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Overcoming Multidrug Resistance in Cancer Stem Cells.

Moitra K - Biomed Res Int (2015)

Bottom Line: These transporters serve as the guardians of the stem cell population in the body.Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy.These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Arts and Sciences, Trinity Washington University, 125 Michigan Avenue NE, Washington, DC 20017, USA.

ABSTRACT
The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC) transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram of a typical ABC transporter (ABCB1/P-glycoprotein) depicting the structural organization of a full transporter. A full transporter typically contains 2 transmembrane domains (TMDs) and 2 nucleotide binding domains (NBDs).
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fig1: Schematic diagram of a typical ABC transporter (ABCB1/P-glycoprotein) depicting the structural organization of a full transporter. A full transporter typically contains 2 transmembrane domains (TMDs) and 2 nucleotide binding domains (NBDs).

Mentions: ATP-binding cassette transporters (ABC transporters) are intricate molecular pumps most of which catalyze the transport of a wide array of substrates across biological membranes against a concentration gradient, by the hydrolysis of ATP. The human genome is known to encode 48 ABC transporter genes categorized into seven subfamilies, ranging from A to G [6]. ABC transporters are classified based on the sequence and organization of their ATP-binding domain(s) that contain specific conserved motifs, Walker A and Walker B (present in all ATP-binding protein); however ABC transporters contain an additional motif, the signature motif or the C-loop that is located upstream of Walker B motif. Functional transporters usually contain two transmembrane domains (TMDs) generally made up of 6–12 membrane-spanning alpha-helices that are primarily responsible for determining substrate specificity. Additionally there are two nucleotide binding domains (NBDs) that bind and hydrolyze ATP providing the energy for substrate translocation (Figure 1). ABC transporters may be expressed in stem/progenitor cells derived from several types of normal tissue and also in hematopoietic cells. Hematopoietic stem cells (HSCs) were found to express high levels of ABCG2 and/or ABCB1 transporters [7]. Mouse knockouts for ABCB1, ABCG2, or ABCC1 revealed that mice are particularly sensitive to some compounds such as mitoxantrone, vinblastine, ivermectin, and topotecan indicating that these transporters may have a role in protecting the stem cells from toxic substances [8]. Using the aid of Taqman low density arrays ABC transporters were also found to be expressed in normal stem cells such as hematopoietic stem cells (HSCs), unrestricted somatic stem cells (USSCs), mesenchymal stem cells (MSCs), and multipotent adult progenitor cells (MAPCs) [9]. HSCs seemed to rely on a different repertoire of these transporters compared to other tissue/cell types based on the fact that gene signatures for ABC transporters were found to be radically different between HSCs and other types of stem cells. 16 transporters in total including ABCB1 and ABCG1 were discovered to be consistently expressed at higher levels in HSCs when compared to other transporters. The transporters ABCA4, ABCA8, ABCC9, and ABCG4 were consistently detected in MSCs and USSCs [9].


Overcoming Multidrug Resistance in Cancer Stem Cells.

Moitra K - Biomed Res Int (2015)

Schematic diagram of a typical ABC transporter (ABCB1/P-glycoprotein) depicting the structural organization of a full transporter. A full transporter typically contains 2 transmembrane domains (TMDs) and 2 nucleotide binding domains (NBDs).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663294&req=5

fig1: Schematic diagram of a typical ABC transporter (ABCB1/P-glycoprotein) depicting the structural organization of a full transporter. A full transporter typically contains 2 transmembrane domains (TMDs) and 2 nucleotide binding domains (NBDs).
Mentions: ATP-binding cassette transporters (ABC transporters) are intricate molecular pumps most of which catalyze the transport of a wide array of substrates across biological membranes against a concentration gradient, by the hydrolysis of ATP. The human genome is known to encode 48 ABC transporter genes categorized into seven subfamilies, ranging from A to G [6]. ABC transporters are classified based on the sequence and organization of their ATP-binding domain(s) that contain specific conserved motifs, Walker A and Walker B (present in all ATP-binding protein); however ABC transporters contain an additional motif, the signature motif or the C-loop that is located upstream of Walker B motif. Functional transporters usually contain two transmembrane domains (TMDs) generally made up of 6–12 membrane-spanning alpha-helices that are primarily responsible for determining substrate specificity. Additionally there are two nucleotide binding domains (NBDs) that bind and hydrolyze ATP providing the energy for substrate translocation (Figure 1). ABC transporters may be expressed in stem/progenitor cells derived from several types of normal tissue and also in hematopoietic cells. Hematopoietic stem cells (HSCs) were found to express high levels of ABCG2 and/or ABCB1 transporters [7]. Mouse knockouts for ABCB1, ABCG2, or ABCC1 revealed that mice are particularly sensitive to some compounds such as mitoxantrone, vinblastine, ivermectin, and topotecan indicating that these transporters may have a role in protecting the stem cells from toxic substances [8]. Using the aid of Taqman low density arrays ABC transporters were also found to be expressed in normal stem cells such as hematopoietic stem cells (HSCs), unrestricted somatic stem cells (USSCs), mesenchymal stem cells (MSCs), and multipotent adult progenitor cells (MAPCs) [9]. HSCs seemed to rely on a different repertoire of these transporters compared to other tissue/cell types based on the fact that gene signatures for ABC transporters were found to be radically different between HSCs and other types of stem cells. 16 transporters in total including ABCB1 and ABCG1 were discovered to be consistently expressed at higher levels in HSCs when compared to other transporters. The transporters ABCA4, ABCA8, ABCC9, and ABCG4 were consistently detected in MSCs and USSCs [9].

Bottom Line: These transporters serve as the guardians of the stem cell population in the body.Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy.These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters.

View Article: PubMed Central - PubMed

Affiliation: Department of Biology, College of Arts and Sciences, Trinity Washington University, 125 Michigan Avenue NE, Washington, DC 20017, USA.

ABSTRACT
The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC) transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed.

No MeSH data available.


Related in: MedlinePlus