EFFECTS OF INDOLE-3-CARBINOL ON THE HEMATOPOIETIC BONE MARROW MICROENVIRONMENT: MODULATION OF MESENCHYMAL STEM CELLS AND LEUKEMIC PROGRESSION
- 1Faculdade de Ciências Farmacêuticas, Universidade de São Paulo (USP), São Paulo, SP, Brazil
Abstract
Hematopoiesis is a dynamic process regulated by the interaction between hematopoietic stem cells (HSCs) and the hematopoietic microenvironment (HM), particularly by mesenchymal stromal stem cells (MSCs). Under adverse conditions, such as in leukemias, neoplastic cells remodel the bone marrow niche, dysregulating cytokine production and signaling pathways, which favors the population dominance of leukemic clones and results in impaired blood cell formation. Evidence indicate that MSCs contribute to leukemic progression by remodeling the HM through dysregulated cytokine secretion, modulation of quiescence, protection against chemotherapeutics, and promotion of survival. Thus, therapies that are not limited to the destruction of leukemic cells, but also modify the HM, emerge as promising approaches. In this context, bioactive compounds have been studied due to their antitumoral and immunomodulatory properties. Among them, Indole-3-Carbinol (I3C), derived from cruciferous vegetables, stands out for displaying antineoplastic properties and modulating critical signaling pathways. This study aims to investigate the role of I3C in modulating MSCs and its impact on the HM in the leukemic context, evaluating whether the compound can affect the inflammatory process, chemoresistance, and tumor survival support induced by leukemic cells. Murine cell lines of MSCs (C3H10T1/2) and leukemic lineage (C1498) were used in vitro, subjected to treatments with 50 µM of I3C and 1 µM of Cytarabine (Ara-C), isolated and combined (groups: Control; I3C; Ara-C; and I3C combined with Ara-C group. The evaluation of metabolism and viability of both lineages was determined by the MTT assay, while apoptosis and the cell cycle were evaluated by flow cytometry. A wound healing assay was also performed to assess the modulation of this treatment on stromal cell recruitment. The MTT assay indicated that I3C treatment led to a metabolic decrease in leukemic lineage starting at a dose of 250 µM, whereas the stromal cell demonstrated higher resistance to the treatment. When combining I3C with Ara-C, a potentiation of Ara-C apoptotic action is observed, demonstrating that I3C significantly increases C1498 lineage death when combined with Ara-C. Regarding the action of the treatment on the cell cycle of these cells, Ara-C fulfills its mechanism of action regarding cell cycle arrest in the active phase of replication; However, when combined with I3C, this mechanism becomes even more relevant. Stromal cells were challenged regarding their migratory capacity under treatment, indicating a decrease in their wound healing capacity when in contact with I3C, a result that demonstrates the modulation of the hematopoietic niche regarding mesenchymal stromal cells. The proposal aims to identify cellular and molecular mechanisms involved in this interaction, generating potentially innovative knowledge for the development of effective complementary therapies for leukemias. This study was conducted with the support of CNPq, CAPES, and FAPESP.
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BibTeX
@article{almeida2026effects,
title = {{EFFECTS OF INDOLE-3-CARBINOL ON THE HEMATOPOIETIC BONE MARROW MICROENVIRONMENT: MODULATION OF MESENCHYMAL STEM CELLS AND LEUKEMIC PROGRESSION}},
author = {Beatriz ALMEIDA and Rosana L. Rodrigues AMON and Edson Naoto MAKIYAMA and Ricardo Ambrósio FOCK},
journal = {Hematology, Transfusion and Cell Therapy},
year = {2026},
month = oct,
doi = {10.1016/j.htct.2026.108174},
url = {https://doi.org/10.1016/j.htct.2026.108174},
note = {CC BY},
}
RIS
TY - JOUR
TI - EFFECTS OF INDOLE-3-CARBINOL ON THE HEMATOPOIETIC BONE MARROW MICROENVIRONMENT: MODULATION OF MESENCHYMAL STEM CELLS AND LEUKEMIC PROGRESSION
AU - Beatriz ALMEIDA
AU - Rosana L. Rodrigues AMON
AU - Edson Naoto MAKIYAMA
AU - Ricardo Ambrósio FOCK
PY - 2026
DA - 2026/10/23
JO - Hematology, Transfusion and Cell Therapy
DO - 10.1016/j.htct.2026.108174
UR - https://doi.org/10.1016/j.htct.2026.108174
AB - Hematopoiesis is a dynamic process regulated by the interaction between hematopoietic stem cells (HSCs) and the hematopoietic microenvironment (HM), particularly by mesenchymal stromal stem cells (MSCs). Under adverse conditions, such as in leukemias, neoplastic cells remodel the bone marrow niche, dysregulating cytokine production and signaling pathways, which favors the population dominance of leukemic clones and results in impaired blood cell formation. Evidence indicate that MSCs contribute to leukemic progression by remodeling the HM through dysregulated cytokine secretion, modulation of quiescence, protection against chemotherapeutics, and promotion of survival. Thus, therapies that are not limited to the destruction of leukemic cells, but also modify the HM, emerge as promising approaches. In this context, bioactive compounds have been studied due to their antitumoral and immunomodulatory properties. Among them, Indole-3-Carbinol (I3C), derived from cruciferous vegetables, stands out for displaying antineoplastic properties and modulating critical signaling pathways. This study aims to investigate the role of I3C in modulating MSCs and its impact on the HM in the leukemic context, evaluating whether the compound can affect the inflammatory process, chemoresistance, and tumor survival support induced by leukemic cells. Murine cell lines of MSCs (C3H10T1/2) and leukemic lineage (C1498) were used in vitro, subjected to treatments with 50 µM of I3C and 1 µM of Cytarabine (Ara-C), isolated and combined (groups: Control; I3C; Ara-C; and I3C combined with Ara-C group. The evaluation of metabolism and viability of both lineages was determined by the MTT assay, while apoptosis and the cell cycle were evaluated by flow cytometry. A wound healing assay was also performed to assess the modulation of this treatment on stromal cell recruitment. The MTT assay indicated that I3C treatment led to a metabolic decrease in leukemic lineage starting at a dose of 250 µM, whereas the stromal cell demonstrated higher resistance to the treatment. When combining I3C with Ara-C, a potentiation of Ara-C apoptotic action is observed, demonstrating that I3C significantly increases C1498 lineage death when combined with Ara-C. Regarding the action of the treatment on the cell cycle of these cells, Ara-C fulfills its mechanism of action regarding cell cycle arrest in the active phase of replication; However, when combined with I3C, this mechanism becomes even more relevant. Stromal cells were challenged regarding their migratory capacity under treatment, indicating a decrease in their wound healing capacity when in contact with I3C, a result that demonstrates the modulation of the hematopoietic niche regarding mesenchymal stromal cells. The proposal aims to identify cellular and molecular mechanisms involved in this interaction, generating potentially innovative knowledge for the development of effective complementary therapies for leukemias. This study was conducted with the support of CNPq, CAPES, and FAPESP.
SN - 2531-1379
SN - 2531-1387
ER -