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Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels.
Oxid Med Cell Longev. 2019; 2019:9561281.OM

Abstract

Ferroptosis is an iron-dependent type of cell death distinct from apoptosis or necrosis characterized by accumulation of reactive oxygen species. The combination of siramesine, a lysosomotropic agent, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced cell death in breast cancer cells mediated by ferroptosis. In this study, we showed that this combination of siramesine and lapatinib induces synergistic cell death in glioma cell line U87 and lung adenocarcinoma cell line A549. This cell death was characterized by the increase in iron content, reactive oxygen species (ROS) production, and lipid peroxidation accumulation after 24 hours of treatment. Moreover, iron chelator DFO and ferrostatin-1, a ferroptosis inhibitor, significantly reduced cell death. The mechanism underlying the activation of the ferroptotic pathway involves lysosomal permeabilization and increase in reactive iron levels in these cells. In addition, the downregulation of heme oxygenase-1 (HO-1) protein occurred. Overexpression of HO-1 resulted in reduction of ROS and lipid peroxidation production and cell death. Furthermore, knocking down of HO-1 combined with siramesine treatment resulted in increased cell death. Finally, we found that the inhibition of the proteasome system rescued HO-1 expression levels. Our results suggest that the induction of ferroptosis by combining a lysosomotropic agent and a tyrosine kinase inhibitor is mediated by iron release from lysosomes and HO-1 degradation by the proteasome system.

Authors+Show Affiliations

Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada R3E OV9. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0J9.Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada R3E OV9. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0J9.Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada R3E OV9.Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada R3E OV9. Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0J9.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31636810

Citation

Villalpando-Rodriguez, Gloria E., et al. "Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis Through Reduced Heme Oxygenase-1 (HO-1) Levels." Oxidative Medicine and Cellular Longevity, vol. 2019, 2019, p. 9561281.
Villalpando-Rodriguez GE, Blankstein AR, Konzelman C, et al. Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels. Oxid Med Cell Longev. 2019;2019:9561281.
Villalpando-Rodriguez, G. E., Blankstein, A. R., Konzelman, C., & Gibson, S. B. (2019). Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels. Oxidative Medicine and Cellular Longevity, 2019, 9561281. https://doi.org/10.1155/2019/9561281
Villalpando-Rodriguez GE, et al. Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis Through Reduced Heme Oxygenase-1 (HO-1) Levels. Oxid Med Cell Longev. 2019;2019:9561281. PubMed PMID: 31636810.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Lysosomal Destabilizing Drug Siramesine and the Dual Tyrosine Kinase Inhibitor Lapatinib Induce a Synergistic Ferroptosis through Reduced Heme Oxygenase-1 (HO-1) Levels. AU - Villalpando-Rodriguez,Gloria E, AU - Blankstein,Anna R, AU - Konzelman,Carmen, AU - Gibson,Spencer B, Y1 - 2019/09/17/ PY - 2019/02/19/received PY - 2019/06/01/revised PY - 2019/06/25/accepted PY - 2019/10/23/entrez PY - 2019/10/23/pubmed PY - 2020/4/3/medline SP - 9561281 EP - 9561281 JF - Oxidative medicine and cellular longevity JO - Oxid Med Cell Longev VL - 2019 N2 - Ferroptosis is an iron-dependent type of cell death distinct from apoptosis or necrosis characterized by accumulation of reactive oxygen species. The combination of siramesine, a lysosomotropic agent, and lapatinib, a dual tyrosine kinase inhibitor (TKI), synergistically induced cell death in breast cancer cells mediated by ferroptosis. In this study, we showed that this combination of siramesine and lapatinib induces synergistic cell death in glioma cell line U87 and lung adenocarcinoma cell line A549. This cell death was characterized by the increase in iron content, reactive oxygen species (ROS) production, and lipid peroxidation accumulation after 24 hours of treatment. Moreover, iron chelator DFO and ferrostatin-1, a ferroptosis inhibitor, significantly reduced cell death. The mechanism underlying the activation of the ferroptotic pathway involves lysosomal permeabilization and increase in reactive iron levels in these cells. In addition, the downregulation of heme oxygenase-1 (HO-1) protein occurred. Overexpression of HO-1 resulted in reduction of ROS and lipid peroxidation production and cell death. Furthermore, knocking down of HO-1 combined with siramesine treatment resulted in increased cell death. Finally, we found that the inhibition of the proteasome system rescued HO-1 expression levels. Our results suggest that the induction of ferroptosis by combining a lysosomotropic agent and a tyrosine kinase inhibitor is mediated by iron release from lysosomes and HO-1 degradation by the proteasome system. SN - 1942-0994 UR - https://www.unboundmedicine.com/medline/citation/31636810/Lysosomal_Destabilizing_Drug_Siramesine_and_the_Dual_Tyrosine_Kinase_Inhibitor_Lapatinib_Induce_a_Synergistic_Ferroptosis_through_Reduced_Heme_Oxygenase_1__HO_1__Levels_ L2 - https://doi.org/10.1155/2019/9561281 DB - PRIME DP - Unbound Medicine ER -