Considerations in the design and development of transport inhibitors as adjuncts to drug therapy

With the realization of the importance of drug efflux transporters in disease processes and treatment, development of inhibitors to these transporters has been sought for use as adjuncts to therapy. To date, inhibitors that have been best studied are modulators of P-glycoprotein, a transporter important in the removal of anticancer agents from cells and overexpression of this transporter results in multidrug resistance. There is a delicate balance between efficacy and toxicity. This review summarizes key learning points in the development of P-glycoprotein inhibitors. Topics covered include specificity of the inhibitor for the target transporter, effect on metabolism of coadministered drugs, pharmacokinetic interactions, toxicity and the salient features needed for efficacy. These points will have general application to the development of inhibitors of transporters.     

The ATP-binding cassette transporters and their implication in drug disposition: a special look at the heart

The passage of drugs across cell membranes dictates their absorption, distribution, metabolism, and excretion. This process is determined by several factors including the molecular weight of the compounds, their shape, degree of ionization, and binding to proteins. Accumulation of xenobiotics into tissues does not depend only on their ability to enter cells, but also on their ability to leave them. For instance, the role of efflux transporters such as ATP-binding cassette (ABC) proteins in the disposition of drugs is now well recognized. Actually, ABC transporters act in synergy with drug-metabolizing enzymes to protect the organism from toxic compounds. The most studied transporter from the ABC transporter superfamily, P-glycoprotein, was found to be overexpressed in tumor cells and associated with an acquired resistance to several anticancer drugs. P-glycoprotein, thought at first to be confined to tumor cells, was subsequently recognized to be expressed in normal tissues such as the liver, kidney, intestine, and heart. Even though information remains rather limited on the functional role of ABC transporters in the myocardium, it is hypothesized that they may modulate efficacy and toxicity of cardioactive agents. This review addresses recent progress on knowledge about the ABC transporters in drug disposition and more precisely their role in drug distribution to the heart.     

Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences.

Intrinsic resistance to anticancer drugs, or resistance developed during chemotherapy, remains a major obstacle to successful treatment. This is the case both for resistance to cytotoxic agents, directed at malignant cells, and for resistance to anti-angiogenic agents, directed at non-malignant endothelial cells. In this review, we will discuss mechanisms of resistance which have a bearing on both these conceptually different classes of drugs. The complexity of drug resistance, involving drug transporters, such as P-glycoprotein, as well as resistance related to the tissue structure of solid tumors and its consequences for drug delivery is discussed. Possible mechanisms of resistance to endothelial cell-targeted drugs, including inhibitors of the VEGF receptor and EGF receptor family, are reviewed. The resistance of cancer cells as well as endothelial cells related to anti-apoptotic signaling events initiated by cell integrin-matrix interactions is discussed. Current strategies to overcome resistance mechanisms are summarized; they include high-dose chemotherapy, tumor targeting of cytotoxics to improve tumor uptake, low-dose protracted (metronomic) chemotherapy and combinations of classical agents with anti-angiogenic agents. This review discusses primarily literature published in 2001 and 2002.     

Overview of SLC22A and SLCO families of drug uptake transporters in the context of cancer treatments

The effectiveness of many anticancer agents is dependent on their disposition to the intracellular space of cancerous tissue. Accumulation of anticancer drugs at their sites of action can be altered by both uptake and efflux transport proteins, however the majority of research on the disposition of anticancer drugs has focused on drug efflux transporters and their ability to confer multidrug resistance. Here we review the roles of uptake transporters of the SLC22A and SLCO families in the context of cancer therapy. The many first-line anticancer drugs that are substrates of organic cation transporters (OCTs) organic cation/carnitine transporters (OCTNs) and organic anion- transporting polypeptides (OATPs) are summarized. In addition, where data is available a comparison of the localization of drug uptake transporters in healthy and cancerous tissues is provided. Expression of drug uptake transporters increases the sensitivity of cancer cell lines to anticancer substrates. Furthermore, early observational studies have suggested a causal link between drug uptake transporter expression and positive outcome in some cancers. Quantification of drug transporters by mass spectrometry will provide an essential technique for generation of expression data during future observational clinical studies. Screening of drug uptake transporter expression in primary tumors may help differentiate between susceptible and resistant cancers prior to therapy.     

Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance in vitro

Drug resistance limits the success of many anticancer drugs. Reduced accumulation of the drug at its intracellular site of action because of overexpression of efflux transporters such as P-glycoprotein (P-gp) is a major mechanism of drug resistance. In this study, we investigated whether photodynamic therapy (PDT) using methylene blue, also a P-gp inhibitor, can be used to enhance doxorubicin-induced cytotoxicity in drug-resistant tumor cells. Aerosol OT (AOT)-alginate nanoparticles were used as a carrier for the simultaneous cellular delivery of doxorubicin and methylene blue. Methylene blue was photoactivated using light of 665 nm wavelength. Induction of apoptosis and necrosis following treatment with combination chemotherapy and PDT was investigated in drug-resistant NCI/ADR-RES cells using flow cytometry and fluorescence microscopy. Effect of encapsulation in nanoparticles on the intracellular accumulation of doxorubicin and methylene blue was investigated qualitatively using fluorescence microscopy and was quantitated using HPLC. Encapsulation in AOT-alginate nanoparticles significantly enhanced the cytotoxicity of combination therapy in resistant tumor cells. Nanoparticle-mediated combination therapy resulted in a significant induction of both apoptosis and necrosis. Improvement in cytotoxicity could be correlated with enhanced intracellular and nuclear delivery of the two drugs. Further, nanoparticle-mediated combination therapy resulted in significantly elevated reactive oxygen species (ROS) production compared to single drug treatment. In conclusion, nanoparticle-mediated combination chemotherapy and PDT using doxorubicin and methylene blue was able to overcome resistance mechanisms and resulted in improved cytotoxicity in drug-resistant tumor cells.     

Role of ABC transporters in the chemoresistance of human gliomas

Malignant gliomas are frequently chemoresistant and this resistance seems to depend on at least two mechanisms. First, the poor penetration of many anticancer drugs across the blood-brain barrier (BBB), the blood-cerebrospinal fluid barrier (BCSFB) and blood-tumor barrier (BTB), due to their interaction with several ATP-binding cassette (ABC) drug efflux transporters that are overexpressed by the endothelial or epithelial cells of these barriers. Second, resistance may involve the tumor cells themselves. Although ABC drug efflux transporters in tumor cells confer multidrug resistance (MDR) on several other solid tumors, their role in gliomas is unclear. This review focuses on astrocytes and summarizes the current state of knowledge about the expression, distribution and function of ABC transporters in normal and tumor astroglial cells. The recognition of anticancer drugs by ABC transporters in astroglial cells and their participation in the multidrug resistance phenotype of human gliomas is discussed.     

Metabolic limitations of the use of nucleoside analogs in cancer therapy may be overcome by application of nanoparticles as drug carriers: A review

Purine and pyrimidine nucleoside analogs (NAs) are antimetabolites commonly used in cancer therapy. Administered as prodrugs, NAs permeate the mambrane using specialized transporters. Following phosphorylation, they interfere with multiple cellular pocessess inducing cytotoxicity. Toxic effects of NAs are dependent on metabolic conversion from a prodrug into the active form. For instance, an exceptionally high activity of deoxycytidine kinase (dCK) in lymphocytes is correlated with a good therapeutic effect of fludarabine in leukemic cells. On the other hand, several studies have shown that nucleoside‐transporter (NT)‐deficient‐cells are highly resistant to NAs. Attempts to overcome the metabolic limitations of chemotherapeutics would result in the use of lower drug doses for effective therapy, reduce side effects, and ensure the independence of drug resistance mechanisms. To meet this need, several nanoparticles have been designed to deliver efficently NAs directly to cancer cells. Such vehicles include liposomes, albumins, and dendritic and linear polymers. Therapeutic agents encapsulated or conjugated to nanoparticles have improved pharmacokinetics, solubility, and stability. These factors improve the efficacy of commonly used drugs. Moreover, modification of nanoparticles with targeting molecules such as sugar moieties or folic acid ensures more specific delivery without affecting healthy tissues. Drug Dev Res 71: 383–394, 2010. © 2010 Wiley‐Liss, Inc.     

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.     

ABC transporters in Leishmania and their role in drug resistance.

ABC transporters have been found in several parasitic protozoa including Leishmania. At least two Leishmania ABC transporters are involved in drug resistance. One is PgpA, which is involved in resistance to arsenic and antimony-containing compounds. Antimonials are the drug of choice against Leishmania infections. Transfection and biochemical studies suggest that PgpA recognizes metals conjugated to thiols. The second ABC transporter is closely related to mammalian P-glycoproteins and confers resistance to anticancer drugs by a mechanism that remains to be elucidated. Additional ABC transporters are likely to be present in Leishmania and these are discussed in relation to the phenomenon of antimony resistance.     

Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.     

Novel insights into targeting ATP-binding cassette transporters for antitumor therapy

ATP-binding cassette (ABC) transporters are a large family of proteins implicated in physiological cellular functions. Selected components of the family play a well-recognized role in extruding conventional cytotoxic antitumor agents and molecularly targeted drugs from cells. Some lines of evidence also suggest links between transporters and tumor cell survival, in part unrelated to efflux. However, the study of the precise mechanisms regulating the function of drug transporters (e.g., posttranslational modifications such as glycosylation) is still in its infancy. A better definition of the molecular events clarifying the regulation of transporter levels including regulation by microRNAs may contribute to provide new molecular tools to target such a family of transporters. The present review focuses on the biological aspects that implicate ABC transporters in resistance of tumor cells, including cancer stem cells. Molecular analysis of well-known preclinical systems as well as of cancer stem cell models supports the notion that ABC transporters represent amenable targets for modulation of the efficacy of antitumor agents endowed with different molecular features. Recent achievements regarding tumor cell biology are expected to provide a rationale for developing novel inhibitors that target ABC transporters implicated in drug resistance.     

Strategies on the development of small molecule anticancer drugs for targeted therapy

The main challenges currently encountered in chemotherapy are the lack of tumor selectivity and drug resistance. The design of novel cytostatic drugs has become the state-of-the-art technology in terms of targeted tumor therapy. This review illustrates the mechanisms and the advantages of representative chemotherapeutic agents, and presents an updated summary of the various drug design strategies developed by modern medicinal chemists during the most recent tumor targeting research which include rational design for overcoming drug resistance, the combi-targeting strategy, the prodrug approach, and tumor specific transporter based drug design. The concept of transporter related tumor targeting strategies for small molecule anticancer drug design discussed in this review may be amenable to predictable drug discovery for targeted therapy.     

肠道药物转运体对药物吸收的研究进展

药物与体内各种转运体的相互作用是药物体内药动学性质的决定性因素之一。本文从肠道转运体出发,介绍了它们在药物吸收过程中的作用,旨在利用肠道转运体的作用增加药物向组织器官的靶向分布;利用转运体的作用改变药物的消除途径,从而减轻其毒副作用;利用转运体的作用进行新药设计从而避免药物间有害相互作用的产生;最后通过构建转运体的高通量筛选系统模型,进行新化合物筛选和候选药物的药动学机制研究,为新药的开发和临床合理化给药提供新的策略和思路。     

Lipid-based drug delivery systems for cancer treatment

It is a fact that chemotherapy agents have little specificity for cancer cells, this leading to low concentrations into the tumor interstititum and severe side effects on healthy tissues. The formulation of lipid-based nanomedicines against cancer has been hypothesized to improve drug localization into the tumor tissue and to increase the anticancer efficacy of concentional drugs, while minimizing their systemic adverse effects. In this review, special attention is devoted to the analysis of the state-of-the-art in the development of lipid-based drug carriers against cancer. Specifically, the most significant in vitro and in vivo results on the use of niosomes, liposomes, and solid lipid nanoparticles are revised. It is concluded that biodistribution profiles of chemotherapy agents can be controlled by their loading to such nanoplatforms. Lipid-based nanomedicines offer an interesting approach to the delivery of anticancer drugs to brain tumors, and to reverse multi-drug resistance of cancer cells. Finally, a deep evaluation of the applicability of drug delivery strategies in the formulation of lipid-based nanoplatforms is carried out. They involve active drug targeting (including ligand-mediated delivery, and stimuli-sensitive carriers), and passive drug targeting (through the enhanced permeability and retention effect) to tumors.     

Role of CNS efflux drug transporters in antiepileptic drug delivery: overcoming CNS efflux drug transport

Experimental support for the transporter hypothesis of drug resistance in epilepsies has triggered efforts developing and validating approaches to overcome enhanced blood-brain barrier efflux transport. Testing in rodent models has rendered proof-of-concept for an add-on therapy with antiepileptic drugs. However, further development of the approach would require tolerability considerations as efflux transporters serve an important protective function throughout the body limiting distribution of harmful xenobiotics. Relevant progress has been made in the elucidation of mechanisms driving up-regulation of the multidrug transporter P-glycoprotein in response to seizure activity. Based on this knowledge, novel strategies have been evaluated targeting the signaling cascade that regulates P-glycoprotein in the epileptic brain. Further concepts might include by-passing blood-brain barrier transporters by intracerebral administration or by encapsulation of antiepileptic drugs in nano-sized carrier systems. It is important to note that the future perspectives of respective approaches are still questionable based on the limited evidence for a clinical relevance of transporter expression. Thus, techniques are urgently needed for non-invasive assessment of blood-brain barrier transporter function. Respective techniques would allow testing for a clinical correlation between pharmacosensitivity and transporter function, validating therapeutic strategies targeting efflux transporters and selecting patients with transporter over-expression for respective clinical trials. Provided that further clinical data render support for the transporter hypothesis, the main question remains whether patients exist in which transporter over-expression is the predominant mechanism of drug resistance and in which overcoming drug efflux is equivalent with overcoming drug resistance. Imaging techniques might provide a tool to address these questions in clinical epileptology. However, the complex pharmacological interactions between antiepileptic drugs, radiotracers, and transporter modulators used in these approaches as well as interindividual differences in the brain pathology might hamper clear-cut conclusions and limit the diagnostic significance.     

Molecular mechanisms for tumour resistance to chemotherapy

Chemotherapy is one of the prevailing methods used to treat malignant tumours, but the outcome and prognosis of tumour patients are not optimistic. Cancer cells gradually generate resistance to almost all chemotherapeutic drugs via a variety of distinct mechanisms and pathways. Chemotherapeutic resistance, either intrinsic or acquired, is caused and sustained by reduced drug accumulation and increased drug export, alterations in drug targets and signalling transduction molecules, increased repair of drug‐induced DNA damage, and evasion of apoptosis. In order to better understand the mechanisms of chemoresistance, this review highlights our current knowledge of the role of altered drug metabolism and transport and deregulation of apoptosis and autophagy in the development of tumour chemoresistance. Reduced intracellular activation of prodrugs (e.g. thiotepa and tegafur) or enhanced drug inactivation by Phase I and II enzymes contributes to the development of chemoresistance. Both primary and acquired resistance can be caused by alterations in the transport of anticancer drugs which is mediated by a variety of drug transporters such as P‐glycoprotein (P‐gp), multidrug resistance associated proteins, and breast cancer resistance protein. Presently there is a line of evidence indicating that deregulation of programmed cell death including apoptosis and autophagy is also an important mechanism for tumour resistance to anticancer drugs. Reversal of chemoresistance is likely via pharmacological and biological approaches. Further studies are warranted to grasp the full picture of how each type of cancer cells develop resistance to anticancer drugs and to identify novel strategies to overcome it.     

Lipid-polymer hybrid nanoparticle with cell-distinct drug release for treatment of stemness-derived resistant tumor

Drug resistance presents one of the major causes for the failure of cancer chemotherapy.Cancer stem-like cells(CSCs),a population of self-renewal cells with high tumorigenicity and innate chemoresistance,can survive conventional chemotherapy and generate increased resistance.Here,we develop a lipid-polymer hybrid nanoparticle for co-delivery and cell-distinct release of the differentiation-inducing agent,all-trans retinoic acid and the chemotherapeutic drug,doxorubicin to overcome the CSC-associ...     

纳米粒给药系统逆转肿瘤多药耐药性的研究进展

多药耐药是导致肿瘤化疗失败的主要原因。对于大多数抗肿瘤药物,肿瘤细胞均会产生多药耐药现象, 但其耐药机制,目前没有统一的看法。本文对纳米粒给药系统逆转肿瘤多药耐药性进行了综述, 包括3种载药系统: 非修饰的、配体修饰的和多功能纳米粒给药系统,并对纳米粒给药系统逆转肿瘤多药耐药性的机制进行探讨。纳米粒通过拮抗和抵消肿瘤细胞主动外排药物的作用,提高肿瘤细胞内的药物浓度,同时减小对正常细胞的毒副作用, 逆转肿瘤的多药耐药性。这种新型的给药系统,结合了纳米技术及主动和被动靶向给药策略,在癌症治疗方面已显示出巨大的应用前景。