Bisphosphonates antagonise bone growth factors' effects on human breast cancer cells survival

Abstract

Bone tissue constitutes a fertile 'soil' for metastatic tumours, notably breast cancer. High concentrations of growth factors in bone matrix favour cancer cell proliferation and survival, and a vicious cycle settles between bone matrix, osteoclasts and cancer cells. Classically, bisphosphonates interrupt this vicious cycle by inhibiting osteoclast-mediated bone resorption. We and others recently reported that bisphosphonates can also induce human breast cancer cell death in vitro, which could contribute to their beneficial clinical effects. We hypothesised that bisphosphonates could inhibit the favourable effects of 'bone -derived' growth factors, and indeed found that bisphosphonates reduced or abolished the stimulatory effects of growth factors (IGFs, FGF-2) on MCF-7 and T47D cell proliferation and inhibited their protective effects on apoptotic cell death in vitro under serum-free conditions. This could happen through an interaction with growth factors' intracellular phosphorylation transduction pathways, such as ERK1/2-MAPK. In conclusion, we report that bisphosphonates antagonised the stimulatory effects of growth factors on human breast cancer cell survival and reduced their protective effects against apoptotic cell death. Bisphosphonates and growth factors thus appear to be concurrent compounds for tumour cell growth and survival in bone tissue. This could represent a new mechanism of action of bisphosphonates in their protective effects against breast cancer-induced osteolysis.

Sequence- and concentration-dependent effects of acute and long-term exposure to the bisphosphonate ibandronate in combination with single and multiple fractions of ionising radiation doses in human breast cancer cell lines

“…Recent in vitro and in vivo data indicate that bisphosphonates may also directly inhibit tumor cell proliferation and induce apoptosis in cell lines derived from various neoplasms. Moreover, they may antagonise the growth stimulation induced by bone-derived growth factors on human breast cancer cells [33]. Our present study confirms that ibandronate is able to inhibit breast cancer cell growth.…”

The bisphosphonate zoledronic acid inhibits the growth of HCT-116 colon carcinoma cells and induces tumor cell apoptosis

“…In this context ZOL is the current clinical standard for the prevention of bone metastases of human cancers. ZOL acts as an inhibitor of farnesyldiphosphate synthase [3], blocking the biosynthesis of precursors needed for the prenylation of small gtp-binding proteins, and thus not only reduces the activity of osteoclasts but also prevents or slows the progression of certain tumor cells into healthy bone tissue [4][5][6]. Besides its well established effect on the formation of bone metastases, there is promising evidence of a broader antitumoral activity [7].…”

Osteonecrosis of the jaw and use of bisphosphonates in adjuvant breast cancer treatment: a metanalysis

“…Furthermore, data from preclinical studies demonstrate that bisphosphonates may have antitumor activity by preventing tumor cell adhesion to bone [11][12][13], by inducing tumor cell apoptosis [14], by antagonising of growth factors [15], and by antiangiogenic effects [16]. In addition, a recent clinical trial evidenced that use of zoledronic acid in adjuvant treatment of early breast cancer setting may prolong disease free survival when compared with non use [17].…”