Bisphosphonates including clodronate and pamidronate have emerged in recent years as a highly effective therapeutic option for the prevention and treatment of skeletal complications secondary to bone metastases commonly seen in breast cancer. Recent studies have shown that bisphosphonates also exhibit direct or indirect antitumor activities, especially the potential antiangiogenic effects. Accumulating evidence indicates that the activation of hypoxia-inducible factor (HIF)-1α pathway plays a pivotal role in both tumor angiogenesis and bone metastases in breast cancer. In this study, we investigated the effect of pamidronate and clodronate on HIF-1α and VEGF expression induced by insulin-like growth factor-1 (IGF-I) in human breast cancer cells (MCF-7). Our results showed that pamidronate and clodronate significantly inhibited IGF-I-induced HIF-1α protein accumulation and up-regulation of VEGF expression in MCF-7 cells. Mechanistically, we found that pamidronate and clodronate inhibited IGF-I induced HIF-1α protein accumulation possibly by promoting its degradation as well as by inhibiting its synthesis via blocking the activation of PI-3K/AKT/mTOR signaling pathways. Functionally, we demonstrated that pamidronate and clodronate obviously abrogated both in vitro and in vivo tumor angiogenesis induced by MCF-7 cells in response to IGF-I. Taken together, our results have provided a novel mechanism of pharmacological actions of pamidronate and clodronate regarding their potential inhibitory effects on tumor angiogenesis in breast cancer. Supported by NIH AR 47359 and CA 128099.

99th AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA