Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia

Kim D. Johnson; Olga V. Glinskii; Valeri V. Mossine; James R. Turk; Thomas P. Mawhinney; Douglas C. Anthony; Carolyn J. Henry; Virginia H. Huxley; Gennadi V. Glinsky; Kenneth J. Pienta; Avraham Raz; Vladislav V. Glinsky

doi:10.1593/neo.07433

Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia

Kim D. Johnson, Olga V. Glinskii, Valeri V. Mossine, James R. Turk, Thomas P. Mawhinney, Douglas C. Anthony, Carolyn J. Henry, Virginia H. Huxley, Gennadi V. Glinsky, Kenneth J. Pienta, Avraham Raz, Vladislav V. Glinsky

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

85 Scopus citations

Abstract

Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a β-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-_L-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 anti-apoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC₅₀ of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells.

Original language	English (US)
Pages (from-to)	662-670
Number of pages	9
Journal	Neoplasia
Volume	9
Issue number	8
DOIs	https://doi.org/10.1593/neo.07433
State	Published - Aug 2007
Externally published	Yes

Keywords

Angiosarcoma
Apoptosis
Chemotherapy
Doxorubicin
Galectin-3

ASJC Scopus subject areas

Cancer Research

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10.1593/neo.07433

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@article{5bced59e60104afc9227d5ee72a8cc64,

title = "Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia",

abstract = "Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a β-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-L-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 anti-apoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC50 of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells.",

keywords = "Angiosarcoma, Apoptosis, Chemotherapy, Doxorubicin, Galectin-3",

author = "Johnson, {Kim D.} and Glinskii, {Olga V.} and Mossine, {Valeri V.} and Turk, {James R.} and Mawhinney, {Thomas P.} and Anthony, {Douglas C.} and Henry, {Carolyn J.} and Huxley, {Virginia H.} and Glinsky, {Gennadi V.} and Pienta, {Kenneth J.} and Avraham Raz and Glinsky, {Vladislav V.}",

note = "Funding Information: Address all correspondence to: Vladislav V. Glinsky, MD, Department of Biochemistry, University of Missouri, M743 Medical Science Building, Columbia, MO 65212. E-mail: glinskiivl@missouri.edu 1This work was supported by the VA Merit Review Program (V. V. Glinsky); a research grant from the Tom and Betty Scott Endowed Program in Veterinary Oncology (K. D. Johnson); National Institutes of Health (NIH) grant RO1 HL078816 and National Aeronautics and Space Administration grant NNJ05HF37G (V. H. Huxley); NIH grant 5RO1 CA89827 (G. V. Glinsky); NIH grants P50 CA69568 SPORE in Prostate Cancer and PO1 CA093900-01A2 (K. J. Pienta); and NIH grant R37 CA046120-19 (A. Raz). Kenneth J. Pienta is an American Cancer Society clinical research professor. Received 21 May 2007; Revised 8 June 2007; Accepted 13 June 2007.",

year = "2007",

month = aug,

doi = "10.1593/neo.07433",

language = "English (US)",

volume = "9",

pages = "662--670",

journal = "Neoplasia",

issn = "1522-8002",

publisher = "Elsevier Inc.",

number = "8",

}

TY - JOUR

T1 - Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia

AU - Johnson, Kim D.

AU - Glinskii, Olga V.

AU - Mossine, Valeri V.

AU - Turk, James R.

AU - Mawhinney, Thomas P.

AU - Anthony, Douglas C.

AU - Henry, Carolyn J.

AU - Huxley, Virginia H.

AU - Glinsky, Gennadi V.

AU - Pienta, Kenneth J.

AU - Raz, Avraham

AU - Glinsky, Vladislav V.

N1 - Funding Information: Address all correspondence to: Vladislav V. Glinsky, MD, Department of Biochemistry, University of Missouri, M743 Medical Science Building, Columbia, MO 65212. E-mail: glinskiivl@missouri.edu 1This work was supported by the VA Merit Review Program (V. V. Glinsky); a research grant from the Tom and Betty Scott Endowed Program in Veterinary Oncology (K. D. Johnson); National Institutes of Health (NIH) grant RO1 HL078816 and National Aeronautics and Space Administration grant NNJ05HF37G (V. H. Huxley); NIH grant 5RO1 CA89827 (G. V. Glinsky); NIH grants P50 CA69568 SPORE in Prostate Cancer and PO1 CA093900-01A2 (K. J. Pienta); and NIH grant R37 CA046120-19 (A. Raz). Kenneth J. Pienta is an American Cancer Society clinical research professor. Received 21 May 2007; Revised 8 June 2007; Accepted 13 June 2007.

PY - 2007/8

Y1 - 2007/8

N2 - Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a β-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-L-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 anti-apoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC50 of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells.

AB - Angiosarcoma (ASA) in humans and hemangiosarcoma (HSA) in dogs are deadly neoplastic diseases characterized by an aggressive growth of malignant cells with endothelial phenotype, widespread metastasis, and poor response to chemotherapy. Galectin-3 (Gal-3), a β-galactoside-binding lectin implicated in tumor progression and metastasis, endothelial cell biology and angiogenesis, and regulation of apoptosis and neoplastic cell response to cytotoxic drugs, has not been studied before in tumors arising from malignant endothelia. Here, we tested the hypothesis that Gal-3 could be widely expressed in human ASA and canine HSA and could play an important role in malignant endothelial cell biology. Immunohistochemical analysis demonstrated that 100% of the human ASA (10 of 10) and canine HSA (17 of 17) samples analyzed expressed Gal-3. Two carbohydrate-based Gal-3 inhibitors, modified citrus pectin (MCP) and lactulosyl-L-leucine (LL), caused a dose-dependent reduction of SVR murine ASA cell clonogenic survival through the inhibition of Gal-3 anti-apoptotic function. Furthermore, both MCP and LL sensitized SVR cells to the cytotoxic drug doxorubicin to a degree sufficient to reduce the in vitro IC50 of doxorubicin by 10.7-fold and 3.6-fold, respectively. These results highlight the important role of Gal-3 in the biology of ASA and identify Gal-3 as a potential therapeutic target in tumors arising from malignant endothelial cells.

KW - Angiosarcoma

KW - Apoptosis

KW - Chemotherapy

KW - Doxorubicin

KW - Galectin-3

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EP - 670

JO - Neoplasia

JF - Neoplasia

IS - 8

ER -

Galectin-3 as a potential therapeutic target in tumors arising from malignant endothelia

Abstract

Keywords

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