Targeting multidrug resistance in cancer

Effective treatment of metastatic cancers usually requires the use of toxic chemotherapy. In most cases, multiple drugs are used, as resistance to single agents occurs almost universally. For this reason, elucidation of mechanisms that confer simultaneous resistance to different drugs with different targets and chemical structures - multidrug resistance - has been a major goal of cancer biologists during the past 35 years. Here, we review the most common of these mechanisms, one that relies on drug efflux from cancer cells mediated by ATP-binding cassette (ABC) transporters. We describe various approaches to combating multidrug-resistant cancer, including the development of drugs that engage, evade or exploit efflux by ABC transporters.     

Doxorubicin-loaded solid lipid nanoparticles to overcome multidrug resistance in cancer therapy

In the present study we developed doxorubicin-loaded solid lipid nanoparticles (SLN-Dox) using biocompatible compounds, assessed the in vitro hemolytic effect, and examined their in vivo effects on drug retention and apoptosis intensity in P-glycoprotein-overexpressing MCF-7/ADR cells, a representative Dox-resistant breast cancer cell line. Our SLNs did not show hemolytic activity in human erythrocytes. In comparison with Dox, SLN-Dox efficiently enhanced apoptotic cell death through the higher accumulation of Dox in MCF-7/ADR cells. Therefore, SLN-Dox have potential to serve as a useful therapeutic approach to overcome the chemoresistance of adriamycin-resistant breast cancer.From the Clinical EditorDoxorubicin loaded solid lipid nanoparticles (SLN-Dox) were studied in a cell line representative of doxorubicin resistant breast cancer. The nanoparticles did not show hemolytic activity; furthermore, they efficiently enhanced apoptotic cell death through higher accumulation of doxorubicin in cancer cells. This approach may be viable in overcoming the chemoresistance of adriamycin resistant breast cancer.     

PEO-PPO block copolymers for passive micellar targeting and overcoming multidrug resistance in cancer therapy

Drug carriers tailored to fit the physicochemical properties of anticancer agents and the therapeutic peculiarities of tumor management are envisioned for improving the effectiveness/toxicity ratio of the current treatments. Polymeric micelles are attracting much attention owing to their unique beneficial features: i) core-shell structure capable to host hydrophobic drugs, raising the apparent solubility in aqueous medium; ii) size adequate for a preferential accumulation (passive targeting) within the tumor, exhibiting enhanced permeability and retention (EPR effect), and iii) unimers that modulate the activity of efflux pumps involved in multidrug resistance (MDR). This review focuses on amphiphilic poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) block copolymers, namely the linear poloxamers (Pluronic? or Lutrol?) and the X-shaped poloxamines (Tetronic?), as components of polymeric micelles able to play these three roles. Specific facets of poloxamers have been highlighted some years ago, but recently their wide range of possibilities is beginning to be fully elucidated and understood. Poloxamines are new excipients in the cancer arena and the comparison of their performance with that of poloxamers may enable to identify aspects of their architecture relevant for the optimization of micellar carriers. Clinical trials in progress indicate that drug-loaded polymeric micelles are beneficial regarding efficiency, safety, and compliance of the treatment and quality of life of the patients. The fact that some copolymers are already approved for internal use and several chemotherapy agents will be off patent soon may help to bring the clinical use of poloxamer- or poloxamine-based micelles into a reality in the coming years.     

Relevance of multidrug resistance proteins on the clinical efficacy of cancer therapy

Variations in drug uptake and efflux, as well as changes in intracellular drug entrapment and distribution may represent important resistance mechanisms to cancer therapy. A variety of ATP binding cassette transporters (ABC) localised in multiple cell membranes is implied in those phenomena, representing a mechanism of protection of cells against xenobiotics. Many cancer cell lines over express some ABC transporters, especially p-glycoprotein, MRP1 and BCRP. This over expression is related to worse cancer treatment outcome and, in some cases, reduced overall survival of cancer patients. This paper reviews the location and physiological role of the three transporters mentioned and also describes the drugs that are substrates of these proteins. The usefulness of animal and cellular models to evaluate the role of these transporters on the uptake and efflux of anticancer drugs is discussed. Finally, the results of preclinical and clinical studies about the utility of some inhibitors of these pumps, as well as the implications of polymorphism of ABC transporters on the efficacy and safety of anticancer therapeutics are reported.     

Nanopreparations to overcome multidrug resistance in cancer

Multidrug resistance is the most widely exploited phenomenon by which cancer eludes chemotherapy. Broad variety of factors, ranging from the cellular ones, such as over-expression of efflux transporters, defective apoptotic machineries, and altered molecular targets, to the physiological factors such as higher interstitial fluid pressure, low extracellular pH, and formation of irregular tumor vasculature are responsible for multidrug resistance. A combination of various undesirable factors associated with biological surroundings together with poor solubility and instability of many potential therapeutic small & large molecules within the biological systems and systemic toxicity of chemotherapeutic agents has necessitated the need for nano-preparations to optimize drug delivery. The physiology of solid tumors presents numerous challenges for successful therapy. However, it also offers unique opportunities for the use of nanotechnology. Nanoparticles, up to 400 nm in size, have shown great promise for carrying, protecting and delivering potential therapeutic molecules with diverse physiological properties. In this review, various factors responsible for the MDR and the use of nanotechnology to overcome the MDR, the use of spheroid culture as well as the current technique of producing microtumor tissues in vitro are discussed in detail.     

The gut-to-breast connection - interdependence of sterols and sphingolipids in multidrug resistance and breast cancer therapy

Almost all classes of bioactive lipids such as cholesterol and cholesterol derivatives, phospholipids and lysophospholipids, eicosanoids, and sphingolipids are critically involved in tumorigenesis. However, a systematic analysis of the distinct tumorigenic functions of lipids is rare. As a general principle, lipids either act directly by binding to receptors and other cell signaling proteins in growth control, or indirectly by regulating membrane organization such as the formation of membrane microdomains (lipid rafts) that modulate receptor or other membrane protein function. Lipid rafts are known to be formed by cholesterol and the sphingolipids or ceramide derivatives sphingomyelin and glucosylceramide (cholesterol-sphingomyelin-glucosylceramide or CSG rafts). In this review, we discuss the interconnection of sphingolipids with cholesterol and its derivatives in breast cancer drug resistance. Bile acids are cholesterol derivatives that are first synthesized in the liver (primary bile acids) and then metabolized by intestinal bacteria giving rise to secondary bile acids. They activate farnesoid X receptor (FXR), which inhibits cholesterol conversion to primary bile acids and induces the expression of drug resistance proteins. We introduce a novel model by which bile acid-mediated activation of FXR may promote the formation of CSG lipid rafts that trans-activate drug resistance proteins in breast cancer. Since breast cancer stem cells express high levels of drug resistance proteins, our model predicts that serum bile acids promote breast cancer stem cell survival and metastasis. Our model also predicts that FXR antagonists in combination with sphingolipid biosynthesis inhibitors may be promising candidates for novel drugs in lipid therapy of breast cancer.     

Revisiting the ABCs of multidrug resistance in cancer chemotherapy

The adenosine tri-phosphate binding cassette (ABC) transporters are one of the largest transmembrane gene families in humans. The ABC transporters are present in a number of tissues, providing protection against xenobiotics and certain endogenous molecules. Unfortunately, their presence produces suboptimal chemotherapeutic outcomes in cancer patient tumor cells. It is well established that they actively efflux antineoplastic agents from cancer cells, producing the multidrug resistance (MDR) phenotype. The inadequate response to chemotherapy and subsequent poor prognosis in cancer patients can be in part the result of the clinical overexpression of ABC transporters. In fact, one of the targeted approaches for overcoming MDR in cancer cells is that directed towards blocking or inhibiting ABC transporters. Indeed, for almost three decades, research has been conducted to overcome MDR through pharmacological inhibition of ABC transporters with limited clinical success. Therefore, contemporary strategies to identify or to synthesize selective "resensitizers" of ABC transporters with limited nonspecific toxicity have been undertaken. Innovative approaches en route to understanding specific biochemical role of ABC transporters in MDR and tumorigenesis will prove essential to direct our knowledge towards more effective targeted therapies. This review briefly discusses the current knowledge regarding the clinical involvement of ABC transporters in MDR to antineoplastic drugs and highlights approaches undertaken so far to overcome ABC transporter-mediated MDR in cancer.     

三苯氧胺对晚期大肠癌多药耐药逆转作用研究

目的 探讨三苯氧胺对多药耐药大肠癌患者外周血淋巴细胞膜P-糖蛋白含量的影响及对FOLFOX4方案化疗效果的影响.方法 选择淋巴细胞膜 P-gp表达阳性大肠癌患者62 例,随机分为三苯氧胺组 (33 例) 和单纯化疗组 (29 例).应用流式细胞免疫学方法对两组患者治疗前后淋巴细胞膜 P-gp含量进行定量研究,观察化疗效果.结果 三苯氧胺能显著降低外周血淋巴细胞膜P-gp 含量(P< 0.01),提高P -g p 转阴率(P< 0.01),显著提高化疗总有效率(P< 0.01)、中位生存期(P< 0.05)和1年生存率(P< 0.01).结论 三苯氧胺能有效逆转晚期大肠癌多药耐药,提高化疗效果.     

Zosuquidar逆转肝癌患者多药耐药性

目的利用第三代P糖蛋白(Pgp)抑制剂zosuquidar.3HC1(LY335979)逆转人肝癌化疗耐药性。方法 60例未经治疗的原发性肝癌患者先后行两次99mTc-甲氧基异丁基异腈(99mTc-MIBI)单光子发射计算机断层成像术(SPECT)检测:经外周静脉注射20 mCi99mTc-MIBI后15、120 min行平面显像,半定量分析肿物部位的摄取比值(UR)。第1次SPECT检测后,口服zosuquidar.3HC1 500 mg/d,连续3 d后进行第2次SPECT检测,两次检测结果进行对照比较。结果 60例中,肿瘤部位99mTc-MIBI被排空50例(83.3%),经zosuquidar.3HC1治疗后第2次SPECT检测发现,肿瘤部位出现明显的99mTc-MIBI浓聚。结论 Zosuquidar.3HC1作为一种新型Pgp逆转剂可有效逆转临床肝癌患者的多药耐药性。     

Reversal of P-glycoprotein and multidrug resistance-associated protein 1 mediated multidrug resistance in cancer cells by HZ08 Isomers, tetrataisohydroquinolin derivatives

Overexpression of P-glycoprotein (Pgp) and multidrug resistance protein 1 (MRP1) by tumors results in multidrug resistance (MDR) to structurally unrelated anti-tumor agents. HZ08, a chiral compound, was a newly synthesized tetraisohydroquinoline derivative to reverse Pgp and MRP1 mediated MDR. In present studies, R, S-HZ08 and their racemate reversed the resistance to adriamycin and vincristine of adriamycin-selected human leukemia (K562/ADM) cells that overexpress Pgp. R, S-HZ08 and their racemate modulated adriamycin cytotoxicity when R, S-HZ08 and their racemate were removed 12 h prior to the cytotoxicity assay. In addition, R, S-HZ08 and their racemate increased intracellular accumulation of Rhodamine123 in Caco-2 cells that overexpress Pgp. Furthermore, using a DNA content analysis and an annexin V binding assay, R, S-HZ08 and their racemate effectively reversed the resistance to adriamycin-induced apoptosis in K562/ADM cells. R, S-HZ08 and their racemate also moderately reversed the resistance to adriamycin and vincristine of MCF-7/ADM cells that overexpress MRP1. However, R, S-HZ08 and their racemate hardly affected intracellular glutathione (GSH) levels and glutathione S-transferase (GST) activities in MCF-7/ADM cells. The result showed that R, S-HZ08 and their racemate possibly reverse MDR1 mediated multidrug resistance by a direct interaction with MRP1, not interaction with MRP1 via GSH. Thus, R, S-HZ08 and their racemate should be useful for treating patients with tumors that overexpress both Pgp and MRP1.     

Overcoming multidrug resistance in human cancer cells by natural compounds

Multidrug resistance is a phenomenon whereby tumors become resistant to structurally unrelated anticancer drugs. P-glycoprotein belongs to the large ATP-binding cassette (ABC) transporter superfamily of membrane transport proteins. P-glycoprotein mediates resistance to various classes of anticancer drugs including vinblastine, daunorubicin, and paclitaxel, by actively extruding the drugs from the cells. The quest for inhibitors of anticancer drug efflux transporters has uncovered natural compounds, including (-)-epigallocatechin gallate, curcumin, capsaicin, and guggulsterone, as promising candidates. In this review, studies on the effects of natural compounds on P-glycoprotein and anticancer drug efflux transporters are summarized.     

Inhibition of multidrug resistance of cancer cells by natural diterpenes, triterpenes and carotenoids

The multidrug resistance (MDR) proteins are member of the ATP-binding cassette superfamily and are present in a majority of human tumors. Their activity is a crucial factor leading to therapeutic failure. It is likely that compounds which inhibit the function of the MDR-efflux proteins such as MDR1 will improve the cytotoxic action of anticancer chemotherapy. Therefore, a search for MDR reversing compounds was conducted among three classes of plant derived compounds such as diterpenes, triterpenes and carotenoids in a hope to find inhibitors without adverse effects in these natural compounds. The inhibition of efflux activity was determined by measuring the accumulation of substrate analogues such as rhodamine in tumor cells in the presence of potential inhibitors. Thus we determined the effect of structurally unrelated diterpenes, triterpenes and carotenoids on reversal of multidrug resistance in MDR-1 gene-transfected L1210 mouse lymphoma cells and MDR mediated multidrug resistance of human breast cancer cells MDA-MB-231 (HTB-26) and MCF-7. The majority of diterpenes, cycloartane triterpenes and carotenoids isolated from vegetables and medicinal plants were able to enhance rhodamine 123 accumulations of MDR-cells. Synergistic interaction was found between epirubicine and resistance modifier terpenoids in vitro. It is supposed that these MDR modulators bind into transmembrane domains and the action of ABC transporters is inhibited by induced conformational changes.     

Collateral sensitivity as a strategy against cancer multidrug resistance

While chemotherapy remains the most effective treatment for disseminated tumors, acquired or intrinsic drug resistance accounts for approximately 90% of treatment failure. Multidrug resistance (MDR), the simultaneous resistance to drugs that differ both structurally and mechanistically, often results from drug efflux pumps in the cell membrane that reduce intracellular drug levels to less than therapeutic concentrations. Expression of the MDR transporter P-glycoprotein (P-gp, MDR1, ABCB1) has been shown to correlate with overall poor chemotherapy response and prognosis. This review will focus on collateral sensitivity (CS), the ability of compounds to kill MDR cells selectively over the parental cells from which they were derived. Insights into CS may offer an alternative strategy for the clinical resolution of MDR, as highly selective and potent CS agents may lead to drugs that are effective at MDR cell killing and tumor resensitization. Four main mechanistic hypotheses for CS will be reviewed, followed by a discussion on quantitative and experimental evaluation of CS.     

多药耐药基因在上皮性卵巢癌组织中的表达及临床意义

目的 探讨多药耐药基因(MDR1)在上皮性卵巢癌组织中的表达及临床意义.方法 采用逆转录-聚合酶链反应测定27例上皮性卵巢癌(A组)、38例卵巢上皮性良性肿瘤(B组)、20例正常卵巢组织(C组)中MDR1的表达,比较三组MDR1表达的差异,并分析其临床意义.结果 C组不表达MDR1,B组.MDR1阳性表达率为15.7%,A组MDR1阳性表达率为74.1%,A、B两组比较,差异有统计学意义(P<0.01),A组中化疗无效者MDR1阳性表达率是90.1%,明显高于化疗有效者的58.8%(P<0.05).结论 MDR1在上皮性卵巢癌组织中有较高的表达,并与化疗疗效有关.     

Microbial multidrug resistance

Multiresistance plasmids and transposons, the integrons, the co-amplification of several resistance genes or finally the accumulation of independent mutations can lead to microorganisms resistant to multiple drugs. On the other hand multidrug resistance is due to an efflux pump conferring resistance to unrelated drugs. These microbial efflux pumps are belonging to various transporter families and are often encoded in microbial genomes. There is mounting evidence that these efflux systems are responsible for clinical multidrug resistance in bacteria, yeasts and parasites.