Role of MRP1 in multidrug resistance in acute myeloid leukemia

Legrand, Ollivier; Zittoun, R; Marie, Jean‐Pierre

doi:10.1038/sj.leu.2401361

Cited by 40 publications

(28 citation statements)

References 28 publications

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“…Apoptosis is an energy requiring suicide programme, which is normally activated in response to cellular damage, or following physiological signals such as death receptor ligation or withdrawal of survival signals. 1,2 Previously studied mechanisms employed by a variety of cells to export or neutralise anti-neoplastic drugs, include p-glycoprotein, 3 the multi-drug resistance-associated protein, 4 and glutathione S-transferases. 5 By effectively reducing the intracellular concentration of drugs, these mechanisms increase cellular tolerance and suppress the normal apoptotic response.…”

Section: Introductionmentioning

confidence: 99%

Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals

et al. 2000

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Drug resistance remains a serious limiting factor in the treatment of acute myeloid leukaemia (AML) either at initial presentation or following primary or subsequent relapses. Using specific kinase inhibitors, this study has investigated the contribution of the Ras/PI3-kinase regulated survival pathways to drug resistance and suppression of apoptosis in a cell line derived from AML (HL60). Inhibition of the Raf/MAP-kinase (ERK) pathway with a specific MAP-kinase inhibitor, apigenin did not sensitise HL60 cells to drug-induced apoptosis, indicating a lack of involvement in chemoresistance. In contrast, the PI3-kinase inhibitors, LY294002 and wortmannin, did induce a significant increase in apoptosis in combination with cytotoxic drugs. The contribution of downstream mediators of PI3-kinase, p70S6-kinase and PKB/Akt were then investigated. While inhibition of p70S6-kinase with rapamycin did not increase drug-induced apoptosis, PI3-kinase inhibition resulted in notable dephosphorylation of PKB, suggesting that the PI3-kinase/PKB survival pathway may play a major role in chemoresistance in AML. This pathway has been reported to mediate heterodimer interactions with the proapoptotic regulator, Bad. In contrast to previous studies, we found no evidence of Bad binding to anti-apoptotic Bcl-2, Bcl-X L or Mcl-1, or of alterations in Bax heterodimers. This suggests that alternative targets of PI3-kinase/PKB, distinct from the Bcl-2 family may be responsible for contributing to survival factor-mediated drug resistance in AML. Leukemia (2000) 14, 602-611.

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Section: Introductionmentioning

confidence: 99%

Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals

et al. 2000

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“…[37][38][39] In cell lines, we have found that JC-1 was not a substrate of MRP1 (unpublished data, 2000), as were Rh123 and calcein-AM.…”

Section: Discussionmentioning

confidence: 99%

JC-1: a very sensitive fluorescent probe to test Pgp activity in adult acute myeloid leukemia

Legrand

Perrot

Simonin

et al. 2001

Blood

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One of the best-characterized resistance mechanisms in acute myeloid leukemia (AML) is the drug extrusion mediated by P-glycoprotein (Pgp). Recently the results of workshops organized by several groups concluded that accurate measurement of low activity of Pgp is a difficult goal in clinical samples. Therefore, highly sensitive and specific assays were developed to assess the functionality of Pgp using JC

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“…Multidrug resistant-related protein 1 (MRP1), another transporter protein, is sometimes expressed in AML [58]. However, the clinical importance of MRP1 is relatively limited among the mechanisms of resistance to GO [59].…”

Section: Drug Resistancementioning

confidence: 99%

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

Takeshita

2013

Int J Hematol

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Seventy to 80 % of patients with acute myeloid leukemia (AML) achieve complete remission following intensive chemotherapy, but more than 50 % of patients in remission subsequently relapse, which is often associated with clinical drug resistance. Therapy based on monoclonal antibodies (mAbs) has been developed to increase the selectivity of cytotoxic agents by conjugating them with a mAb. Gemtuzumab ozogamicin (GO) is a conjugate of a cytotoxic agent, a calicheamicin derivative, linked to a recombinant humanized mAb directed against the CD33 antigen, which is expressed on leukemia cells from more than 90 % of patients with AML. This conjugated mAb was introduced following promising results from phase I and II studies. However, the initial phase III study did not confirm the efficacy of GO in combination with conventional chemotherapies. Several subsequent phase III studies have shown the efficacy of GO in favorable and intermediate risk AML. Several resistance mechanisms against GO have been reported. Multidrug resistant (MDR) P-glycoprotein (P-gp), a trans-membrane glycoprotein that pumps out many anti-leukemic agents from cells, also affects GO. For this reasons, GO has been used in combination with MDR modifiers, such as cyclosporine, and in cases without P-gp. Several investigators have reported successful results of the use of GO in acute promyelocytic leukemia (APL). GO has also been described as effective in cases relapsed after treatment with all-trans retinoic acid (ATRA), arsenic acid and conventional chemotherapeutic agents. The efficacy of GO will be studied mainly in a favorable risk of AML, such as core binding factor leukemia and APL. In addition, suitable combinations with other chemotherapies and administration schedules should be discussed.

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Role of MRP1 in multidrug resistance in acute myeloid leukemia

Cited by 40 publications

References 28 publications

Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals

Sensitisation of HL60 human leukaemic cells to cytotoxic drug-induced apoptosis by inhibition of PI3-kinase survival signals

JC-1: a very sensitive fluorescent probe to test Pgp activity in adult acute myeloid leukemia

Efficacy and resistance of gemtuzumab ozogamicin for acute myeloid leukemia

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