Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration
Standard
Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration. / Chapuy, B; Koch, R; Radunski, U; Corsham, S; Cheong, N; Inagaki, N; Ban, N; Wenzel, D; Reinhardt, D; Zapf, A; Schweyer, S; Kosari, F; Klapper, W; Truemper, L; Wulf, G G.
In: LEUKEMIA, Vol. 22, No. 8, 08.2008, p. 1576-1586.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Intracellular ABC transporter A3 confers multidrug resistance in leukemia cells by lysosomal drug sequestration
AU - Chapuy, B
AU - Koch, R
AU - Radunski, U
AU - Corsham, S
AU - Cheong, N
AU - Inagaki, N
AU - Ban, N
AU - Wenzel, D
AU - Reinhardt, D
AU - Zapf, A
AU - Schweyer, S
AU - Kosari, F
AU - Klapper, W
AU - Truemper, L
AU - Wulf, G G
PY - 2008/8
Y1 - 2008/8
N2 - Multidrug resistance (MDR) seriously limits the efficacy of chemotherapy in patients with cancer and leukemia. Active transport across membranes is essential for such cellular drug resistance, largely provided by ATP-binding cassette (ABC) transport proteins. Intracellular drug sequestration contributes to MDR; however, a genuine intracellular ABC transport protein with MDR function has not yet been identified. Analyzing the intrinsic drug efflux capacity of leukemic stem cells, we found the ABC transporter A3 (ABCA3) to be expressed consistently in acute myeloid leukemia (AML) samples. Greater expression of ABCA3 is associated with unfavorable treatment outcome, and in vitro, elevated expression induces resistance toward a broad spectrum of cytostatic agents. ABCA3 remains localized within the limiting membranes of lysosomes and multivesicular bodies, in which cytostatics are efficiently sequestered. In addition to AML, we also detected ABCA3 in a panel of lymphohematopoietic tissues and transformed cell lines. In conclusion, we identified subcellular drug sequestration mediated by the genuinely intracellular ABCA3 as being a clinically relevant mechanism of intrinsic MDR.
AB - Multidrug resistance (MDR) seriously limits the efficacy of chemotherapy in patients with cancer and leukemia. Active transport across membranes is essential for such cellular drug resistance, largely provided by ATP-binding cassette (ABC) transport proteins. Intracellular drug sequestration contributes to MDR; however, a genuine intracellular ABC transport protein with MDR function has not yet been identified. Analyzing the intrinsic drug efflux capacity of leukemic stem cells, we found the ABC transporter A3 (ABCA3) to be expressed consistently in acute myeloid leukemia (AML) samples. Greater expression of ABCA3 is associated with unfavorable treatment outcome, and in vitro, elevated expression induces resistance toward a broad spectrum of cytostatic agents. ABCA3 remains localized within the limiting membranes of lysosomes and multivesicular bodies, in which cytostatics are efficiently sequestered. In addition to AML, we also detected ABCA3 in a panel of lymphohematopoietic tissues and transformed cell lines. In conclusion, we identified subcellular drug sequestration mediated by the genuinely intracellular ABCA3 as being a clinically relevant mechanism of intrinsic MDR.
KW - ATP-Binding Cassette Transporters
KW - Acute Disease
KW - Base Sequence
KW - Cell Line, Tumor
KW - DNA Primers
KW - Drug Resistance, Multiple
KW - Drug Resistance, Neoplasm
KW - Flow Cytometry
KW - Humans
KW - Leukemia, Myeloid, Acute
KW - Lysosomes
KW - Polymerase Chain Reaction
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/leu.2008.103
DO - 10.1038/leu.2008.103
M3 - SCORING: Journal article
C2 - 18463677
VL - 22
SP - 1576
EP - 1586
JO - LEUKEMIA
JF - LEUKEMIA
SN - 0887-6924
IS - 8
ER -
