A small molecule antagonist of the αυβ 3 integrin suppresses MDA-MB-435 skeletal metastasis

John F. Harms, Danny R. Welch, Rajeev S. Samant, Lalita A. Shevde, Mary E. Miele, Geetha R. Babu, Steven F. Goldberg, Virginia R. Gilman, Donna M. Sosnowski, Dianalee A. Campo, Carol V. Gay, Lynn R. Budgeon, Robin Mercer, Jennifer Jewell, Andrea M. Mastro, Henry J. Donahue, Nuray Erin, Michael T. Debies, William J. Meehan, Amy L. Jones & 11 others Gabriel Mbalaviele, Allen Nickols, Neil D. Christensen, Robert Melly, Lisa N. Beck, Julia Kent, Randall K. Rader, John J. Kotyk, Mark "Marty" Pagel, William F. Westlin, David W. Griggs

Research output: Contribution to journalArticle

101 Citations (Scopus)

Abstract

Introduction: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The αvβ3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the αvβ3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. Materials and methods: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100 mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. Results and conclusions: IC50 for S247 adhesion to αvβ3 or αIIBβ 3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 μM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50% of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the αvβ3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that αvβ3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

Original languageEnglish (US)
Pages (from-to)119-128
Number of pages10
JournalClinical and Experimental Metastasis
Volume21
Issue number2
DOIs
StatePublished - 2004
Externally publishedYes

Fingerprint

Integrins
Neoplasm Metastasis
Breast Neoplasms
Bone and Bones
Neoplasms
Osteoclasts
Poisons
Bone Resorption
Fluorescence Microscopy
Nude Mice
Inhibitory Concentration 50
Heart Ventricles
Actins
Histology
Quality of Life
Injections

Keywords

  • Bone
  • Breast cancer
  • Green fluorescent protein
  • MDA-MB-435
  • Metastasis

ASJC Scopus subject areas

  • Cancer Research

Cite this

Harms, J. F., Welch, D. R., Samant, R. S., Shevde, L. A., Miele, M. E., Babu, G. R., ... Griggs, D. W. (2004). A small molecule antagonist of the αυβ 3 integrin suppresses MDA-MB-435 skeletal metastasis. Clinical and Experimental Metastasis, 21(2), 119-128. https://doi.org/10.1023/B:CLIN.0000024763.69809.64

A small molecule antagonist of the αυβ 3 integrin suppresses MDA-MB-435 skeletal metastasis. / Harms, John F.; Welch, Danny R.; Samant, Rajeev S.; Shevde, Lalita A.; Miele, Mary E.; Babu, Geetha R.; Goldberg, Steven F.; Gilman, Virginia R.; Sosnowski, Donna M.; Campo, Dianalee A.; Gay, Carol V.; Budgeon, Lynn R.; Mercer, Robin; Jewell, Jennifer; Mastro, Andrea M.; Donahue, Henry J.; Erin, Nuray; Debies, Michael T.; Meehan, William J.; Jones, Amy L.; Mbalaviele, Gabriel; Nickols, Allen; Christensen, Neil D.; Melly, Robert; Beck, Lisa N.; Kent, Julia; Rader, Randall K.; Kotyk, John J.; Pagel, Mark "Marty"; Westlin, William F.; Griggs, David W.

In: Clinical and Experimental Metastasis, Vol. 21, No. 2, 2004, p. 119-128.

Research output: Contribution to journalArticle

Harms, JF, Welch, DR, Samant, RS, Shevde, LA, Miele, ME, Babu, GR, Goldberg, SF, Gilman, VR, Sosnowski, DM, Campo, DA, Gay, CV, Budgeon, LR, Mercer, R, Jewell, J, Mastro, AM, Donahue, HJ, Erin, N, Debies, MT, Meehan, WJ, Jones, AL, Mbalaviele, G, Nickols, A, Christensen, ND, Melly, R, Beck, LN, Kent, J, Rader, RK, Kotyk, JJ, Pagel, MM, Westlin, WF & Griggs, DW 2004, 'A small molecule antagonist of the αυβ 3 integrin suppresses MDA-MB-435 skeletal metastasis', Clinical and Experimental Metastasis, vol. 21, no. 2, pp. 119-128. https://doi.org/10.1023/B:CLIN.0000024763.69809.64
Harms, John F. ; Welch, Danny R. ; Samant, Rajeev S. ; Shevde, Lalita A. ; Miele, Mary E. ; Babu, Geetha R. ; Goldberg, Steven F. ; Gilman, Virginia R. ; Sosnowski, Donna M. ; Campo, Dianalee A. ; Gay, Carol V. ; Budgeon, Lynn R. ; Mercer, Robin ; Jewell, Jennifer ; Mastro, Andrea M. ; Donahue, Henry J. ; Erin, Nuray ; Debies, Michael T. ; Meehan, William J. ; Jones, Amy L. ; Mbalaviele, Gabriel ; Nickols, Allen ; Christensen, Neil D. ; Melly, Robert ; Beck, Lisa N. ; Kent, Julia ; Rader, Randall K. ; Kotyk, John J. ; Pagel, Mark "Marty" ; Westlin, William F. ; Griggs, David W. / A small molecule antagonist of the αυβ 3 integrin suppresses MDA-MB-435 skeletal metastasis. In: Clinical and Experimental Metastasis. 2004 ; Vol. 21, No. 2. pp. 119-128.
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abstract = "Introduction: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The αvβ3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the αvβ3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. Materials and methods: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100 mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. Results and conclusions: IC50 for S247 adhesion to αvβ3 or αIIBβ 3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 μM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50{\%} of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the αvβ3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that αvβ3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.",
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TY - JOUR

T1 - A small molecule antagonist of the αυβ 3 integrin suppresses MDA-MB-435 skeletal metastasis

AU - Harms, John F.

AU - Welch, Danny R.

AU - Samant, Rajeev S.

AU - Shevde, Lalita A.

AU - Miele, Mary E.

AU - Babu, Geetha R.

AU - Goldberg, Steven F.

AU - Gilman, Virginia R.

AU - Sosnowski, Donna M.

AU - Campo, Dianalee A.

AU - Gay, Carol V.

AU - Budgeon, Lynn R.

AU - Mercer, Robin

AU - Jewell, Jennifer

AU - Mastro, Andrea M.

AU - Donahue, Henry J.

AU - Erin, Nuray

AU - Debies, Michael T.

AU - Meehan, William J.

AU - Jones, Amy L.

AU - Mbalaviele, Gabriel

AU - Nickols, Allen

AU - Christensen, Neil D.

AU - Melly, Robert

AU - Beck, Lisa N.

AU - Kent, Julia

AU - Rader, Randall K.

AU - Kotyk, John J.

AU - Pagel, Mark "Marty"

AU - Westlin, William F.

AU - Griggs, David W.

PY - 2004

Y1 - 2004

N2 - Introduction: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The αvβ3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the αvβ3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. Materials and methods: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100 mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. Results and conclusions: IC50 for S247 adhesion to αvβ3 or αIIBβ 3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 μM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50% of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the αvβ3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that αvβ3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

AB - Introduction: Breast cancer is one of the most common malignancies affecting women in the United States and Europe. Approximately three out of every four women with breast cancer develop metastases in bone which, in turn, diminishes quality of life. The αvβ3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the αvβ3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases. Materials and methods: Cells were treated in vitro with S247 and assessed for viability and adhesion to matrix components. Athymic mice received intracardiac (left ventricle) injections of human MDA-MB-435 breast carcinoma cells expressing enhanced green-fluorescent protein. Mice were treated with vehicle (saline) or S247 (1, 10, or 100 mg/kg/d) using osmotic pumps beginning either one week before or one week after tumor cell inoculation. Bones were removed and examined by fluorescence microscopy and histology. The location and size of metastases were recorded. Results and conclusions: IC50 for S247 adhesion to αvβ3 or αIIBβ 3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 μM. However, osteoclast cultures treated with S247 exhibited marked morphological changes and impaired formation of the actin sealing zone. When S247 was administered prior to tumor cells, there was a significant, dose-dependent reduction (25-50% of vehicle-only-treated mice; P = 0.002) in osseous metastasis. Mice receiving S247 after tumor cell inoculation also developed fewer bone metastases, but the difference was not statistically significant. These data suggest that, in the MDA-MB-435 model, the αvβ3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that αvβ3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.

KW - Bone

KW - Breast cancer

KW - Green fluorescent protein

KW - MDA-MB-435

KW - Metastasis

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