Abstract
Zoledronic acid, a potent nitrogen-containing bisphosphonate (NBP), has been extensively used to limit bone turnover in a various diseases including tumors. Recent clinical studies have demonstrated direct anti-cancer effects of zoledronic acid, in addition to its clinical benefits for skeletal-related events. Here we investigated the effects of 4 clinically available NBPs on human tumor cell proliferation. Our data demonstrate a potent anti-proliferative effect of zoledronic acid against glioblastoma (GBM) cell lines, breast cancer cells and GBM patient-derived lines. Zoledronic acid also effectively inhibited GBM tumor growth in xenograft mouse models. Zoledronic acid strongly stimulated autophagy but not apoptotic signals in all tested cells. Only one intermediate product of cholesterols synthesis pathway, geranylgeranyl diphosphate (GGPP) rescued cells from the cytotoxic effects of zoledronic acid. To further investigate the effect of GGPP, we knocked down RABGGTA, which encodes a subunit of the Rabgeranylgeranyltransferase protein. This knockdown induced an effect similar to zoledronic acid in cancer cell lines. These data are promising and suggested a potential for zoledronic acid as an anti-cancer agent, through its ablation of the function of Rab proteins.
Highlights
Bisphosphonates (BPs) are synthetic analogues of pyrophosphate, that bind bone with high affinity
We aimed to determine if zoledronic acid can inhibit human cancer cell proliferation, in primary tumor cells derived from GBM patients as well as highly metastasizing cancer; we elucidated the underlying molecular mechanisms of tumor cells death induced by nitrogen-containing bisphosphonate (NBP)
We determined the effect of NBPs on proliferation of cancer cell lines by alamar blue assay in vitro as reported previously [22, 23]; we calculated IC50 values for 4 NBPs (Zoledronic acid, Risedronic acid, Alendronate, Ibandronate) in various cancer cell lines
Summary
Bisphosphonates (BPs) are synthetic analogues of pyrophosphate, that bind bone with high affinity. BPs has been used to reduce skeletal complications and pain in multiple myeloma and the bone metastatic phase of a variety of solid tumors, including breast [1], prostate [2, 3] and lung cancer [4]. Zoledronate (Zoledronic acid) is a NBP with highest activity against osteoclasts, when compared to other drugs [7]. Zoledronic acid can reduce and delay bone complications from bone metastases, and has been used in over 4 million patients worldwide for bone metastases from solid tumors and bone complications from multiple myeloma [8]. Zoledronic acid as well as other NBPs have been demonstrated to have additional anticancer effects [9]. The possible mechanisms of zoledronic acid action include inhibition of angiogenesis factors such as VEGF, and inducing microenvironment changes that attenuate tumor growth [10, 11, 12]
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