Cantharidin (CAN), a compound derived from Lytta vesicatoria reveals profound cytotoxicity against tumor cells. We investigated molecular mechanisms that determine the cellular response to CAN. Alkaline and neutral comet assays showed that CAN induces DNA single and double-strand breaks that were repaired in a dose- and concentration-dependent manner. Cell lines harboring endogeneous wild-type (CHO-9), mutant (43-3B), or wild-type transfected ERCC1 (43-3B/ERCC1) were, however, similar sensitive to CAN indicating that the nucleotide excision repair pathway is not responsible for repair of CAN-induced DNA damage. CAN was less active in WTK1 lymphoblastoid cells with mutated p53 than in TK1 lymphoblastoid cells expressing wild-type p53. Multidrug-resistant MDR1-expressing CEM/ADR5000 cells did not exhibit cross-resistance to CAN as compared to drug-sensitive parental cells. The IC50 values for CAN did not correlate with the mRNA expression of the MDR1 gene in 60 cell lines of the National Cancer Institute (N.C.I.) indicating no role of the MDR-phenotype for CAN. Mining the microarray database of the NCI by standard and reverse COMPARE analyses provided 50 out of 9706 genes whose mRNA expression correlated with IC50 values for CAN in the NCI cell line panel. If the mRNA expression of the 50 genes was subjected to hierarchical cluster analysis, sensitivity or resistance of the 60 cell lines to CAN could be predicted. The present investigation represents a starting point to dissect the genes and molecular pathways involved in cellular response to CAN in greater detail.

[Proc Amer Assoc Cancer Res, Volume 45, 2004]