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One of the major causes of low efficiency of the therapy for acute myeloid leukemia is drug resistance of leukemic cells. Microenvironment plays a key role in formation of the phenotype of leukemic cell drug resistance. Investigation of the mechanisms of microenvironment-mediated drug resistance is important to identify novel pharmacological targets for the acute myeloid leukemia therapy. We studied the role of cell aggregation in the drug resistance of leukemic cells. We showed the increased resistance of acute myeloid leukemia cells THP-1 to bortezomib, doxorubicin and fludarabine in multicellular aggregates. In the multicellular aggregates of THP-1 with the higher drug resistance, cell proliferation activity did not change, while the intracellular level of anti-apoptotic protein Bcl-2 increased. Inhibition of the aggregation of THP-1 cells prevented drug resistance. This work demonstrates the involvement of cell aggregation in the formation of drug resistance phenotype in leukemic cells.

TRAIL (TNF-alpha Related Apoptosis-Inducing Ligand) is an attractive candidate for anticancer therapy. TRAIL selectively kills tumor cells, without damaging normal cells. It is known that cancer cells can acquire resistance to chemotherapeutic drugs, oxidative stress in high density culture. This phenomenon appears as a multi-cell resistance, cell adhesion-dependent resistance, or density-dependent resistance of tumor cells. However, it is unclear whether such resistance appears in TRAIL-induced apoptosis. We observed that the resistance to izTRAIL of all tumor cell lines used was considerably increased in confluent cultures. The increase in tumor cell resistance in dense populations is not related to their proliferative status. It was shown that the dissociation of calcium-dependent cell-cell contacts with EGTA did not suppress tumor cell resistance to izTRAIL in confluent cultures. This phenomenon of cancer cells resistance to TRAIL-induced apoptosis should be considered in the development of methods of anticancer therapy.