Bisphosphonates inhibit the adhesion of breast cancer cells to bone matrices in vitro.

Abstract

Bisphosphonates are used with increasing frequency in the management of skeletal complications in patients with breast cancer. In this paper, we have investigated whether bisphosphonates, besides their known beneficial effects on tumor-associated osteoclastic resorption, are capable of inhibiting breast cancer cell adhesion to bone matrix. For that we used two in vitro models for bone matrix (cortical bone slices and cryostat sections of trabecular bone from neonatal mouse tails).Four bone matrix-bound nitrogen-containing bisphosphonates (pamidronate, olpadronate, alendronate, and ibandronate) inhibited adhesion and spreading of breast cancer cells to bone dose-dependently, whereas etidronate and clodronate had little or no effect. Strikingly, the relative order of potency of the bisphosphonates in inhibiting the adhesion of cancer cells to cortical and trabecular bone corresponded to their relative antiresorptive potencies in vivo as well as their ranking in in vitro bone resorption assays with predictive value for their clinical efficacy. It appears that nitrogen-containing bisphosphonates alter selectively the adhesive properties of the extracellular bone matrix preventing the attachment of breast cancer cells to it.Besides the beneficial effects of bisphosphonates on tumor-induced osteoclastic resorption, the previously unrecognized effect presented in this paper makes these agents suitable for earlier pharmacologic intervention in patients with breast cancer at risk of developing bone metastases.

In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates

“…28 In summary, the two bisphosphonates Pamidronate and Zoledronate were found to be cytotoxic to MM plasma cells at concentrations between 10 and 100 M. These results, coupled with our earlier study demonstrating a survival advantage in Pamidronate-treated patients, suggest these agents may induce an anti-tumor effect in addition to their supportive effects on skeletal function. The ability of bisphosphonates to induce anti-tumor effects in animals 28,30,34 further supports this possibility. This hypothesis should be further tested in appropriate studies that are relevant to myeloma.…”

“…A similar inhibitory effect on breast cancer cell adhesion to bone was detected when bone slices were pre-incubated with several different bisphosphonates, including Pamidronate. 30 An additional anti-tumor effect might occur secondary to effects on MM cell growth factors. The bone marrow is an environment rich in potential tumor cell growth factors and bisphosphonates can potentially inhibit the production/release of these factors.…”

New insights into the actions of bisphosphonate zoledronic acid in breast cancer cells by dual RhoA-dependent and -independent effects

“…u-PAR is a ligand for vitronectin, which is a common protein in mature bone microenvironment . Consequently, the decrease of u-PAR by ZOL could contribute to the previously reported prevention of breast-cancer cell attachment onto bone matrices (van der Pluijm et al, 1996;Boissier et al, 1997).…”

Sequence‐ and schedule‐dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells

“…7 In addition to their inhibitory effect on osteoclasts, there is increasing preclinical data to indicate that bisphosphonates have direct antitumor activity. These include inhibition of tumor cell growth and induction of cancer cell apoptosis, 8 -12 inhibition of tumor cell adhesion and invasion [13][14][15] and, more recently, antiangiogenic activity. 16,17 In preclinical testing, zoledronic acid has been shown to be the most potent inhibitor of bone resorption compared to other bisphosphonates 18 and this potency is also reflected in the various antitumor activities investigated to date.…”