Quercetin as a Potential Modulator of P-Glycoprotein Expression and Function in Cells of Human Pancreatic Carcinoma Line Resistant to Daunorubicin

Abstract

P-glycoprotein (P-gp) is one of the ABC transporters responsible for the resistance of several tumours to successful chemotherapy. Numerous agents are capable of interfering with the P-gp-mediated export of drugs but unfortunately most of them produce serious side effects. Some plant polyphenols, including the flavonol quercetin (Q), manifest anti-neoplastic activity mainly due to their influence on cell cycle control and apoptosis. Reports are also available which show that Q may intensify action of cytostatic drugs and suppress the multidrug resistance (MDR) phenomenon. The study aimed at determination if Q sensitizes cells resistant to daunorubicin (DB) through its effect on P-gp expression and action. The experiments were conducted on two cell lines of human pancreatic carcinoma, resistant to DB EPP85-181RDB and sensitive EPP85-181P as a comparison. Cells of both lines were exposed to selected concentrations of Q and DB, and then membranous expression of P-gp and its transport function were examined. The influence on expression of gene for P-gp (ABCB1) was also investigated. Results of the studies confirmed that Q affects expression and function of P-gp in a concentration-dependent manner. Moreover it decreased expression of ABCB1. Thus, Q may be considered as a potential modulator of P-gp.

Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics?

“…In cancer, besides the association of drugs commonly used in chemotherapy have also been investigated the combined effect of these drugs with natural compounds. So, there are already different studies in which is intended to clarify the therapeutic effect of quercetin in combination with several drugs used in the cancer treatment like doxorubicin [75,76], 5-fluorouracil [77][78][79], cisplatin [80][81][82][83], dacarbazin [84], etoposide [77], daunorubicin [85], temozolomide [85], camptothecin [77], gemcitabine [55,86], lapatinib [87], oxaliplatin [83], sorafenib [88], tamoxifen [89] and trichostatin A [90] (Table 1).…”

“…Emphasizing the potential that this kind of combined therapies has in the treatment of oncological diseases, studies of combination therapy with quercetin have been carried out in several types of cancers such as prostate cancer [77], colorectal cancer [78], hepatocellular carcinoma (HCC) [75,81], lung cancer [82,90], pancreatic carcinoma [53,85] and breast cancer [74,87,89] (Table 1).…”

The effect of quercetin and doxorubicin combination in inhibiting resistance in mcf-7 cell

“…It was found that Quercetin is a xenobiotic that competitively inhibits GSH and GST P1-1 enzymatic activities via reversible covalent binding to Cys17 residue. 30 (2) According to Borska et al 15 who investigated quercetin effects on the expression and function of P-gp, the combination of doxorubicin and quercetin had been significantly reduce the percentage of viable MCF-7 cell and not significantly downregulated P-gp expression. Even though it was not significantly downregulated P-gp expression, it might be affect transport of doxorubicin.…”

“…12,13 Another group found that quercetin is a potential modulator of P-gp to restore chemotherapy resistance via inhibitation of P-gpfacilitated efflux of doxorubicin, so that enhancing doxorubicin concentration in MCF-7/ADR-RES cancer cell model. 14,15 Apart from its controversial effect, quercetin is still considered to be effective to reduce insensitivity of neoplastic cells to chemotherapeutic agents. In this study, we have evaluated the effect of quercetin and doxorubicin combination in preventing the development of resistance by evaluating the sensitivity of MCF-7 cell and expression of P-gp in MCF-7 cell.…”

3,5-Di(-O-acetyl)-3′,4′,7-tri[-O-(2-O-acetylethyl)]quercetin

“…Quercetin (3,3',4',5,7-pentahydroxyflavone) and its derivatives have a wide range of biological activity, such as antioxidant [1][2][3][4], anticarcinogenesis [5][6][7][8][9][10], vasodilatation [11][12][13], inhibition of various enzymes [14][15][16], UV-shielding properties [17][18], etc. Troxerutin (trihydroxy-ethylrutoside), which serves as a drug, is known as a radical scavenger with antioxidant effects, so that treatment with it increases the healing of capillary endothelial defects [19].…”