Guggulsterone and bexarotene induce secretion of exosome‐associated breast cancer resistance protein and reduce doxorubicin resistance in MDA‐MB‐231 cells

Abstract

Many breast cancer cells acquire multidrug resistance (MDR) mediated by ABC transporters such as breast cancer resistance protein (BCRP/ABCG2). Here we show that incubation of human breast cancer MDA-MB-231 cells with farnesoid X receptor antagonist guggulsterone (gug) and retinoid X receptor agonist bexarotene (bex) elevated ceramide, a sphingolipid known to induce exosome secretion. The gug+bex combination reduced cellular levels of BCRP to 20% of control cells by inducing its association and secretion with exosomes. Exogenous C6 ceramide also induced secretion of BCRP-associated exosomes, while siRNA-mediated knockdown or GW4869-mediated inhibition of neutral sphingomyelinase 2 (nSMase2), an enzyme generating ceramide, restored cellular BCRP. Immunocytochemistry showed that ceramide elevation and concurrent loss of cellular BCRP was prominent in Aldefluor-labeled breast cancer stem-like cells. These cells no longer excluded the BCRP substrate Hoechst 33342 and showed caspase activation and apoptosis induction. Consistent with reduced BCRP, ABC transporter assays showed that gug+bex increased doxorubicin retention and that the combination of gug+bex with doxorubicin enhanced cell death by more than 5-fold. Taken together, our results suggest a novel mechanism by which ceramide induces BCRP secretion and reduces MDR, which may be useful as adjuvant drug treatment for sensitizing breast cancer cells and cancer stem cells to chemotherapy.

Cisplatin-resistant lung cancer cell–derived exosomes increase cisplatin resistance of recipient cells in exosomal miR-100–5p-dependent manner

“…16 More importantly, exosomes-shuttling miRNAs probably conferred this resistance delivery. Followed by these studies, more and more evidence confirmed this observation in other cancers including breast cancer, prostate cancer, hepatocellular cancer, [17][18][19][20] and so on. However, similar to our previous study, most of these literatures mainly reported this phenomenon and few researchers 13 conduct in-depth study and systematically explore its detailed mechanism.…”

Inhibitors of the sphingomyelin cycle: Sphingomyelin synthases and sphingomyelinases

“…It was validated in cell culture by blocking the effect of TNF on SM hydrolysis and accumulation of ceramide (Luberto et al, 2002a) and attenuated signs of TNFinduced apoptosis (Clarke et al, 2006). It has been employed in several studies proving or suggesting a role for nSMase2 in hyaluronic acid secretion (Qin et al, 2012), in reducing secretion of miRNAs, in decreasing A peptides, in lipoprotein regulation (Dinkins et al, 2014;Kolmakova et al, 2004), in cancer biology (Kong et al, 2015), and in Wnt signaling among several other functions (Chairoungdua et al, 2010). Another family of nSMase2 inhibitors are guanidinium derivatives containing a variable lipophilic moiety.…”

Mechanisms of tumor cell resistance to the current targeted-therapy agents

“…Moreover, the presence of several drug transporters in these vesicles, such as ATP7A/B and MRP2, increases the efflux of drugs from cancer cells [78,80]. The presence of drugresistant proteins has been shown in several malignancies, such as P-gp in docetaxel-resistant prostate cancer cells [81] and paclitaxel-resistant ovarian cancer cell line [82], MRP1 transporter in ALL [83], ABCG2 in doxorubicin-resistant breast cancer cells [84], and ABCA3 in rituximab-resistant B-cell lymphoma cells [85], which are responsible for induction of drug resistance in these tumors [78].…”