Cells from chronic myelogenous leukaemia patients at presentation exhibit multidrug resistance not mediated by either MDR1 or MRP1

Abstract

Summary. Tetramethylrosamine (TMR) is excluded from Pglycoprotein (MDR1)-enriched cell lines, but it stains efficiently MDR1-poor parent lines. Application of the TMR resistance assay to cells obtained from chronic myelogenous leukaemia (CML) patients revealed, in all individuals, a significant resistance compared with healthy donors (P , 0´001). Cells from the same patients at later phases exhibited a further increase in TMR resistance. Doxorubicin was excluded from all cell samples obtained from CML patients at presentation. The resistance to TMR and doxorubicin was energy-dependent, and was not modulated by inhibitors of MDR1 and multidrug-resistance protein-1 (MRP1). Transcription of mRNAs suspected as relevant to multidrug resistance was assessed using comparative reverse transcription polymerase chain reaction. All cells from the CML patients transcribed high levels of MRP3, MRP4 and MRP5 compared with healthy donors. Low levels of MDR1, MRP1, MRP2, MRP6, lung resistancerelated protein and anthracycline resistance-associated protein were equally transcribed in cells from healthy donors and CML patients. These results indicated that neither MDR1 nor MRP1 mediate the resistance in these cells. Our results shed light on a resistance mechanism operative in CML patients, which, together with the resistance to apoptosis, is responsible for the lack of response of CML patients to induction-type protocols used to treat acute myeloid leukaemia patients.

Revisiting the ABCs of Multidrug Resistance in Cancer Chemotherapy

“…The possible explanations for these discrepant results may be attributable in part to the different methods used, difference in the various thresholds of positivity and the small number of patients. There are reports in the literature which suggest that ABCC1 does not mediate drug resistance in the cells from CML patients [171], neither does it influence the induction outcome in CML patients [176]. Presently, little is known about the role of ABCG2 in mediating clinical drug resistance that occurs during CML treatment, although an up-regulation of ABCG2 expression was reported in CML CD34 + cell [177].…”

“…The data regarding the relevance of ABCB1 expression in CML patients is controversial. The majority of published data suggest that ABCB1 expression is unlikely to be significantly correlated with prognosis and clinical outcome [162,163,170,171]. However, the results of the other studies in the CML patients suggest that ABCB1 expression may be regarded as an unfavorable prognostic factor in the blastic phase CML [125,164,[172][173][174][175] or CR for the chronic phase CML [176].…”

ABCG2 (BCRP) expression in normal and malignant hematopoietic cells

“…70 Although no studies have reported ABCG2 expression in CML, one study identified the frequent presence of doxorubicin efflux and resistance in CML samples which was not associated with MDR1 or MRP1-6 expression, suggesting that the presence of another transporter, such as ABCG2 was causing the doxorubicin efflux. 71 In one study of treated and untreated patients with chronic lymphoctyic leukemia (CLL), there was frequent detection of low amounts of ABCG2-mediated efflux, but no correlation was found between ABCG2 activity and previous treatment status, Rai stage or disease progression. 72 Few studies of ABCG2 expression in non-hematologic malignancies have been reported.…”

P-glycoprotein and survivin simultaneously regulate vincristine-induced apoptosis in chronic myeloid leukemia cells

“…Classical MDR is characterized by the overexpression of ATP-binding cassette (ABC) drug transporter proteins (1,2). Some of these proteins, such as P-glycoprotein (Pgp, ABCB1, MDR1), multidrug resistance-associated protein (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2), have been closely related to poor treatment response and prognosis in many malignancies (3)(4)(5)(6).…”