Doxorubicin paradoxically ameliorates tumor-induced inflammation in young mice

Ibrahim Y. Abdelgawad; Marianne K.O. Grant; Flavia E. Popescu; David A. Largaespada; Beshay N. Zordoky

doi:10.3390/ijms22169023

Doxorubicin paradoxically ameliorates tumor-induced inflammation in young mice

Ibrahim Y. Abdelgawad, Marianne K.O. Grant, Flavia E. Popescu, David A. Largaespada, Beshay N. Zordoky

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

Doxorubicin (DOX) is one of the most widely used chemo-therapeutic agents in pediatric oncology. DOX elicits an inflammatory response in multiple organs, which contributes to DOX-induced adverse effects. Cancer itself causes inflammation leading to multiple pathologic conditions. The current study investigated the inflammatory response to DOX and tumors using an EL4-lymphoma, immunocompetent, juvenile mouse model. Four-week old male C57BL/6N mice were injected subcutaneously with EL4 lymphoma cells (5 × 10⁴ cells/mouse) in the flank region, while tumor-free mice were injected with vehicle. Three days following tumor implantation, both tumor-free and tumor-bearing mice were injected intraperitoneally with either DOX (4 mg/kg/week) or saline for 3 weeks. One week after the last DOX injection, the mice were euthanized and the hearts, livers, kidneys, and serum were harvested. Gene expression and serum concentration of inflammatory markers were quantified using real-time PCR and ELISA, respectively. DOX treatment significantly suppressed tumor growth in tumor-bearing mice and caused significant cardiac atrophy in tumor-free and tumor-bearing mice. EL4 tumors elicited a strong inflammatory response in the heart, liver, and kidney. Strikingly, DOX treatment ameliorated tumor-induced inflammation paradoxical to the effect of DOX in tumor-free mice, demonstrating a widely divergent effect of DOX treatment in tumor-free versus tumor-bearing mice.

Original language	English (US)
Article number	9023
Journal	International journal of molecular sciences
Volume	22
Issue number	16
DOIs	https://doi.org/10.3390/ijms22169023
State	Published - Aug 2 2021

Bibliographical note

Funding Information:
This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740 and the National Institutes of Health?s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Acknowledgments: Experiments using the NanoDrop 8000, and QuantStudio7 were conducted with staff support at the University of Minnesota Genomics Center. Experiments using the Luminex platform were conducted with staff support at the University of Minnesota Cytokine Reference Laboratory. Experiments using the Vevo 2100 echocardiography system were conducted with staff support at the University of Minnesota Imaging Center. Histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Pathology report was prepared by Davis M. Seelig, DVM, PhD, board-certified veterinary pathologist and the director of the Comparative Pathology Shared Resource.

Funding Information:
Funding: This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740 and the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

Doxorubicin
Inflammation
Tumor

PubMed: MeSH publication types

Journal Article

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms22169023

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title = "Doxorubicin paradoxically ameliorates tumor-induced inflammation in young mice",

abstract = "Doxorubicin (DOX) is one of the most widely used chemo-therapeutic agents in pediatric oncology. DOX elicits an inflammatory response in multiple organs, which contributes to DOX-induced adverse effects. Cancer itself causes inflammation leading to multiple pathologic conditions. The current study investigated the inflammatory response to DOX and tumors using an EL4-lymphoma, immunocompetent, juvenile mouse model. Four-week old male C57BL/6N mice were injected subcutaneously with EL4 lymphoma cells (5 × 104 cells/mouse) in the flank region, while tumor-free mice were injected with vehicle. Three days following tumor implantation, both tumor-free and tumor-bearing mice were injected intraperitoneally with either DOX (4 mg/kg/week) or saline for 3 weeks. One week after the last DOX injection, the mice were euthanized and the hearts, livers, kidneys, and serum were harvested. Gene expression and serum concentration of inflammatory markers were quantified using real-time PCR and ELISA, respectively. DOX treatment significantly suppressed tumor growth in tumor-bearing mice and caused significant cardiac atrophy in tumor-free and tumor-bearing mice. EL4 tumors elicited a strong inflammatory response in the heart, liver, and kidney. Strikingly, DOX treatment ameliorated tumor-induced inflammation paradoxical to the effect of DOX in tumor-free mice, demonstrating a widely divergent effect of DOX treatment in tumor-free versus tumor-bearing mice.",

keywords = "Doxorubicin, Inflammation, Tumor",

author = "Abdelgawad, {Ibrahim Y.} and Grant, {Marianne K.O.} and Popescu, {Flavia E.} and Largaespada, {David A.} and Zordoky, {Beshay N.}",

note = "Funding Information: This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740 and the National Institutes of Health?s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Acknowledgments: Experiments using the NanoDrop 8000, and QuantStudio7 were conducted with staff support at the University of Minnesota Genomics Center. Experiments using the Luminex platform were conducted with staff support at the University of Minnesota Cytokine Reference Laboratory. Experiments using the Vevo 2100 echocardiography system were conducted with staff support at the University of Minnesota Imaging Center. Histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Pathology report was prepared by Davis M. Seelig, DVM, PhD, board-certified veterinary pathologist and the director of the Comparative Pathology Shared Resource. Funding Information: Funding: This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740 and the National Institutes of Health{\textquoteright}s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: {\textcopyright} 2021 by the authors. Licensee MDPI, Basel, Switzerland.",

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AU - Popescu, Flavia E.

AU - Largaespada, David A.

AU - Zordoky, Beshay N.

N1 - Funding Information: This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740 and the National Institutes of Health?s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Acknowledgments: Experiments using the NanoDrop 8000, and QuantStudio7 were conducted with staff support at the University of Minnesota Genomics Center. Experiments using the Luminex platform were conducted with staff support at the University of Minnesota Cytokine Reference Laboratory. Experiments using the Vevo 2100 echocardiography system were conducted with staff support at the University of Minnesota Imaging Center. Histopathological analysis was performed with staff support at the Comparative Pathology Shared Resource, University of Minnesota Masonic Cancer Center. Pathology report was prepared by Davis M. Seelig, DVM, PhD, board-certified veterinary pathologist and the director of the Comparative Pathology Shared Resource. Funding Information: Funding: This research is supported by the National Heart, Lung, and Blood Institute, grant R01HL151740 and the National Institutes of Health’s National Center for Advancing Translational Sciences, grant UL1TR002494. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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N2 - Doxorubicin (DOX) is one of the most widely used chemo-therapeutic agents in pediatric oncology. DOX elicits an inflammatory response in multiple organs, which contributes to DOX-induced adverse effects. Cancer itself causes inflammation leading to multiple pathologic conditions. The current study investigated the inflammatory response to DOX and tumors using an EL4-lymphoma, immunocompetent, juvenile mouse model. Four-week old male C57BL/6N mice were injected subcutaneously with EL4 lymphoma cells (5 × 104 cells/mouse) in the flank region, while tumor-free mice were injected with vehicle. Three days following tumor implantation, both tumor-free and tumor-bearing mice were injected intraperitoneally with either DOX (4 mg/kg/week) or saline for 3 weeks. One week after the last DOX injection, the mice were euthanized and the hearts, livers, kidneys, and serum were harvested. Gene expression and serum concentration of inflammatory markers were quantified using real-time PCR and ELISA, respectively. DOX treatment significantly suppressed tumor growth in tumor-bearing mice and caused significant cardiac atrophy in tumor-free and tumor-bearing mice. EL4 tumors elicited a strong inflammatory response in the heart, liver, and kidney. Strikingly, DOX treatment ameliorated tumor-induced inflammation paradoxical to the effect of DOX in tumor-free mice, demonstrating a widely divergent effect of DOX treatment in tumor-free versus tumor-bearing mice.

AB - Doxorubicin (DOX) is one of the most widely used chemo-therapeutic agents in pediatric oncology. DOX elicits an inflammatory response in multiple organs, which contributes to DOX-induced adverse effects. Cancer itself causes inflammation leading to multiple pathologic conditions. The current study investigated the inflammatory response to DOX and tumors using an EL4-lymphoma, immunocompetent, juvenile mouse model. Four-week old male C57BL/6N mice were injected subcutaneously with EL4 lymphoma cells (5 × 104 cells/mouse) in the flank region, while tumor-free mice were injected with vehicle. Three days following tumor implantation, both tumor-free and tumor-bearing mice were injected intraperitoneally with either DOX (4 mg/kg/week) or saline for 3 weeks. One week after the last DOX injection, the mice were euthanized and the hearts, livers, kidneys, and serum were harvested. Gene expression and serum concentration of inflammatory markers were quantified using real-time PCR and ELISA, respectively. DOX treatment significantly suppressed tumor growth in tumor-bearing mice and caused significant cardiac atrophy in tumor-free and tumor-bearing mice. EL4 tumors elicited a strong inflammatory response in the heart, liver, and kidney. Strikingly, DOX treatment ameliorated tumor-induced inflammation paradoxical to the effect of DOX in tumor-free mice, demonstrating a widely divergent effect of DOX treatment in tumor-free versus tumor-bearing mice.

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Doxorubicin paradoxically ameliorates tumor-induced inflammation in young mice

Abstract

Bibliographical note

Keywords

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Small Animal Imaging

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Doxorubicin paradoxically ameliorates tumor-induced inflammation in young mice

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

Find It

Other files and links

Fingerprint

University Assets

Small Animal Imaging

University Imaging Centers

Vevo 2100

Cite this