Antitumor effect of sunitinib against skeletal metastatic renal cell carcinoma through inhibition of osteoclast function

Abstract

We investigated the inhibitory effect of sunitinib, a newly approved multitargeted tyrosine kinase inhibitor, against the progression of renal cell cancer (RCC) bone metastases in vivo. In vitro cell proliferation was determined using the MTS assay. To investigate the inhibitory effects of sunitinib in vivo, we established luciferase-labeled ACHN Luc cells derived from papillary RCC. Mice in which ACHN Luc cells had been transplanted into the left ventricle to establish bone metastases were treated orally with 40 mg/kg/day sunitinib or vehicle control for 3 weeks. Growth of the cancer cells was monitored using an in vivo imaging system. In addition, 16 patients with metastatic RCC were treated with sunitinib, and serum and urine levels of amino-terminal telopeptide (NTx) were measured as markers of bone resorption. Sunitinib did not inhibit the growth of RCC cells in vitro at clinically or experimentally achievable serum levels (100 nM-1 lM). To investigate the inhibitory effect of sunitinib in vivo, we established luciferase-labeled human RCC cells (ACHN Luc ). Sunitinib prevented the growth of ACHN Luc RCC cells in the bone metastatic mouse model. The number of osteoclasts in sunitinib-treated mice was significantly less than that in control mice. Serum and urine levels of NTx in patients with metastatic RCC declined significantly during the first 4 weeks of sunitinib treatment (p 5 0.027). Sunitinib is a potent anticancer agent for RCC bone metastases, at least for papillary RCC.Bone is a common site of metastasis, with the frequency of solitary or multiple metastases to bone ranging from 24 to 51% in patients with metastatic renal cell cancer (RCC). 1-3 Although bone metastasis is not an independent prognostic factor associated with poor survival, the prognosis of patients with bone metastasis is not favorable when they are treated with cytokines, with an average life expectancy of 8-16 months. [2][3][4] Moreover, bone metastases are associated with poor performance status due to intractable pain and pathological fractures. 5 Because treatment options for RCC patients with bone metastasis are limited, appropriate treatment strategies are desired.Sunitinib is a newly approved, multitarget, small-molecule tyrosine kinase inhibitor for the treatment of metastatic RCC. It inhibits various receptor tyrosine kinases, including vascular endothelial growth factor (VEGF) receptors 1, 2 and 3; stem cell factor receptor (KIT) and PDGF receptors a and b. 6-8 Moreover, sunitinib has been known to inhibit the phosphorylation of colony-stimulating factor (CSF)-1R, resulting in the prevention of osteoclast function and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. 9,10 These findings led us to propose the hypothesis that sunitinib may inhibit tumor growth and osteolysis in bone metastatic lesions in RCC patients.Although establishing a treatment strategy for bone metastases from RCC is important for urologists, the assessment of inhibitory effects on the growth of bone metastases is oft...

Sunitinib enhances antitumor effects against chemotherapy-resistant bladder cancer through suppression of ERK1/2 phosphorylation

“…The antitumor activity of sunitinib has been shown in preclinical and clinical studies (7,18). Tumor regression has been shown in different xenograft models of colon cancer, breast cancer, non-small cell lung cancer, melanoma, glioblastoma and renal carcinoma (18,(29)(30)(31)(32)(33). Sunitinib clearly inhibited cell proliferation in vitro and tumor growth in vivo in the present study (Figs.…”

“…Sunitinib is an oral inhibitor with antiangiogenic and antitumor activities and inhibits multiple receptor tyrosine kinases, including VEGF receptors, PDGF receptors and c-KIT, which are involved in angiogenesis (7). The antitumor activity of sunitinib has been shown in preclinical and clinical studies (7,18). Tumor regression has been shown in different xenograft models of colon cancer, breast cancer, non-small cell lung cancer, melanoma, glioblastoma and renal carcinoma (18,(29)(30)(31)(32)(33).…”

“…Sunitinib (Sutent) was obtained from Pfizer (New York, NY). For the in vitro and in vivo studies, sunitinib was prepared as described previously (18). Mouse interferon-α (IFN-α) was supplied by Dainippon Sumitomo Pharma Co., Ltd. (Osaka, Japan).…”

Inverse Virtual Screening in Drug Repositioning: Detailed Investigation and Case Studies

“…5.3c) of sunitinib with the native ligand shows dotted lines representing H-bonds with the target protein. Further, very recent reports presented the use of sunitinib for renal cell carcinoma bone metastases [27], an activity related to bone resorption. This likeliness of the data made us search further for similarity in the acquired results and experimental results.…”

Prognostic Significance of Bone Metastases and Bisphosphonate Therapy in Patients with Renal Cell Carcinoma

“…Maita et al demonstrated that sunitinib prevented the growth of RCC cells in a bone metastatic mouse model and caused significant declines in bone turnover markers in patients treated with sunitinib. (9) Additionally, the lower rate of SREs could reflect an underestimation of actual events given that the database was not designed to capture SREs and adverse event monitoring occurred only during the period for which patients were on the clinical trial. We did not observe a correlation between SRE rate and survival.…”