Inhibition of tumor formation by snake venom disintegrin
Rong-Sen Yang1, Chih-Hsin Tang, Woei-Jer Chuang
1Department of Orthopaedics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Abstract:
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in nude mice, histological examination of the tibia of control group revealed that most of the cancellous bone had been replaced by the breast cancer cells after 28 days' inoculation.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.
Insights
Snake venom disintegrins inhibit cancer cell adhesion, migration, and invasion. These compounds show promise as a novel therapy to prevent and treat bone metastasis in breast and prostate cancers.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Bone metastasis is a significant complication of breast and prostate cancers.
- Tumor cell adhesion, migration, and invasion are key processes in bone metastasis.
- Disintegrins, derived from snake venom, are known to inhibit cell adhesion.
Purpose of the Study:
- To investigate the efficacy of snake venom-derived disintegrins in inhibiting the bone metastasis of breast and prostate cancer cells.
- To explore the mechanism of action of disintegrins, specifically rhodostomin, on tumor cell behavior and integrin binding.
Main Methods:
- Assessing the effect of rhodostomin on the adhesion of breast and prostate carcinoma cells to bone extracellular matrices.
- Evaluating the impact of rhodostomin on tumor cell migration and invasion.
- Investigating the specific integrin targets of rhodostomin using monoclonal antibodies.
- Administering trigramin alongside breast cancer cells in a mouse model of bone metastasis.
Main Results:
- Rhodostomin dose-dependently inhibited the adhesion of breast and prostate carcinoma cells to bone matrices without affecting cell viability.
- Rhodostomin significantly reduced tumor cell migration and invasion.
- Rhodostomin specifically inhibited the binding of MoAb 7E3 to integrin alphavbeta3.
- Co-administration of trigramin suppressed tumor growth and bone destruction in a mouse model.
Conclusions:
- Disintegrins effectively inhibit critical steps in bone metastasis, including cancer cell adhesion, migration, and invasion.
- Disintegrins demonstrate therapeutic potential for managing bone metastasis in breast and prostate cancers.
- Disintegrins may represent a novel therapeutic strategy for preventing and treating cancer spread to bone.
