Enhanced invasiveness in multidrug resistant leukemic cells is associated with overexpression of P-glycoprotein and cellular inhibitor of apoptosis protein

Abstract

Multidrug resistance (MDR) and multi-organ infiltration are the major obstacles to the successful treatment of leukemia. It is known that the drug efflux protein, P-glycoprotein (P-gp), and inhibitors of apoptosis proteins (IAPs) are involved in the MDR of leukemic cells, but their roles in leukemia infiltration have not been clearly elucidated. In this study, leukemic cell lines K562 and HL60 and their MDR variants K562R and HL60R have been used to analyze their infiltrative ability. MDR variants display enhanced invasion compared with parental cells. Results from xenografts in SCID (severe combined immunodeficiancy) mice are consistent with these in vitro observations. Furthermore, P-gp and cIAP are overexpressed and co-localize with protein kinase C-ε (PKC-ε) in MDR variants. Our study shows that overexpression of P-gp and cIAP may enhance the infiltration of leukemic cells.

Phosphoproteomic Analysis of Leukemia Cells under Basal and Drug-treated Conditions Identifies Markers of Kinase Pathway Activation and Mechanisms of Resistance

“…7). PKCs have been implicated in the biology of AML (55) and can contribute to the resistance to chemotherapeutic drugs by interfering with the cell response triggered by these drugs or by increasing their clearance as a result of activating P-glycoprotein (56,57). Here we provide evidence that PKCs may also be implicated in AML resistance to different kinase inhibitors for the first time.…”

Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation

“…Studies of pediatric ALL and AML cells did not demonstrate a definitive link between P-gp and BCRP expression and drug resistance in vitro (Svirnovski et al, 2009). However, studies with leukemia cell lines and severe combined immunodeficiency mouse xenograft models demonstrated that P-gp overexpression may be associated with enhanced leukemia cell invasiveness (Hu et al, 2011).…”

Protein Kinase C (PKC) Isozymes and Cancer

“…PKC isozymes and cancer, PKC isozymes, especially PKC and , are involved in the Pgp-mediated MDR in several types of cancer, such as colon cancer [119][120][121], pancreatic cancer [399], gastric cancer [157], breast cancer [55], leukemia [513], and prostate cancer [447]. In general, inhibition of PKC isozymes that regulate P-gp leads to reduced MDR and enhanced cancer cell apoptosis.…”