Emodin As an Effective Agent in Targeting Cancer Stem-Like Side Population Cells of Gallbladder Carcinoma

Abstract

Side population (SP) cells are previously identified from bone marrow based on their capacity to efflux of the fluorescent dye Hoechst 33342. Recent studies demonstrate that SP cells isolated from various cancer cell lines and primary tumors possess stem-cell-like properties. Thus, targeting tumor SP cells may provide new strategies for treatment in clinic. We previously showed that 1,3,8-trihydroxy-6-methylanthraquinone (emodin), a reactive oxygen species (ROS) generator, enhanced sensitivity of gallbladder cancer SGC-996 cells to cisplatin (CDDP) via generation of ROS and downregulation of multidrug-resistance-associated protein 1 (MRP1). To determine whether emodin also acts effectively on cancer stem cells of gallbladder carcinoma, we use SP cells as a model of cancer stem-cell-like cells. Here, we found that emodin, via ROS-related mechanism and suppressing the function of ATP-binding cassette super-family G member (ABCG2), which is known to be associated with Hoechst dye efflux activity of SP cells, not only reduced the ratio, inhibited clone formation, and eliminated sphere formation of SP cells effectively, but also promoted obviously the intracellular accumulation of doxorubicin, the main substrate of the efflux pump ABCG2. In addition, emodin could sensitize CDDP, via inhibition of expression of ABCG2, to overcome chemoresistance of SP cells. Importantly, similar to the experiment in vitro, emodin/CDDP co-treatment in vivo suppressed the tumor growth derived from SP cells through downregulating ABCG2 expression. Our results suggest that emodin is an effective agent targeting cancer stem-like SP cells of gallbladder carcinoma, either alone or acts as a chemotherapy enhancer.

Emodin Suppresses Maintenance of Stemness by Augmenting Proteosomal Degradation of Epidermal Growth Factor Receptor/Epidermal Growth Factor Receptor Variant III in Glioma Stem Cells

“…Downregulation of Wnt/b-catenin signaling was also observed in breast CSCs treated with sulforaphane, a component of broccoli and broccoli sprouts [25]. Emodin was previously reported to target the stem-like side population of gallbladder carcinoma by suppressing expression of the ATP-binding cassette superfamily G member ABCG2 [26]. Our data showed that emodin effectively suppressed the self-renewal capacity of GSCs and indicated that this occurred through suppression of critical stemness signaling pathways.…”

“…Therefore, to overcome the therapeutic resistance of CSCs, it is necessary to find compounds that target CSCs for combination therapy with conventional treatments. One promising source of CSC-targeting agents is naturally occurring dietary compounds because several reports have shown that some of these compounds affect the self-renewal capacity of CSCs [20][21][22][23][24][25][26]. In the present study, we investigated the effect of emodin, an anthraquinone compound present in rhubarb, on the biology of GSCs.…”

“…Given that numerous natural dietary compounds with antitumorigenic potential also target self-renewal pathways of CSCs [20][21][22][23][24][25], it seems highly possible that emodin might affect crucial signaling pathways of CSCs. There is only one report addressing the effect of emodin on stem-like cancer cells derived from a side population of gallbladder cancer cells [26]. Therefore, we investigated whether emodin has the potential to target GSCs, and in particular, the specific selfrenewal pathways of these cells.…”

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment

“…For example, aldehyde dehydrogenase 1 (ALDH1), a soluble protein is used detect CSCs in various cancers, including leukaemia [37], breast cancer [38], colon cancer [39], liver cancer [40], lung cancer [41] and pancreatic cancer [42]. SP-cells, are a population of cells which are capable of efflux of Hoechst 33,342 dye, which is another non-cell-surface marker that has also been used for detection of normal stem cells as well as CSCs [43,44]. Bio-molecules used for the detection and isolation of CSCs in different cancers to date are summarised in Table 2 along their functions in normal tissues.…”

Molecular Docking and ADMET Study of Emodin Derivatives as Anticancer Inhibitors of NAT2, COX2 and TOP1 Enzymes

“…Emodin is an anthraquinone, is naturally distributed and well known to possess broad pharmacological activities [2]. Emodin (D1) has been reported to inhibit the proliferation of many cancer cells which include; Colon cancer [3] [4], breast cancer [5] [6], gall bladder cancer [7] [8], pancreatic cancer [9], lung cancer [10] [11] and human cervical cancer [12]. Poor bioavailability and toxicity in vivo have been documented to limit emodin as cancer chemotherapy [13].…”