Abstract
The present study reports the reversing effects of extracts from P. americana on multidrug resistance of BEL-7402/5-FU cells, as well as a preliminary investigation on their mechanism of action. A methylthiazolyl tetrazolium (MTT) method was applied to determine the multidrug resistance of BEL-7402/5-FU, while an intracellular drug accumulation assay was used to evaluate the effects of a column chromatography extract (PACC) and defatted extract (PADF) from P. americana on reversing multi-drug resistance. BEL-7402/5-FU reflected high resistance to 5-FU; PACC and PADF could promote drug accumulation in BEL-7402/5-FU cells, among which PADF was more effective than PACC. Moreover, results from the immunocytochemical method showed that PACC and PADF could downregulate the expression of drug resistance-associated proteins (P-gp, MRP, LRP); PACC and PADF had no effects on the expression of multidrug resistance-associated enzymes (GST-π), but PACC could increase the expression of multidrug resistance-associated enzymes (PKC). Results of real-time fluorescence quantitative PCR revealed that PACC and PADF were able to markedly inhibit the expression of multidrug resistance-associated genes (MDR1, LRP and MRP1); PACC presented a significant impact on the gene expression of multidrug resistance-associated enzymes, which increased the gene expression of GST-π and PKC. However, PADF had little impact on the expression of multidrug resistance-associated enzymes. These results demonstrated that PACC and PADF extracted from P. americana could effectively reverse MDR in BEL-7402/5-FU cells, whose mechanism was to inhibit the expression of P-gp, MRP, and LRP, and that PADF was more effective in the reversal of MDR than did PACC. In addition, some of extracts from P. americana altered (sometimes increasing) the expression of multidrug resistance-associated enzymes.
Highlights
Hepatocellular carcinoma (HCC), which has the features of high degradation, high recurrence, and metastasis rates and whose mortality ranks third among global cancers, is the seventh most common malignant tumor type [1,2]
PADF had little impact on the expression of multidrug resistance-associated enzymes. These results demonstrated that PACC and PADF extracted from P. americana could effectively reverse Multidrug resistance (MDR) in BEL-7402/5-FU cells, whose mechanism was to inhibit the expression of P-gp, MRP, and LRP, and that PADF was more effective in the reversal of MDR than did PACC
MDR in tumor cells were as follows: (1) drug efflux mediated by transport proteins [14,15], such as of MDR in tumor cells were as follows: (1) drug efflux mediated by transport proteins [14,15], MRP, LRP, BCRP, and P-gp; (2) MDR mediated by enzymes [16], including topoisomerase (TOPO), such as MRP, LRP, BCRP, and P-gp; (2) MDR mediated by enzymes [16], including topoisomerase glutathione-S-transferase (GST), and protein kinase C (PKC); (3) MDR mediated by apoptosis-associated (TOPO), glutathione-S-transferase (GST), and protein kinase C (PKC); (3) MDR mediated by genes [17], such as the Bcl-2 gene family, c-myc, p53, and others; (4) DNA damage repair [18]
Summary
Hepatocellular carcinoma (HCC), which has the features of high degradation, high recurrence, and metastasis rates and whose mortality ranks third among global cancers, is the seventh most common malignant tumor type [1,2]. There are about 500 thousands new cases each year in the world, and 50% of them occur in China, with an yearly upward trend [3,4] Chemotherapy, such as the administration of 5-fluorouracil (5-FU), plays a critical role in the therapeutic protocol for HCC. Multidrug resistance (MDR) refers to the fact that tumor cells can develop resistance against multiple antitumor drugs during the process of receiving chemotherapy [5,6]. Resistance to chemotherapeutic drugs is a major barrier in the treatment of HCC [7,8], reversing MDR is deemed to be the drugs is a major barrier in the treatment of HCC [7,8], reversing MDR is deemed to be the key to improving the efficacy of chemotherapy [9]. In recent years, selecting active components with low toxicity and high efficiency from natural medicines that can reverse MDR has attracted increasing low toxicity and high efficiency from natural medicines that can reverse MDR has attracted increasing attention in the field of HCC research [10]
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