P-glycoprotein in Acute Myeloid Leukaemia: Therapeutic Implications of its Association With Both a Multidrug-resistant and an Apoptosis-resistant Phenotype

Pallis, Monica; Turzanski, J.; Higashi, Y.; Russell, Nigel H.

doi:10.1080/10428190290026277

Cited by 81 publications

(59 citation statements)

References 81 publications

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“…Whatever is the exact mechanism of action of these MDR proteins (decrease of intracellular drug accumulation or attenuation of the consequences of intracellular drug accumulation), the final outcome is a resistance to chemotherapeutic drug-induced apoptosis (reviewed in Sietsma et al 36 , Pallis et al . 37 ). The present investigation illustrates for the first time the involvement of SphK1 in chemoresistance of acute myeloid leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

et al. 2005

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We examined the involvement of sphingosine kinase-1, a critical regulator of the sphingolipid balance, in susceptibility to antineoplastic agents of either sensitive or multidrugresistant acute myeloid leukemia cells. Contrary to parental HL-60 cells, doxorubicin and etoposide failed to trigger apoptosis in chemoresistant HL-60/Doxo and HL-60/VP16 cells overexpressing MRP1 and MDR1, respectively. Chemosensitive HL-60 cells displayed sphingosine kinase-1 inhibition coupled with ceramide generation. In contrast, chemoresistant HL-60/ Doxo and HL-60/VP16 had sustained sphingosine kinase-1 activity and did not produce ceramide during treatment. Enforced expression of sphingosine kinase-1 in chemosensitive HL-60 cells resulted in marked inhibition of apoptosis that was mediated by blockade of mitochondrial cytochrome c efflux hence suggesting a control of apoptosis at the premitochondrial level. Incubation with cell-permeable ceramide of chemoresistant cells led to a sphingosine kinase-1 inhibition and apoptosis both prevented by sphingosine kinase-1 overexpression. Furthermore, F-12509a, a new sphingosine kinase inhibitor, led to ceramide accumulation, decrease in sphingosine 1-phosphate content and caused apoptosis equally in chemosensitive and chemoresistant cell lines that is inhibited by adding sphingosine 1-phosphate or overexpressing sphingosine kinase-1. F-12509a induced classical apoptosis hallmarks namely nuclear fragmentation, caspase-3 cleavage as well as downregulation of antiapoptotic XIAP, and release of cytochrome c and SMAC/Diablo. Leukemia (2006) 20, 95-102.

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Section: Discussionmentioning

confidence: 99%

Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

et al. 2005

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“…For instance, recent studies have indicated that Pgp and MRPs may protect astrocytes and other cell types from apoptosis. 111,112 Nevertheless, transient inhibition of ABC transporters such as Pgp by short-term administration of inhibitors may be a useful strategy to reverse or prevent pharmacoresistance due to overexpression of such transporters.…”

Section: How Can Understanding Of Bbb Abc Transporters Be Used To Incmentioning

confidence: 99%

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

2005

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Summary:The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.

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“…In this context, it is noteworthy that an anti-apoptotic role for ABCB1 has been demonstrated recently promoting cell survival by inhibiting caspase activation. [42][43][44][45] Physiological function of other ABC transporters in HSC. Characterization of molecules with tightly controlled expression patterns during differentiation represents an important approach to understanding the regulation of HSC commitment.…”

Section: Abc Transporter Activity As Marker Of Hematopoietic Stem Cellsmentioning

confidence: 99%

ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia

Raaijmakers

2007

Leukemia

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ATP-binding-cassette (ABC) transporters are evolutionary extremely well-conserved transmembrane proteins that are highly expressed in hematopoietic stem cells (HSCs). The physiological function in human stem cells is believed to be protection against genetic damage caused by both environmental and naturally occurring xenobiotics. Additionally, ABC transporters have been implicated in the maintenance of quiescence and cell fate decisions of stem cells. These physiological roles suggest a potential role in the pathogenesis and biology of stem cell-derived hematological malignancies such as acute and chronic myeloid leukemia. This paper reviews the (patho)physiological role of ABC transporters in human normal and malignant HSCs and discusses its implications for their utility as therapeutical targets to eradicate leukemic stem cells in these diseases.

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P-glycoprotein in Acute Myeloid Leukaemia: Therapeutic Implications of its Association With Both a Multidrug-resistant and an Apoptosis-resistant Phenotype

Cited by 81 publications

References 81 publications

Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

Overcoming MDR-associated chemoresistance in HL-60 acute myeloid leukemia cells by targeting shingosine kinase-1

Blood-brain barrier active efflux transporters: ATP-binding cassette gene family

ATP-binding-cassette transporters in hematopoietic stem cells and their utility as therapeutical targets in acute and chronic myeloid leukemia

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