Disruption of gap junctions attenuates acute myeloid leukemia chemoresistance induced by bone marrow mesenchymal stromal cells
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Springer Nature
Abstract
The bone marrow (BM) niche impacts the progression of acute myeloid leukemia (AML) by favoring the chemoresistance of AML cells. Intimate interactions between leukemic cells and BM mesenchymal stromal cells (BM-MSCs) play key roles in this process. Direct intercellular communications between hematopoietic cells and BM-MSCs involve connexins, components of gap junctions. We postulated that blocking gap junction assembly could modify cell–cell interactions in the leukemic niche and consequently the chemoresistance. The comparison of BM-MSCs from AML patients and healthy donors revealed a specific profile of connexins in BM-MSCs of the leukemic niche and the effects of carbenoxolone (CBX), a gap junction disruptor, were evaluated on AML cells. CBX presents an antileukemic effect without affecting normal BM-CD34+ progenitor cells. The proapoptotic effect of CBX on AML cells is in line with the extinction of energy metabolism. CBX acts synergistically with cytarabine (Ara-C) in vitro and in vivo. Coculture experiments of AML cells with BM-MSCs revealed that CBX neutralizes the protective effect of the niche against the Ara-C-induced apoptosis of leukemic cells. Altogether, these results suggest that CBX could be of therapeutic interest to reduce the chemoresistance favored by the leukemic niche, by targeting gap junctions, without affecting normal hematopoiesis. © 2019, The Author(s).
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Animals, Anti-ulcer agents, Antimetabolites, antineoplastic, Apoptosis, Carbenoxolone, Cell proliferation, Cytarabine, Drug resistance, neoplasm, Drug therapy, combination, Gap junctions, Humans, Leukemia, myeloid, acute, Mesenchymal stem cells, Mice, Mice, inbred nod, Mice, scid, Tumor cells, cultured, Tumor microenvironment, Xenograft model antitumor assays, Gap junction protein, Rna, Antineoplastic antimetabolite, Antiulcer agent, Acute myeloid leukemia, Animal experiment, Animal model, Antileukemic activity, Article, Bone marrow mesenchymal stromal cell, Cell cycle, Cell differentiation, Cell interaction, Cell protection, Cell viability, Coculture, Controlled study, Drug effect, Drug potentiation, Drug resistance, Energy metabolism, Flow cytometry, Gap junction, Human, Human cell, In vitro study, In vivo study, Leukemia cell, Mesenchymal stroma cell, Mouse, Mtt assay, Nonhuman, Priority journal, Protein expression, Reverse transcription polymerase chain reaction, Rna extraction, Animal, Combination drug therapy, Cytology, Drug screening, Mesenchymal stem cell, Metabolism, Nonobese diabetic mouse, Pathology, Scid mouse, Tumor cell culture