Increasing evidence suggests that
tumors are composed of a heterogeneous cell population with a small subset of cancer stem cells (CSCs) that sustain
tumor formation and growth, and are hypothesized to account for therapeutic resistance. Based on the expression of the surface markers CD44, CD24, and
EPCAM, putative CSCs have also been identified in
pancreatic cancers. It has been well established that aberrant activation of β-
catenin signaling pathway may contribute to the maintenance of CSCs.
Cantharidin is an active constituent of mylabris, a
traditional Chinese medicine. In our previous studies, we demonstrated that
cantharidin treatment induced phosphorylation of β-
catenin, leading to repression on β-
catenin pathway. Therefore, in the present study, we investigated whether
cantharidin and its derivant,
norcantharidin, could repress the stemness of
pancreatic cancer cells through repression on β-
catenin pathway. By using microarray and flow cytometry, we found that treatment with
cantharidin and
norcantharidin repressed the expression of CD44, CD24, and
EPCAM at both
mRNA and
protein levels, leading to decreased CD44(+)/CD24(+)/
EPCAM(+) proportion, the putative pancreatic CSC subset. Pretreatment with the β-
catenin pathway inhibitor
FH535, attenuated the
cantharidin- and
norcantharidin-induced repression on CD44, CD24, and
EPCAM, suggesting
cantharidin and its derivant repressed stemness of
pancreatic cancer cells in β-
catenin pathway-dependent manner. Furthermore,
cantharidin and
norcantharidin strengthened the cytotoxicity of
gemcitabine and
erlotinib, two well established pharmacotherapeutics against
pancreatic cancers, indicating
cantharidin and
norcantharidin could be promising candidates for reversing drug resistance in
pancreatic cancers. In conclusion, we presently propose that
cantharidin and
norcantharidin hold their promise in
pancreatic cancer therapy through repression on stemness and strengthening the cytotoxicity of the present
therapeutics.