The Increase in the Drug Resistance of Acute Myeloid Leukemia THP-1 Cells in High-Density Cell Culture Is Associated with Inflammatory-like Activation and Anti-Apoptotic Bcl-2 Proteins

Abstract

It is known that cell culture density can modulate the drug resistance of acute myeloid leukemia (AML) cells. In this work, we studied the drug sensitivity of AML cells in high-density cell cultures (cell lines THP-1, HL-60, MV4-11, and U937). It was shown that the AML cells in high-density cell cultures in vitro were significantly more resistant to DNA-damaging drugs and recombinant ligand izTRAIL than those in low-density cell cultures. To elucidate the mechanism of the increased drug resistance of AML cells in high-density cell cultures, we studied the activation of Bcl-2, Hif-1alpha, and NF-kB proteins, as well as cytokine secretion, the inflammatory immunophenotype, and the transcriptome for THP-1 cells in the low-density and high-density cultures. The results indicated that the increase in the drug resistance of proliferating THP-1 cells in high-density cell cultures was associated with the accumulation of inflammatory cytokines in extracellular medium, and the formation of NF-kB-dependent inflammatory-like cell activation with the anti-apoptotic proteins Bcl-2 and Bcl-xl. The increased drug resistance of THP-1 cells in high-density cultures can be reduced by ABT-737, an inhibitor of Bcl-2 family proteins, and by inhibitors of NF-kB. The results suggest a mechanism for increasing the drug resistance of AML cells in the bone marrow and are of interest for developing a strategy to suppress this resistance.