Abstract
Vinegar-baked Radix Bupleuri (VBRB) is reportedly used to treat liver cancer when combined with traditional chemotherapy and data show that this combination may modify drug transport. We isolated clerosterol from VBRB and studied its effect on drug transporters in normal or transporter-overexpressing cells. Transporter activity was assayed using cellular substrate concentration and transporter expression with Western blot and RT-qPCR. Clerosterol decreased cisplatin uptake in BRL cells mainly through increasing Mrp2 gene expression. Clerosterol also decreased the uptake of colchicine in HEK 293 cells by increasing both Pgp and Mrp1 activity; in detail, it could increase Pgp protein but had marginal effects on Mrp1 protein and gene expression. Further study showed clerosterol increased OCT2 activity in HEK293-Pgp cells by increasing OCT2 protein and mRNA. Clerosterol could suppress Pgp overexpression but not by regulating protein and gene expression. And clerosterol had marginal effects on Mrp2 and Mrp1 activity in Mrp2- and Mrp1-overexpressing HEK293 cells. Thus, Clerosterol may be an active constituent of VBRB and may work against cancer multidrug resistance by inhibiting Pgp activity.
Highlights
Liver cancer is often fatal, as patients are often diagnosed at late stages of the disease
Viability was assessed in BRL and HEK293 cells treated with clerosterol (0.24–243.0 μM) and data showed no inhibitory effects of clerosterol treatment on BRL cells up to 24.3 μM and in HEK293 cells up to 121.5 μM, so these thresholds were used for additional experiments
Since Vinegar-baked Radix Bupleuri (VBRB) is usually used as powder directly, we hypothesized that there are some hydrophilic components in VBRB active at the VBRB-induced herb-drug interaction, we investigated ethyl acetate parts of VBRB, and clerosterol was found in VBRB for the first time
Summary
Liver cancer is often fatal, as patients are often diagnosed at late stages of the disease. For those who can be treated, surgical resection is often the first-line treatment, frequently accompanied by chemotherapy [1]. Drugs used to treat hepatic cancers have many side effects and inter-individual therapeutic efficacy, and drug resistance is an increasing problem. VBRB with traditional chemotherapy may be promising as a novel treatment for liver cancer [2, 3]. Data show that Xiao Caihu Tang (a VBRB representative) with chemotherapy, such as cyclophosphamide (CTX) or cisplatin, improves the quality of life in animals as well as inhibits cell growth and promotes hepatic tumor apoptosis [4, 5]; the effective constituents in VBRB and its mechanism of action are unclear
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