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.

Studying Signaling Pathway Activation in TRAIL-Resistant Macrophage-Like Acute Myeloid Leukemia Cells

“…It is well known that the main intracellular positive regulators of AML cell resistance to TRAIL-induced apoptosis are members of the BCL-2 and IAPs families, which block apoptosis at the mitochondrial and effector caspase levels [ 18 , 54 , 55 ]. PPI networks were built to determine the potential interaction of the identified hub genes with anti-apoptotic members of the IAPs and BCL-2 families.…”

“…Previously, we showed that in AML THP-1 cells under in vitro conditions, in a three-dimensional high-density culture simulating homotypic intercellular communication in the hyperplasia of leukemic blasts in the bone marrow, there was an increase in the production of proinflammatory cytokines, chemokines, and growth factors; activation of proinflammatory NF-kB-dependent signaling pathways; and a reversible increase in resistance to TRAIL-induced death and to the action of chemotherapeutic drugs [ 17 , 18 ]. In addition, we have shown that macrophagelike clones THP-1ad with constitutive resistance to TRAIL-induced death appear in a three-dimensional high-density culture of these cells [ 19 ].…”

Piplartine eliminates CD34 + AML stem/progenitor cells by inducing oxidative stress and suppressing NF-κB signalling

“…Similarly, PL and paclitaxel have synergistic cytotoxic effects on human intestinal cancer cells [ 36 ], and PL can also synergistically enhance the anticancer effects of oxaliplatin on human colorectal cancer [ 37 ]. All of these chemical drugs, including ARA-C [ 38 – 40 ], cause oxidative stress. Critically, they also activate the NF-κB signalling pathway as a mechanism of chemoresistance [ 41 – 46 ].…”

Recent Advances in Nanomaterials-Based Targeted Drug Delivery for Preclinical Cancer Diagnosis and Therapeutics

“…The Bcl-2 and nuclear factor kappa B (NF-KB) pathways are frequently dysregulated, which activates the defective apoptotic machinery. Bcl-2 is a thoroughly researched anti-apoptotic protein that is also a major contributor to drug resistance [156]. These factors together imply that Bcl-2 may be a good target for reversing medication resistance.…”