The ATP-binding cassette (ABC) transporters constitute a large family of membrane proteins, which transport a variety of compounds through the membrane against a concentration gradient at the cost of ATP hydrolysis. Substrates of the ABC transporters include lipids, bile acids, xenobiotics, and peptides for antigen presentation. As they transport exogenous and endogenous compounds, they reduce the body load of potentially harmful substances. One by-product of such protective function is that they also eliminate various useful drugs from the body, causing drug resistance. This review is a brief summary of the structure, function, and expression of the important drug resistance-conferring members belonging to three subfamilies of the human ABC family; these are ABCB1 (MDR1/P-glycoprotein of subfamily ABCB), subfamily ABCC (MRPs), and ABCG2 (BCRP of subfamily ABCG), which are expressed in various organs. In the text, the transporter symbol that carries the subfamily name (such as ABCB1, ABCC1, etc.) is used interchangeably with the corresponding original names, such as MDR1P-glycoprotein, MRP1, etc., respectively. Both nomenclatures are maintained in the text because both are still used in the transporter literature. This helps readers relate various names that they encounter in the literature. It now appears that P-glycoprotein, MRP1, MRP2, and BCRP can explain the phenomenon of multidrug resistance in all cell lines analyzed thus far. Also discussed are the gene structure, regulation of expression, and various polymorphisms in these genes. Because genetic polymorphism is thought to underlie interindividual differences, including their response to drugs and other xenobiotics, the importance of polymorphism in these genes is also discussed.

https://journals.sagepub.com/doi/pdf/10.1080/10915810600746023

Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters.

RNA interference (RNAi) is a powerful gene-silencing process that holds great promise in the field of cancer therapy. The discovery of RNAi has generated enthusiasm within the scientific community, not only because it has been used to rapidly identify key molecules involved in many disease processes including cancer, but also because RNAi has the potential to be translated into a technology with major therapeutic applications. Our evolving understanding of the molecular pathways important for carcinogenesis has created opportunities for cancer therapy employing RNAi technology to target the key molecules within these pathways. Many gene products involved in carcinogenesis have already been explored as targets for RNAi intervention, and RNAi targeting of molecules crucial for tumor-host interactions and tumor resistance to chemo- or radiotherapy has also been investigated. In most of these studies, the silencing of critical gene products by RNAi technology has generated significant antiproliferative and/or proapoptotic effects in cell-culture systems or in preclinical animal models. Nevertheless, significant obstacles, such as in vivo delivery, incomplete suppression of target genes, nonspecific immune responses and the so-called off-target effects, need to be overcome before this technology can be successfully translated into the clinical arena. Significant progress has already been made in addressing some of these issues, and it is foreseen that early phase clinical trials will be initiated in the very near future.

Prospects of RNA interference therapy for cancer.

Gene therapy represents a potential efficient approach of disease prevention and therapy. However, due to their poor in vivo stability, gene molecules need to be associated with delivery systems to overcome extracellular and intracellular barriers and allow access to the site of action. Cationic polymeric nanoparticles are popular carriers for small interfering RNA (siRNA) and DNA-based therapeutics for which efficient and safe delivery are important factors that need to be optimized. Micelle-like nanoparticles (MNP) (half micelles, half polymeric nanoparticles) can overcome some of the disadvantages of such cationic carriers by unifying in one single carrier the best of both delivery systems. In this review, we will discuss how the unique properties of MNP including self-assembly, condensation and protection of nucleic acids, improved cell association and gene transfection, and low toxicity may contribute to the successful application of siRNA- and DNA-based therapeutics into the clinic. Recent developme...

/pdf/micelle-like-nanoparticles-as-carriers-for-dna-and-sirna-3jsm2gxyx6.pdf

Micelle-like nanoparticles as carriers for DNA and siRNA.

Angiogenesis, the generation of new blood capillaries from preexisting blood vessels, is tightly regulated in the adult organism. Although many of the initial studies were performed on solid tumors, increasing evidence indicates that angiogenesis also plays an important role in hematologic malignancies. Overexpression of angiogenic factors in particular VEGF and bFGF in most hematologic malignancies may explain the increased angiogenesis found in these malignancies and correlate with poor prognosis as well as decreased overall survival. In this review, we focus on the current literature of angiogenesis and antiangiogenic therapy in hematologic malignancies, and finally describe advances and potential challenges in antiangiogenic treatment in hematologic malignancies.

Angiogenesis and antiangiogenic therapy in hematologic malignancies

Isatin (1H-indole-2,3-dione) and its derivatives are responsible for a broad spectrum of biological activities. Among these the cytotoxic and antineoplastic properties have been the most widely reported. The synthetic versatility of the isatin, due to its privileged scaffold, has led to the generation of a large number of structurally diverse derivatives which include analogues derived from either mono-, di-, and tri- substitution of the aryl ring A, and/or those obtained by derivatisation of the isatin nitrogen and C2/C3 carbonyl moieties. These compounds inhibit cancer cell proliferation and tumour growth via interaction with a variety of intracellular targets such as DNA, telomerase, tubulin, P-glycoprotein, protein kinases and phosphatases. Herein we review recent highlights in the development of isatin-based compounds as anticancer agents with a particular focus on the cytotoxicity and structure activity relationships.

/pdf/recent-highlights-in-the-development-of-isatin-based-2fy1jxnjc8.pdf

Recent highlights in the development of isatin- based anticancer agents

Anti-angiogenesis effects of meisoindigo on chronic myelogenous leukemia in vitro

The multidrug resistance (MDR) mediated by P-glycoprotein (P-gp), the MDR1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a MDR1-targeted small interfering RNA (si-MDR1) approach for reversal of P-gp-mediated MDR in the MDR human leukemia cell line k562/A02. It was found that si-MDR1 significantly inhibited MDR1 expression at both mRNA and protein levels. Depletion of MDR1 by si-MDR1 correlated with the increased sensitivity of the cells to cytotoxic agents and with the enhanced intracellular retention of daunorubicin (DNR). One base-pair mutated control (si-MDR1-Mut) lost the effect of si-MDR1 on both the degradation of mdr1 mRNA and the reduction of P-gp expression. These findings indicate that siRNA specifically and efficiently interferes with the expression of mdr1 and could be used as a molecularly defined therapeutic approach for MDR in the treatment of leukemia.

Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells

Recent investigations support the idea that angiogenesis is involved in the pathophysiology of hematologic malignancies, including chronic myeloid leukemia (CML). The aim of the present study was to evaluate plasma levels of VEGF and bFGF in a cohort of 51 chronic-phase CML patients at the time of diagnosis, as well as to investigate the effect of imatinib therapy on VEGF amounts in CML patients. Plasma VEGF levels were significantly higher in patients studied as compared with the 20 healthy subjects (p<0.001), the median plasma VEGF level detected in patients analysed and healthy controls was 433.4 pg mL−1 (range 65.2–2452.7 pg mL−1) and 81.6 pg mL−1 (range 44.2–338.7 pg mL−1), respectively. On the other hand, no difference in bFGF plasma levels could be found between chronic-phase CML patients and the control group. There were significant associations between plasma VEGF levels and some characteristics of patients evaluated, with trends for higher VEGF values in patients with enlarged spleens (p = 0.02)...

Elevated plasma levels of vascular endothelial growth factor is associated with marked splenomegaly in chronic myeloid leukemia.

Objective To investigate the effect of small interference RNA (siRNA) on mdr1 and P-glyco-protein (P-gp) expression of multi-drug resistance (MDR) human leukemia cell line K562/A02. Methods Three si RNAs (si-mdr1-1, si-mdr1-2, si-mdr1-3) which were specifically targeted mdr1 gene were synthesized and transfected into K562/A02 cells. Expression of mdr1 mRNA was assayed by RT-PCR. P-gp expression and intracellular daunorubicin (DNR) concentration were determined by flow cytometry. 50% inhibition concentration (IC(50)) of doxorubicin (ADM) on K562/A02 was determined by MTT method. Results Treatment of K562/A02 cell with the 3 kinds of siRNAs resulted in a reversal of MDR of a different extent. The third siRNA was more effective in the suppression of mdr1 with a significant reduction of (58.0 +/- 1.54)% of the mdr1 mRNA expression. Positive expression rate of p170 decreased from (76.0 +/- 1.0)% to (19.6 +/- 1.9)%, and the relative efficiency of K562/A02 to ADM was 70.4%. The intracellular accumulation of DNR increased after siRNA treatment. Conclusion The siRNA could effectively restore the sensitivity of K562/A02 cells to conventional chemotherapeutic agents.

[Reversal of multi-drug resistance in K562/A02 cells by small interference RNA of mdr1 gene].

BACKGROUND OBJECTIVE: To investigate the expression of vascular e ndothelial growth factor (VEGF) basic fibroblast growth factor (bFGF) in prima ry acute myeloid leukemia (AML) cells,and study plasma VEGFbFGF concentration in patients with AML and the two factorsclinical significance. METHODS: VEGF bFGF and their receptors mRNA expression were detected by RT-PCR; VEGF bFGF p lasma level was analyzed by ELISA. RESULTS: In 107 AML patients,the positive mRN A expression rate of VEGF,KDR and Flt1 was 56.1%,49.5%,and 2.8%,respectively; for bFGF and FGFR1～4,the positive rate was 21.5%,35.5%,9.4%,35.5%and 23.4 %,respectively. VEGF concentration in AML (154.75±109.98)pg/ml was significant ly higher than that in AML-CR (72.05±23.39)pg/ml and the normal control (99.9 1±41.87)pg/ml (P 0.05). Nevertheless,the level of bFGF had no significant d ifference among AML,AML-CR and the normal control. VEGF level (124.05±76.57) pg/ml in patients,who got complete remission (CR) after 2 cycles of chemotherapy ,was remarkably lower than that (211.243±169.88)pg/ml in patients without CR (P 0.05). Furthermore,the higher the concentration of VEGF bFGF,the shorter the survival was. CONCLUSION: VEGFbFGF and their receptors mRNA in leukemic p atients could be expressed to some degree,and our investigation suggested VEGF bFGF and their receptors probably be produced by autocrine or paracrin. Abnorm ally high level of VEGF may be a poor factor for chemotherapy and survival in AM L. The prognosis of patients with AML may be improved by treating VEGF and their receptors as therapy targets.

Expression of angiogenic factors and their clinical significances in acute myeloid leukemia

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