Acquisition of MDR phenotype by leukemic cells is associated with increased caspase‐3 activity and a collateral sensitivity to cold stress

Abstract

The acquisition of a multidrug-resistant (MDR) phenotype by tumor cells that renders them unsusceptible to anti-neoplasic agents is one of the main causes of chemotherapy failure in human malignancies. The increased expression of P-glycoprotein (MDR1, P-gp, ABCB1) in tumor cells contributes to drug resistance by extruding chemotherapeutic agents or by regulating programmed cell death. In a study of MDR cell survival under cold stress conditions, it was found that resistant leukemic cells with P-gp over-expression, but not their sensitive counterparts, are hypersensitive to cold-induced cell death when exposed to temperatures below 4 °C. The transfection of parental cells with a P-gp-expressing plasmid makes these cells sensitive to cold stress, demonstrating an association between P-gp expression and cell death at low temperatures. Furthermore, we observed increased basal expression and activity of effector caspase-3 at physiological temperature (37 °C) in MDR cells compared with their parental cell line. Treatment with a caspase-3 inhibitor partially rescues MDR leukemic cells from cold-induced apoptosis, which suggests that the cell death mechanism may require caspase-3 activity. Taken together, these findings demonstrate that P-gp expression plays a role in MDR cell survival, and is accompanied by a collateral sensitivity to death induced by cold stress. These findings may assist in the design of specific therapeutic strategies to complement current chemotherapy treatment against cancer.

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

“…Furthermore, this and other transporters actively efflux xenobiotics to protect the cells from cytotoxic agents (11). This includes the capacity to expel a variety of drugs outside the cancer cells, thus inducing chemoresistance in numerous solid tumors and hematological malignancies (13,109,110). In that way, ABCB1 contributes to the acquisition of a multidrug resistant (MDR) phenotype since it can bind and extrude a huge repertoire of drugs, thus leading to treatment failure and tumor relapse.…”

“…Other roles attributed to these proteins include the transport of ABC proteins to intracellular (e.g., cytoplasmic vesicles) or extracellular (e.g., exosomes) compartments to improve drug sequestration (111,112); tumor cell proliferation, invasion, and deregulation of the pathways involved in apoptosis or complement-mediated cytotoxicity (109,110,(113)(114)(115)(116).…”

Metabolic Reprogramming During Multidrug Resistance in Leukemias

“…Death evasion to a number of chemotherapeutic drugs is the characteristic of cells displaying the MDR phenotype. Defects in the apoptotic process involving caspase activation to induce cell death have been observed in a number of multidrug resistant cell lines ( 62 , 71 ).…”

Detection approaches for multidrug resistance genes of leukemia

“…In addition to exporting chemotherapeutic agents, P-gp is able to transport a broad range of substrates, including amino acids, sugars, peptides, organic ions, metabolites, and numerous hydrophobic compounds 16,17. Several reports suggest that P-gp may regulate apoptosis, chloride channel activity, cholesterol metabolism, differentiation, proliferation, adhesion, and immune cell function 18. Significantly, elevated P-gp expression was found in chronic B-cell leukemia patients.…”