Abstract
Nasopharyngeal carcinoma (NPC) is an important issue in Asia because of its unique geographical and ethnic distribution. Cisplatin-based regimens are commonly the first-line used chemotherapy, but resistance and toxicities remain a problem. Therefore, the use of anticancer agents derived from natural products may be a solution. Asiatic acid (AA), extracted from Centella asiatica, was found to have anticancer activity in various cancers. The aim of this study is to examine the cytotoxic effect and mediated mechanism of AA in cisplatin-resistant NPC cells. The results shows that AA significantly reduce the cell viability of cisplatin-resistant NPC cell lines (cis NPC-039 and cis NPC-BM) in dose and time dependent manners caused by apoptosis through the both intrinsic and extrinsic apoptotic pathways, including altered mitochondrial membrane potential, activated death receptors, increased Bax expression, and upregulated caspase 3, 8, and 9. The Western blot analysis of AA-treated cell lines reveals that the phosphorylation of MAPK pathway proteins is involved. Further, the results of adding inhibitors of these proteins indicates that the phosphorylation of p38 are the key mediators in AA-induced apoptosis in cisplatin-resistant human NPC cells. This is the first study to demonstrate the AA-induced apoptotic pathway through the phosphorylation p38 in human cisplatin-resistant nasopharyngeal carcinoma. AA is expected to be another therapeutic option for cisplatin-resistant NPC because of the promising anti-cancer effect and fewer toxic properties.
Highlights
Nasopharyngeal carcinoma (NPC) is an important and widely studied issue in Asia, especially in Eastern Asia and South-Eastern Asia, because of its unique geographical distribution
We assessed the cell viability of two kinds of cisplatin-resistant human NPC cell lines, cis NPC-039 and cis NPC-BM, by MTT assay. These cell lines were treated with an increasing concentration of Asiatic acid (AA) (0, 25, 50, and 75 μM) with or without cisplatin for 24, 48, and 72 h
Cell viability was significantly reduced in concentration of 50 and 75 μM compared to control (0 μM)
Summary
Nasopharyngeal carcinoma (NPC) is an important and widely studied issue in Asia, especially in Eastern Asia and South-Eastern Asia, because of its unique geographical distribution. Different from other head and neck cancer, the primary and only curative treatment for NPC is radiotherapy instead of surgery for early-stage disease. Chemotherapeutic agents are used as concurrent chemoradiotherapy (CCRT), adjuvant chemotherapy, or induction chemotherapy in locoregionally advanced disease and metastatic disease [3]. Proposed that the overall survival (OS) and disease-free survival by CCRT had statistically significant improvement with five-year OS of about 70% in non-metastatic stage III and IV disease, but the efficacy of chemotherapy varied markedly among different trials [4]. Chemoradiotherapy leads to various side effects including hematological acute toxicity, mucositis, xerostomia, loss of taste, dysphagia, skin damage, skull bone damage, sensorineural hearing loss, and osteoradionecrosis. New effective treatments with fewer toxicities need to be identified
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