Curcumin reverses doxorubicin resistance via inhibition the efflux function of ABCB4 in doxorubicin‑resistant breast cancer cells

Abstract

Doxorubicin is one of the most widely used chemotherapy agents for the treatment of breast cancer. However, the development of doxorubicin resistance limits the long-term treatment benefits in patients with breast cancer. Curcumin, a well-known dietary polyphenol derived from the rhizomes of turmeric ( Curcuma longa ), enhances the sensitivity of breast cancer cells to chemotherapeutic agents; however, the mechanisms underlying this phenomenon remain unclear. The aim of the present study was to evaluate the effect of curcumin on chemoresistance in doxorubicin-resistant breast cancerMCF-7/DOX and MDA-MB-231/DOX cell lines. Cell Counting Kit-8, monolayer transport, western blot and ATPase activity assays were performed during the study. The results revealed that curcumin significantly enhanced the effect of doxorubicin in doxorubicin-resistant breast cancer cells. The intracellular accumulation of doxorubicin was substantially increased following curcumin treatment in doxorubicin-resistant breast cancer cells, in a manner that was inversely dependent on the activity of ATP binding cassette subfamily B member 4 (ABCB4). Treatment with a combination of curcumin and doxorubicin decreases the efflux of doxorubicin in ABCB4-overexpressing cells. Furthermore, curcumin inhibited the ATPase activity of ABCB4 without altering its protein expression. In conclusion, curcumin reversed doxorubicin resistance in human breast cancer MCF-7/DOX and MDA-MB-231/DOX cells by inhibiting the ATPase activity of ABCB4. The study highlights the promising use of curcumin as a chemosensitizer in the treatment of breast cancer.

Structure of the human lipid exporter ABCB4 in a lipid environment

“…When first discovered, ABCB4 was assumed to be a multi-drug exporter due to its high sequence conservation (76% identity, 86% similarity) to ABCB1 34 (P-glycoprotein), and ABCB4 is still often referred to as multidrug-resistance-protein 3 (MDR3). However, while various studies have shown ABCB4 to be capable of recognizing and transporting some ABCB1 substrates (albeit with low capacity) 35,36 , the data regarding its role in conferring drug resistance is inconclusive [37][38][39][40] . Similarly, ABCB1 has only been shown to flip short-chain, fluorescently labelled lipid analogues in cellular assays 41 , and despite its canalicular expression 3 , ABCB1 is unable to compensate for loss of ABCB4 function 1 .…”

Alleviation of Multidrug Resistance by Flavonoid and Non-Flavonoid Compounds in Breast, Lung, Colorectal and Prostate Cancer

“…Based on the reported data, polyphenols overcome multidrug resistance by affecting different pathways in different types of cancer [243]. For example: (i) quercetin increases apoptosis, inhibits angiogenesis (in colorectal cancer cells) [244], inhibits P-gp activity (in breast cancer cells) [245]; (ii) curcumin down-regulates P-gp and Hsp27, induces autophagy, reduces the markers of cancer stem cells (colon cancer cells) [246][247][248], inhibits the activity of ABCB4 pump, inhibits epithelial-mesenchymal transition (breast cancer cells) [249,250], inhibits JNK pathway, suppresses invasion by inhibition of STAT3 activity (prostate cancer) [251,252] or induces apoptosis (lung cancer cells) [253]; (iii) resveratrol down-regulates the expression of survivin (in prostate cancer cells) [254] and inhibits MAPK kinase in prostate and lung cancer cells [255]; (iv) EGCG inhibits drug efflux (in prostate cancer cells), increases drug concentration in cancer cells by inhibition of enzymes involved in drug metabolism (in colorectal cancer cells), increased ROS production (in colorectal cancer cells)-thus it is responsible for AMPK activation-and induces epigenetic restoration of estrogen receptors through histone modifications (in breast cancer cells) [256]. Nevertheless, based on reported data, some polyphenols can target the same molecule in different cancer cell lines.…”

Role of Curcumin and (−)-Epigallocatechin-3-O-Gallate in Bladder Cancer Treatment: A Review

“…Curcumin also inhibited the ATPase activity of ABCB4, without altering its protein expression, and slightly stimulated basal ATP hydrolysis by ABCB4 at low concentrations (0.25-1 µM). At higher concentrations, the activity of ATPase was inhibited [81]. In another study, in order to sensitize multidrug resistant breast cancer cells to cisplatin, MCF-7 and MCF-7/DDP cell lines were used.…”