HOXB4 knockdown reverses multidrug resistance of human myelogenous leukemia K562/ADM cells by downregulating P-gp, MRP1 and BCRP expression via PI3K/Akt signaling pathway

Abstract

Multidrug resistance (MDR) plays a pivotal role in human chronic myelogenous leukemia (CML) chemotherapy failure. MDR is mainly associated with the overexpression of drug efflux transporters of the ATP-binding cassette (ABC) proteins. Phosphoinositide 3-kinase (PI3K)/Akt signaling cascade is involved in the MDR phenotype and is correlated with multidrug resistance 1 (MDR1)/P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) expression in many human malignancies. Homeobox (HOX) B4, a member of the HOX gene family, has been reported to be correlated with occurrence, development, poor prognosis and drug resistance of human leukemia. In the present study, HOXB4 expression was analyzed in K562 cell line and its MDR subline K562/ADM. Compared with K562 cells, drug-resistant K562/ADM cells demonstrated evidently higher HOXB4 expression. In addition, we firstly investigated the reversal effect of HOXB4 deletion on K562/ADM cells and the underlying mechanism. The Cell Counting kit-8 (CCK-8) and flow cytometry assays showed that knockdown of HOXB4 enhanced chemosensitivity and decreased drug efflux in K562/ADM cells. Moreover, HOXB4 knockout led to downregulation of P-gp, MRP1 and BCRP expression and PI3K/Akt signaling activity, suggesting that repression of HOXB4 might be a key point to reverse MDR of K562/ADM cells.

Synergistic Effect of Baicalin and Adriamycin in Resistant HL-60/ADM Leukaemia Cells

“…Therefore, it was deduced that baicalin reduces resistance to ADM by increasing the intracellular accumulation of ADM in HL-60/ADM cells. Our results are in accordance with previous studies [16,17] (Fig. 3).…”

“…3). It has been reported that administration of osthol [17] or suppressing the expression of the HOXB4 gene [16] increases the intracellular accumulation of ADM in K562/ADM cells. The consistent results from studies using different treatments and different ADM-resistant cell lines suggested that increasing the intracellular levels of ADM is a common mechanism of combination therapy with ADM, reversing resistance to ADM.…”

“…It has been well documented that overexpression of drug resistance-related genes, like multidrug resistance related protein 1 (MDR1), multidrug resistance protein 1 (MRP1), lung resistance-related protein (LRP) and breast cancer-related protein (BCRP) strongly extrudes chemotherapeutic agents crossing the cellular membrane and reduces the intracellular bioavailability and concentration of drugs, leading to MDR [16]. In this regard, downregulation of the expression of these genes may be an important strategy against MDR in leukaemia.…”

“…In this regard, downregulation of the expression of these genes may be an important strategy against MDR in leukaemia. Recent studies have shown that down-regulating the expression of the MDR1 gene by osthol [17], or MDR1, MRP1 and BCRP genes by homeobox B4 knockdown (HOXB4) [16] share the same mechanisms, that is, inhibition of the PI3K/Akt signalling pathway can reverse resistance to ADM in myelogenous K562/ADM leukaemic cells. HL-60 is another leukaemic cell line widely used in MDR research.…”

ATP‑binding cassette transporter A1: A promising therapy target for prostate cancer (Review)

“…MDR is a major cause of failure of prostate cancer chemotherapy and is associated with an increased mortality risk (53). The PI3K/Akt signaling cascade may be correlated with MDR1/P-glycoprotein (P-gp) and plays a critical role in Figure 1.…”