A small molecule antagonist of the alpha(v)beta3 integrin suppresses MDA-MB-435 skeletal metastasis.
BACKGROUND
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 alpha(v)beta3 integrin has previously been implicated in multiple aspects of tumor progression, metastasis and osteoclast bone resorption. Therefore, we hypothesized that the alpha(v)beta3-selective inhibitor, S247, would decrease the development of osteolytic breast cancer metastases.


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.


CONCLUSIONS
IC50 for S247 adhesion to alpha(v)beta3 or alpha(IIB)beta3a substrates was 0.2 nM vs. 244 nM, respectively. Likewise, S247 was not toxic at doses up to 1000 microM. 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 alpha(v)beta3 integrin plays an important role in early events (e.g., arrest of tumor cells) in bone metastasis. Furthermore, the data suggest that alpha(v)beta3 inhibitors may be useful in the treatment and/or prevention of breast cancer metastases in bone.
Harms
John F
JF
Jake Gittlen Cancer Research Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
Welch
Danny R
DR
Samant
Rajeev S
RS
Shevde
Lalita A
LA
Miele
Mary E
ME
Babu
Geetha R
GR
Goldberg
Steven F
SF
Gilman
Virginia R
VR
Sosnowski
Donna M
DM
Campo
Dianalee A
DA
Gay
Carol V
CV
Budgeon
Lynn R
LR
Mercer
Robin
R
Jewell
Jennifer
J
Mastro
Andrea M
AM
Donahue
Henry J
HJ
Erin
Nuray
N
Debies
Michael T
MT
Meehan
William J
WJ
Jones
Amy L
AL
Mbalaviele
Gabriel
G
Nickols
Allen
A
Christensen
Neil D
ND
Melly
Robert
R
Beck
Lisa N
LN
Kent
Julia
J
Rader
Randall K
RK
Kotyk
John J
JJ
Pagel
M D
MD
Westlin
William F
WF
Griggs
David W
DW
D000199:Actins / Q000032:analysis; D000310:Adrenal Gland Neoplasms / Q000556:secondary; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000150:complications / Q000517:prevention & control / Q000556:secondary*; D001932:Brain Neoplasms / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology*; D044584:Carcinoma, Ductal / Q000150:complications / Q000517:prevention & control / Q000556:secondary*; D045744:Cell Line, Tumor / Q000637:transplantation; D005260:Female; D006321:Heart; D006801:Humans; D015918:Infusion Pumps, Implantable; D007267:Injections; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D051379:Mice; D008856:Microscopy, Fluorescence; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009928:Organ Specificity; D009930:Organic Chemicals / Q000494:pharmacology / Q000627:therapeutic use*; D010010:Osteoclasts / Q000187:drug effects / Q000648:ultrastructure; D010014:Osteolysis / Q000209:etiology / Q000517:prevention & control; D010051:Ovarian Neoplasms / Q000556:secondary; D023041:Xenograft Model Antitumor Assays
D000199:Actins; D000970:Antineoplastic Agents; D039302:Integrin alphaVbeta3; D009363:Neoplasm Proteins; D009930:Organic Chemicals; C474314:S 247 compound