The antiporter system xc− imports the amino acid cystine, the oxidized form of cysteine, into cells with a 1:1 counter-transport of glutamate. It is composed of a light chain, xCT, and a heavy chain, 4F2 heavy chain (4F2hc), and, thus, belongs to the family of heterodimeric amino acid transporters. Cysteine is the rate-limiting substrate for the important antioxidant glutathione (GSH) and, along with cystine, it also forms a key redox couple on its own. Glutamate is a major neurotransmitter in the central nervous system (CNS). By phylogenetic analysis, we show that system xc− is a rather evolutionarily new amino acid transport system. In addition, we summarize the current knowledge regarding the molecular mechanisms that regulate system xc−, including the transcriptional regulation of the xCT light chain, posttranscriptional mechanisms, and pharmacological inhibitors of system xc−. Moreover, the roles of system xc− in regulating GSH levels, the redox state of the extracellular cystine/cysteine re...

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The cystine/glutamate antiporter system xc- in health and disease: From molecular mechanisms to novel therapeutic opportunities

It is generally accepted that recent advances in anticancer agents have contributed significantly to the improvement of both the disease-free survival and quality of life in cancer patients. However, in many instances, a favorable initial response to treatment changes afterwards, thereby leading to cancer relapse and recurrence. This phenomenon of acquired resistance to therapy, it is a major problem for totally efficient anticancer therapy. The failure to obtain an initial response reflects a form of intrinsic resistance. Specific cell membrane transporter proteins are implicated in intrinsic drug resistance by altering drug transport and pumping drugs out of the tumor cells. Moreover, the gradual acquisition of specific genetic and epigenetic abnormalities in cancer cells could contribute greatly to acquired drug resistance. A critical issue in the clinical setting, is that the problem of drug resistance appears to have a negative effect on also the new molecularly-targeted anticancer drugs. Several ongoing efforts are being made by the medical community aimed to the identification of such resistance mechanisms and the development of novel drugs that could overcome them. In this review, the major drug resistance mechanisms and strategies to overcome them are critically discussed, and also possible future directions are suggested.

The challenge of drug resistance in cancer treatment: a current overview.

Recent development of biotin conjugation in biological imaging, sensing, and target delivery

Anticancer drugs are often nonselective antiproliferative agents (cytotoxins) that preferentially kill dividing cells by attacking their DNA at some level. The lack of selectivity results in significant toxicity to noncancerous proliferating cells. These toxicities along with drug resistance exhibited by the solid tumors are major therapy limiting factors that result into poor prognosis for patients. Prodrug and conjugate design involves the synthesis of inactive drug derivatives that are converted to an active form inside the body and preferably at the site of action. Classical prodrug and conjugate design have focused on the development of prodrugs that can overcome physicochemical (e.g., solubility, chemical instability) or biopharmaceutical problems (e.g., bioavailability, toxicity) associated with common anticancer drugs. The recent targeted prodrug and conjugate design, on the other hand, hinge on the selective delivery of anticancer agents to tumor tissues thereby avoiding their cytotoxic effects on noncancerous cells. Targeting strategies have attempted to take advantage of low extracellular pH, elevated enzymes in tumor tissues, the hypoxic environment inside the tumor core, and tumor-specific antigens expressed on tumor cell surfaces. The present review highlights recent trends in prodrug and conjugate rationale and design for cancer treatment. The various approaches that are currently being explored are critically analyzed and a comparative account of the advantages and disadvantages associated with each approach is presented.

/pdf/recent-trends-in-targeted-anticancer-prodrug-and-conjugate-dxkfbzqjwn.pdf

Recent trends in targeted anticancer prodrug and conjugate design.

Chemotherapy is one of the principal modes of treatment for cancer patients. Clinically, many tumors present a satisfactory response when they are first exposed to the chemotherapeutic drugs. However, drug resistance occurs sooner or later in these tumors, and the majority of the patients develop progressive disease. The mechanisms of treatment failure of chemotherapeutic drugs have been well studied. Via a unique protection system, i.e. multidrug resistance (MDR), the cancer cells can escape the toxic effect of most commonly used cancer drugs in spite of their different chemical structures and different mechanisms of intracellular activity. There are two classes of transporter proteins at the cellular surface which are responsible for MDR in tumors. One is the adenosine triphosphate-binding cassette transporter superfamily, which is an energy-requiring efflux pump with the function of extruding toxic chemotherapeutic drugs from the cancer cells. The other is the solute carrier transporter superfamily, which mediates the cellular uptake of anticancer drugs, and drug resistance may result from decreased activity of these transporters. Although transporters of MDR are responsible for the tumor resistance to many chemotherapeutic drugs currently used in cancer therapy, the mechanisms of resistance to platinum-based antitumor agents are through different pathways. In this article, the mechanisms of MDR transporters mediating resistance to the commonly used chemotherapeutic drugs and to platinum-based agents are reviewed. Finally, with the finding of cancer stem cells in more and more solid tumors, it is recognized that the cancer stem cell is spared along with its normal tissue stem cell counterparts with very subtle differences. One characteristic of the normal tissue stem cell is the self-protection ability through innate MDR transporters. Therefore, the essential self-protection property is also present in the cancer stem cells. The quiescent tumor stem cell with constitutive MDR is the main barrier to therapy. Successful cancer therapy will depend on the ability to discern the subtle differences between the tumor and normal stem cells so that approaches can be developed to eliminate the tumor stem cells without excessive toxicity to normal stem cells.

Mechanisms of Chemotherapeutic Drug Resistance in Cancer Therapy-A Quick Review

Inter-individual variability in drug response and the emergence of adverse drug reactions are main causes of treatment failure in cancer therapy. Recently, membrane transporters have been recognized as an important determinant of drug disposition, thereby affecting chemosensitivity and -resistance. Genetic factors contribute to inter-individual variability in drug transport and targeting. Therefore, pharmacogenetic studies of membrane transporters can lead to new approaches for optimizing cancer therapy. This review discusses genetic variations in efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (MDR1, P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP), and uptake transporters of the solute carrier (SLC) family such as SLC19A1 (RFC1) and SLCO1B1 (SLC21A6), and their relevance to cancer chemotherapy. Furthermore, a pharmacogenomic approach is outlined, which using correlations between the growth inhibitory potency of anticancer drugs and transporter gene expression in multiple human cancer cell lines, has shown promise for determining the relevant transporters for any given drugs and predicting anticancer drug response.

Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy

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Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy