Abstract
Cisplatin is one of the first line anti-cancer drugs prescribed for treatment of solid tumors; however, the chemotherapeutic drug resistance is still a major obstacle of cisplatin in treating cancers. Yu Ping Feng San (YPFS), a well-known ancient Chinese herbal combination formula consisting of Astragali Radix, Atractylodis Macrocephalae Rhizoma and Saposhnikoviae Radix, is prescribed as a herbal decoction to treat immune disorders in clinic. To understand the fast-onset action of YPFS as an anti-cancer drug to fight against the drug resistance of cisplatin, we provided detailed analyses of intracellular cisplatin accumulation, cell viability, and expressions and activities of ATP-binding cassette transporters and glutathione S-transferases (GSTs) in YPFS-treated lung cancer cell lines. In cultured A549 or its cisplatin-resistance A549/DDP cells, application of YPFS increased accumulation of intracellular cisplatin, resulting in lower cell viability. In parallel, the activities and expressions of ATP-binding cassette transporters and GSTs were down-regulated in the presence of YPFS. The expression of p65 subunit of NF-κB complex was reduced by treating the cultures with YPFS, leading to a high ratio of Bax/Bcl-2, i.e. increasing the rate of cell death. Prim-O-glucosylcimifugin, one of the abundant ingredients in YPFS, modulated the activity of GSTs, and then elevated cisplatin accumulation, resulting in increased cell apoptosis. The present result supports the notion of YPFS in reversing drug resistance of cisplatin in lung cancer cells by elevating of intracellular cisplatin, and the underlying mechanism may be down regulating the activities and expressions of ATP-binding cassette transporters and GSTs.
Highlights
Lung cancer is the most diagnosed cancer with overwhelming mortality among all types of cancers, which can be classified into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC)
Our previous study has shown that Yu Ping Feng San (YPFS) could increase intracellular accumulation of the active ingredients, i.e. calycosin and formononetin, within 3 h in the cultures: these compounds were the substrates of efflux transporters, as that of cisplatin (Du, 2014)
We hypothesized that the synergy of YPFS with cisplatin in inducing toxicity of cancer cells could be related to Glutathione S-transferases (GSTs) and efflux drug transporter
Summary
Lung cancer is the most diagnosed cancer with overwhelming mortality among all types of cancers, which can be classified into non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC accounts for over 85% of total lung cancer incidents (Siegel et al, 2014). Most of the anti-cancer drugs exhibit resistance by cancer cells, and which results in failure of chemotherapy and/or tumor recurrence. Multidrug resistance (MDR) is a major impediment to chemotherapeutic efficacy in cancer patients. At the beginning of chemotherapeutic treatment, intrinsic drug resistance is causing unresponsiveness of cancer cell to chemotherapy. The acquired resistance arises in recurrence of tumor, and which thereafter displays resistance to a broad range of structural and functional diverse chemicals. The transformation of tumor with MDR could be mediated by various parameters, e.g. regulating drug efflux/influx, changing drug detoxification system, expressing gene/protein in apoptosis and drug distribution (Larsen et al, 2000; Baird and Kaye, 2003)
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