Abstract
Cancer cells can acquire resistance to a wide variety of diverse and unrelated drugs, this phenomenon is termed multidrug resistance (MDR). Multidrug resistance has been an obstacle to the success of cancer chemotherapy. The present study investigated the reversal effect of Y6, a new compound obtained by chemically modifying the structure of epigallocatechin-3-gallate (EGCG) extracted from green tea. Y6 was proven to be effective in inhibiting cell proliferation and reversing drug resistance in doxorubicin (DOX) resistant human hepatocellular carcinoma cells (BEL-7404/DOX). BEL-7404/DOX cells were treated with either doxorubicin combination regimen (doxorubicin plus Y6 or epigallocatechin-3-gallate or verapamil separately) or doxorubicin alone. The results showed that cell proliferation was inhibited and late cell apoptosis increased in the combination treatment group, especially in the group treated with doxorubicin plus Y6. Further analysis revealed that the expressions of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein decreased at both messenger RNA and protein levels by treatments with combined drugs compared to doxorubicin alone. Our results indicated that Y6, as a drug resistance reversal agent, increased the sensitivity of drug resistant cells to doxorubicin. The mechanisms of actions of Y6 in reversal effect were associated with the decreased expression of hypoxia-inducible factor-1α and multidrug resistance 1/P-glycoprotein.
Highlights
Liver cancer is a malignancy of high incidence and mortality
The MTT assay results showed that the IC50 values for doxorubicin was significantly reduced from 44.14 to 8.39 μM by verapamil, to 8.04 μM by EGCG, and to 5.74 μM and 4.36 μM by Y6 (10 μM) and Y6 (15 μM) respectively in the BEL-7404/ DOX cells compared with doxorubicin alone, representing drug resistance folds decreasing from 29.2 to 5.6, 5.3, 3.8, and 2.9 respectively (Table 1)
These results indicated that the capability of Y6 in reversing drug resistance was higher than that of EGCG combined with doxorubicin (#p < 0.05) (Table 1, Figure 2)
Summary
Liver cancer is a malignancy of high incidence and mortality. It is estimated that nearly 750,000 new cases and more than 690,000 cancer deaths occur annually worldwide. Hepatocellular carcinoma (HCC) is the major histological subtype Various anticancer drugs such as tamoxifen, octreotide, interferon, and interleukin-2 are used in the treatment of HCC; these drugs are not specific for HCC and demonstrate low treatment efficacy [2]. The mechanisms of resistance to anticancer drugs consist of changes of pharmacokinetic or tumor microenvironment, cancer cell-specific factors which include increased drug efflux or decreased drug influx, drug inactivation, drug target modification, and apoptosis evasion [4]. Of these mechanisms, the increased drug efflux/ reduced drug accumulation in the tumor cell appears to be a very common mechanism of MDR. Overexpression of P-gp/ABCB1 can produce MDR in cancer cells [11]
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