Synergistic Effects of Atractylodes-Derived Sesquiterpenes and Polyacetylene on Chemotherapeutic Sensitivity in Cholangiocarcinoma: Impact on Transporter Gene Expression.

Atractylodes lancea (AL) has been shown to be a promising candidate for the treatment of cholangiocarcinoma (CCA). The study explored the potential of atractylodin (AT) and β-eudesmol (BE) to chemosensitize the effects of standard chemotherapeutics in CCA. The cytotoxicities of AT and BE on CL6, HuCCT1, and HuH28 when used in combination with 5-fluorouracil (5FU), gemcitabine (GEM), and cisplatin (Cis) were assessed by MTT assay. The modulatory effects of both compounds on mRNA expression of the reuptake and efflux transporters were determined by real-time PCR. The FIC (Fractional Inhibitory Concentration) indices indicated synergistic interactions (AT-5FU in all cell lines and BE-5FU in HuH28) and antagonistic interactions (BE-Cis in all cell lines and AT-Cis or AT-GEM in HuCCT1). The synergistic interactions observed with the AT-5FU and BE-5FU combinations were well correlated with the significant upregulation of the mRNA expression of the reuptake transporter genes hENT1 (2.64-fold) and hOCT3 (5.02-fold) and the significant downregulation of the mRNA expression of the efflux transporter gene ABCC2 (0.33-fold). AT and BE, when purified or present as significant components in AL, may benefit CCA treatment when used as adjunct therapy to standard chemotherapeutic drugs, particularly 5FU. The mechanism of synergistic activity may, at least in part, involve modulation of transporter gene expression and activity.