Expression of P-gp in acute myeloid leukemia and the reversal function of As2O3 on drug resistance

Abstract

To study the expression of P-glycoprotein (P-gp) and the reversal function of As2O3, the active ingredient of arsenic, on drug resistance in acute myeloid leukemia (AML) patients, P-gp and cluster of differentiation 34 (CD34) were examined in primary mononuclear and resistant cells, with or without As2O3. In addition, multidrug resistance gene 1 (MDR1) mRNA expression was investigated in K562/D cells and AML patients. In total, 28.6% of newly-treated (NT) patients and 59.1% of relapsed/refractory (RR) patients were P-gpfunction+, and 31.7% of NT patients and 59.1% of RR patients were CD34+. The positivity rate of P-gpfunction and CD34+ expression in the RR group were significantly higher compared with that in the NT group (P<0.05). In addition, higher CD34+, P-gpexpression+ and P-gpfunction+ values were observed in older patients compared with younger patients. MDR1 expression was downregulated in certain patients following treatment with AS2O3. In the present study, the overexpression of P-gp was the primary cause of drug resistance in the AML patients, and MDR1 expression was downregulated by As2O3 in primary leukemia and drug-resistant cells.

Characteristics of doxorubicin-selected multidrug-resistant human leukemia HL‑60 cells with tolerance to arsenic trioxide and contribution of leukemia stem cells

“…Previous studies have revealed that conventional MDR leukemia cells exhibit increased sensitivity to As 2 O 3 instead of manifesting cross-resistance. This is possibly because As 2 O 3 is not a P-gp substrate and may even inhibit P-gp expression and activity (2)(3)(4)27). However, unlike other ADM-selected P-gp-overexpressing MDR tumor cells, including K562/ADM cells (2,3,27), the HL-60/RS cells established in the present study demonstrated cross-resistance to As 2 O 3 , which is a unique feature in MDR cells.…”

“…MDR is currently a major and unresolved impediment to leukemia therapy (1)(2)(3)10). Although numerous extensive studies have investigated leukemia drug-resistance, regulatory pathways and intervention measures, the underlying mechanisms remain to be fully understood and few effective or clinically practical countermeasures have been identified (23)(24)(25).…”

“…Previous studies have revealed that the majority of MDR leukemia cells have increased sensitivity to As 2 O 3 , rather than cross-resistance (3,4). One potential explanation for this is that As 2 O 3 may not be a substrate of P-gp and may inhibit P-gp activity (2,(18)(19)(20)(21)(22).…”

“…-and CD123 + phenotypes (3,(13)(14)(15)(16)(17). Previous studies demonstrated that CD123 was aberrantly expressed on acute myeloid leukemia CD34 + CD38 -cells but was not detected on healthy CD34 + CD38 -cells.…”

“…However, chemotherapy-induced multidrug resistance (MDR) frequently induces therapy failure or tumor recurrence (1)(2)(3). MDR involves various mechanisms including, adenosine triphosphate-binding cassette (ABC) transporters, P-glycoprotein (P-gp), multidrug-resistance-related protein (MRP) and breast-cancer-resistance protein (BCRP) overexpression, which function to efflux certain molecules out of the cells (4)(5)(6)(7)(8).…”