaceutical Sciences, 1989
- Functional macrophage cell lines transformed by abelson leukemia virusCell, 1978
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976