Abstract
Cholangiocarcinoma (CC) is a chemoresistant intrahepatic bile duct carcinoma with a poor prognosis. The aims of this study were to identify molecular pathways that enhance sesquiterpene lactone parthenolide (PTL)-induced anticancer effects on CC cells. The effects of PTL on apoptosis and hemoxygenase-1 (HO-1) induction were examined in CC cell lines. The enhancement of PTL-mediated apoptosis by modulation of HO-1 expression and the mechanisms involved were also examined in an in vitro cell system. Low PTL concentrations (5 to 10 microM) led to Nrf2-dependent HO-1 induction, which attenuated the apoptogenic effect of PTL in Choi-CK and SCK cells. PTL-mediated apoptosis was enhanced by the protein kinase C-alpha inhibitor Ro317549 (Ro) through inhibition of expression and nuclear translocation of Nrf2, resulting in blockage of HO-1 expression. Finally, HO-1 silencing resulted in enhancement of apoptotic cell death in CC cells. The combination of PTL and Ro efficiently improved tumor growth inhibition compared to treatment with either agent alone in an in vivo subcutaneous tumor model. In conclusion, the modulation of HO-1 expression substantially improved the anticancer effect of PTL. The combination of PTL and Ro could prove to be a valuable chemotherapeutic strategy for CC.
Highlights
Cholangiocarcinoma (CC), a malignant tumor derived from the bile duct epithelium, currently accounts for approximately 15% of all cases of liver cancer worldwide, and its incidence is rising (Blendis and Halpern, 2004; Shaib et al, 2004)
We observed that heme oxygenase-1 (HO-1) was highly expressed during PTL-induced apoptosis in CC cells, and we propose that this induction may contribute to cellular resistance against chemo-oxidative stress
We previously found that 10 μM PTL effectively induced apoptotic cell death in a time- and dosedependent manner in CC cells in which oxidative stress plays a pivotal role in PTL-induced apoptosis (Kim et al, 2005)
Summary
Cholangiocarcinoma (CC), a malignant tumor derived from the bile duct epithelium, currently accounts for approximately 15% of all cases of liver cancer worldwide, and its incidence is rising (Blendis and Halpern, 2004; Shaib et al, 2004). But only 25% of patients have resectable tumors at diagnosis, and a majority of these patients relapse within two years (Vauthey and Blum gart, 1994). Chemotherapeutic drugs exert their antitumor effects by inducing apoptosis in cancer cells. Oxidative stress has been shown to contribute to PTL-induced apoptosis in a glutathione-sensitive manner (Wen et al, 2002). We found that the sesquiterpene lactone, PTL, effectively induced apoptosis in CC cells through oxidative stress and that susceptibility of CC cells to PTL is modulated by the Bcl-2-related family of proteins (Kim et al, 2005), the molecular mechanism behind PTL-induced apoptosis remains unclear. We observed that heme oxygenase-1 (HO-1) was highly expressed during PTL-induced apoptosis in CC cells, and we propose that this induction may contribute to cellular resistance against chemo-oxidative stress. A high dose of PTL alone or a low dose of PTL in
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