Inhibition of tumor formation by snake venom disintegrin.
The metastasis of tumor cells to bone involves migration, invasion and adhesion to bone. Breast and prostate cancer cells have predilection for spreading to bone. Snake venom-derived arginine-glycine-aspartic acid (RGD)-containing disintegrins (e.g. rhodostomin) have been demonstrated to inhibit cell adhesion. Here, we found that rhodostomin inhibited the adhesion of breast and prostate carcinoma cells to both unmineralized and mineralized bone extracellular matrices in a dose-dependent manner, without affecting the viability of tumor cells. In addition, rhodostomin also inhibited the migration and invasion of breast and prostate carcinoma cells. It specifically inhibited the binding of monoclonal antibody (MoAb) 7E3, which recognizes integrin alphavbeta3, to tumor cells, but not those of other MoAbs against other integrin subunits such as alpha2, alpha3, alpha5 and beta1. As breast cancer cells MDA-MB-231 were locally injected into tibia in nude mice, histological examination of the tibia of control group revealed that most of the cancellous bone had been replaced by the breast cancer cells after 28 days' inoculation. In contrast, co-administration of trigramin with cancer cells markedly inhibited tumor growth and bone destruction. Taken together, disintegrins strongly inhibit the adhesion, migration, invasion of tumor cells and also tumor growth of human breast cancer cells in bone as well. Therefore, disintegrins may be developed as alternate therapy for bone metastasis of cancer cells.
Yang
Rong-Sen
RS
Department of Orthopaedics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Tang
Chih-Hsin
CH
Chuang
Woei-Jer
WJ
Huang
Tsang-Hai
TH
Peng
Hui-Chin
HC
Huang
Tur-Fu
TF
Fu
Wen-Mei
WM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary*; D001943:Breast Neoplasms / Q000503:physiopathology*; D002448:Cell Adhesion / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D019483:Disintegrins / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005453:Fluorescence; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D010455:Peptides / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000503:physiopathology*; D051381:Rats; D013977:Tibia / Q000473:pathology; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D019483:Disintegrins; D036341:Intercellular Signaling Peptides and Proteins; D010455:Peptides; C054194:trigramin