Hematology, transfusion and cell therapy · 2025
Mechanistic insights into the antiproliferative effect of the redox-active iron chelator Dp44mT on multiple myeloma cell lines.
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Sharma Aarti, Pathangey Latha, Chirackal Sinto Sebastian, Mangalaparthi Kiran K, Pandey Akhilesh, Fonseca Rafael, Swaminathan Sundararaman
Аннотация
BACKGROUND: Impaired iron metabolism has been linked to the pathogenesis of multiple myeloma. Redox active iron chelators have gained attention as potential anti-cancer agents as they target the high iron dependency of cancer cells. This study explored the potential mechanisms underlying the anti-multiple myeloma effect of the redox active iron chelator Dp44mT (Di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone).
METHODS: The effect of Dp44mT was tested on both immunomodulatory drug-sensitive and drug-resistant multiple myeloma cell lines using the MTT assay. Proteomic and phosphoproteomics characterization were utilized to explore the mechanisms of Dp44mT action on multiple myeloma cells. In addition, a real-time polymerase chain reaction assay was performed to examine the expressions of major iron metabolism genes. Reactive oxygen species, lipid peroxidation, mitochondrial membrane potential, and intracellular iron compartmentalization were measured using flow-cytometry.
RESULTS: The high potency of Dp44mT in killing multiple myeloma cell lines was confirmed. Treatment with Dp44mT showed evidence of deregulated cellular iron metabolism, reactive oxygen species homeostasis, and mitochondrial membrane potential in multiple myeloma cell lines. As possible mechanistic pathways of Dp44mT, there was overrepresentation of the AMPK pathway, cell cycle, endoplasmic stress, and down regulation of ACSL4 (acyl-CoA synthetase long chain family member 4).
CONCLUSION: This study suggests an in vitro, anti-multiple myeloma effect of Dp44mT that appears to be mediated by dysregulated iron metabolism, reactive oxygen species, and other biological pathways.
METHODS: The effect of Dp44mT was tested on both immunomodulatory drug-sensitive and drug-resistant multiple myeloma cell lines using the MTT assay. Proteomic and phosphoproteomics characterization were utilized to explore the mechanisms of Dp44mT action on multiple myeloma cells. In addition, a real-time polymerase chain reaction assay was performed to examine the expressions of major iron metabolism genes. Reactive oxygen species, lipid peroxidation, mitochondrial membrane potential, and intracellular iron compartmentalization were measured using flow-cytometry.
RESULTS: The high potency of Dp44mT in killing multiple myeloma cell lines was confirmed. Treatment with Dp44mT showed evidence of deregulated cellular iron metabolism, reactive oxygen species homeostasis, and mitochondrial membrane potential in multiple myeloma cell lines. As possible mechanistic pathways of Dp44mT, there was overrepresentation of the AMPK pathway, cell cycle, endoplasmic stress, and down regulation of ACSL4 (acyl-CoA synthetase long chain family member 4).
CONCLUSION: This study suggests an in vitro, anti-multiple myeloma effect of Dp44mT that appears to be mediated by dysregulated iron metabolism, reactive oxygen species, and other biological pathways.