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  • A number of studies have shown that zoledronic


    A number of studies have shown that zoledronic enolase has the ability to potentiate effects of anti-tumor agents such as doxorubicin [21] or everolimus [22]. In a recent paper the combination of chemotherapy with a single infusion of 4mg zoledronic acid in patients with breast cancer was shown to result in a greater suppression of VEGF levels at day 5 than with chemotherapy alone [23]. The combination of an anti-angiogenic therapy with zoledronic acid may be an attractive option in some cases. However, this therapy has been associated with an increased rate of osteonecrosis of the jaw (ONJ) [24]. ONJ is a complication of anti-resorptive therapy, while it is rarely seen when BP are given for the treatment of osteoporosis, it is more common when given in oncologic doses [25]. While the pathogenesis of ONJ remains unclear, angiogenic suppression in osteoclasts following BP is one proposed mechanism [26,27]. This hypothesis is supported by a recent finding, that patients with highest suppression of VEGF levels following BP administration were prone to ONJ [28].
    Role of the funding source This work was supported by the DAdorW/Amgen Bone Fellowship and the MedDrive Start-Up Grant from the TU Dresden to TDR, and Grants RA 2151/2-1 (to TDR and LCH) and Forschergruppe-1586 SKELMET to LCH from the Deutsche Forschungsgemeinschaft.
    Conflict of Interest statement
    Introduction Between 65% and 75% of patients with metastatic breast cancer will have decreased 5-year survival and increased morbidity due to cancer relapse in bone [1,2]. Bone metastases phenotype results from an unbalanced bone remodeling, where in a “vicious cycle” the tumor cells stimulate osteoclast activity, and have increased proliferation due to growth factors released from bone matrix upon bone resorption [3]. Re-establishing the apoptotic program in tumor cells is a promising strategy for cancer therapy. Inhibitor-of-apoptosis proteins (IAPs) are inhibitors of caspases’ pathways that prevent cells from undergoing apoptosis. IAPs are frequently overexpressed in cancer and contribute to tumor cell survival, chemoresistance, disease progression and poor prognosis. IAPs are also potent regulators of nuclear factor k-B (NF-kB) and tumor-necrosis factor (TNF) receptor signaling pathways [4–6]. Cells have natural IAP antagonists, like Smac (second mitochondria-derived activator of caspases)/DIABLO in mammals, that bind to caspases preventing further IAPs binding [7,8]. Based on enolase this, Smac mimetics have been designed to antagonize IAPs and cause cancer cells to undergo apoptosis [9–11]. Also, it has been shown that IAPs are direct activators of tumor cell motility and metastatic genes independently of their roles in cytoprotection, suggesting that IAP antagonists could provide antimetastatic therapies for patients with cancer [12]. AT-406 (formerly SM-406) is a potent and orally bioavailable Smac mimetic and an antagonist of IAPs [11]. This compound binds to XIAP, cIAP1, and cIAP2 proteins, induces rapid degradation of IAPs, and inhibits cancer cell growth in various human cancer cell lines. AT-406 is currently in phase I clinical trial for the treatment of human cancer (NCT01078649). In this work we explored the use of AT-406 to target the tumor compartment of bone metastases, using an in vitro model of breast cancer. Since cIAP1 and cIAP2 were originally identified through their ability to interact directly with TNF-family [13], and MDA-MB-231 breast cancer cells express the receptor activator of NF-κB (RANK) [14–18] and are sensitive to RANK ligand (RANKL) that induces the activation of RANK–TRAF-dependent pathways [14–16,19,20], we also explored the activation of RANKL–RANK pathway in these cells and its significance on AT-406 effect. Given that IAPs also play a role in osteoclastogenesis, the effect of IAP antagonists on osteoclasts needs to be addressed if AT-406 is used in the context of bone metastatic disease. Recently, it was demonstrated that IAPs negatively regulate osteoclastogenesis by inhibiting NFATc1 mRNA expression [21]. It was also shown that IAP antagonists induce high turnover osteoporosis characterized by enhanced osteoclast and osteoblast activities, in mice, and may increase tumor growth and metastasis in the bone by stabilizing NF-κB inducing kinase (NIK) and activating the alternative NF-κB pathway in osteoclasts [22]. Therefore we also addressed the effects of AT-406 in osteoclastogenesis and osteoclast activity in vitro.