Inhibitory Effect Of Sunitinib Research Articles

The pharmacokinetic interaction between irinotecan and sunitinib

The previous clinical trials found that the co-administration of irinotecan with sunitinib exhibited a synergistic antitumor effect. In the current study, we aimed to investigate whether the synergistic effect is related to a potential pharmacokinetic interaction between sunitinib and irinotecan. The inhibitory effects of sunitinib on SN-38 glucuronidation were determined by measuring the formation rates for SN38 glucuronide using recombinant human UGT isoforms and human liver microsomes (HLMs) in the absence or presence of sunitinib. Our data indicated that sunitinib exhibited competitive inhibition against SN-38 glucuronidation by UGT1A1, but inhibitory effects of sunitinib were weak in pooled human liver microsomes (HLMs) (Ki = 119.00μM) and recombinant UGT1A1 (Ki = 42.71μM). Our further prediction study partly explains the possible mechanism of synergistic antitumor activity of sunitinib and irinotecan in the combined treatment and provides a basis for design of clinical studies for the development and optimization of this combination.

Effect of the monoclonal antibody TRC105 in combination with Sunitinib on renal tumor derived endothelial cells.

Anti-angiogenic therapy is an important strategy to limit growth, development and expansion of solid tumors. However, resistance to VEGF-targeting agents may develop, due to activation of alternative pro-angiogenic pathways, indicating the need of multiple target strategy. Here we obtained tumor endothelial cells (TEC) either from total renal carcinomas or from renal cancer stem cells (CSC-TEC) and we tested the effect of a CD105 targeting monoclonal antibody, TRC105, alone or in association with anti-VEGF drugs. We demonstrated that TRC105 impaired the ability of TEC and CSC-TEC to organize in tubular structures, whereas it did not limit proliferation or survival. The combination of TRC105 with different anti-angiogenic drugs showed a synergistic effect of TRC105 only in combination with the tyrosine kinase inhibitor Sunitinib. In particular, TRC105 plus Sunitinib reduced tubulogenesis, proliferation and survival of CSC-TEC and tumor-derived TEC in a similar manner. At a molecular level, we showed that the combination of TRC105 and Sunitinib induced the phosphorylation of Smad 2/3 to promote endothelial cell death. Moreover, TRC105 enhanced the inhibitory effect of Sunitinib on VEGF signaling and reduced VEGFR2-Akt-Creb activation, suggesting a molecular cooperation between the two drugs. Our results highlight that the combined inhibition of VEGF and TGF-β pathway may have a potential use in renal cell carcinoma therapy.

Sunitinib Induces Growth Inhibition and Apoptosis in Breast Cancer MDA‐MB‐231 Cells through FOXO3a Signaling Pathway

Sunitinib (SUN) is a new multi‐targeted oral tyrosine kinase inhibitor that been recently approved against gastrointestinal stromal tumors and advanced renal cell carcinoma. Yet, the protective effect of SUN against breast cancer is poorly investigated. In this study, we have investigated the anti‐cancer properties of SUN against breast cancer and the possible role of Forkhead box type O (FOXO3a) transcription factor in SUN‐mediated effect using MDA‐MB‐231 cells as an in vitro model. Treatment of MDA‐MB‐231 cells with SUN caused a dose‐dependent cell growth suppression due to apoptosis as mediated by activation of caspase‐3 and p53 mRNA and protein levels using quantitative polymerase chain reaction and Western blot analyses. In addition, the percentage of cells undergoing apoptosis/necrosis determined by staining with annexinV–FITC and PI using flow cytometer was increased significantly. This inhibitory effect of SUN on MDA‐MB‐231 cell growth was associated with cell cycle arrest, downregulation of cell proliferator genes such as CyclinD1, and induction of oxidative stress markers such as heme oxygenase 1. Importantly, knockdown of FOXO3a expression using small interfering RNA (siRNA) significantly rescued MDA‐MB‐231 cells from SUN‐induced cell‐proliferative arrest, apoptosis, and oxidative stress at the mRNA and protein expression levels. In conclusion, the results clearly suggest that SUN‐induced inhibition of cell proliferation and apoptosis in MDA‐MB‐231 breast cancer cells is mediated through modulation of FOXO3a expression.

Therapeutic effects of sunitinib, one of the anti-angiogenetic drugs, in a murine arthritis

Objectives. The purpose of this study was to confirm the inhibitory effects of sunitinib, an angiogenesis inhibitor that targets tyrosine kinases of vascular endothelial growth factor receptor (VEGFR) family and platelet-derived growth factor receptor (PDGFR) family, on arthritis in mice with type II collagen-induced arthritis (CIA).Methods. Sunitinib at a concentration of 30 or 60 mg/kg/day was intraperitoneally administered to mice with CIA. We compared the changes in arthritis score over time, pathological score, bone density, and microvascular density in synovial membrane between the vehicle and treatment groups.Results. In the sunitinib-treated groups, the arthritis score decreased in a dose-dependent manner in comparison with that in the vehicle group. Furthermore, improvement in the pathological score, inhibitory tendency of loss in the bone density, and a decrease in the synovial microvascular density were also observed in the sunitinib-treated groups.Conclusions. Sunitinib remarkably inhibited arthritis, particularly synovial angiogenesis in a murine CIA model. This compound may be useful for treating arthritis.

Abstract 351: Tumor kinome profiling of early systemic disease dissemination in rectal cancer

Abstract Tumor hypoxia as common determinant of resistance to cytotoxic therapies and metastatic behavior is an emerging hypothesis. In baseline tumor biopsy specimens from rectal cancer patients receiving preoperative chemoradiotherapy, using peptide arrays with 144 tyrosine kinase substrates, we have recently shown [Folkvord et al., Int J Radiat Oncol Biol Phys 2010] that phosphopeptide levels generated by tumors with poor response to the chemoradiotherapy were significantly higher than substrate phosphorylation resulting from tumors with good treatment response. The elevated kinase activity in poor-responding tumors was suppressed by the ex vivo addition of the tyrosine kinase inhibitor sunitinib and proved to represent signaling mediated by VEGFR, EGFR, and PI3K/AKT, which is known to be implicated in experimental radiation resistance. Given that these signaling pathways might be involved in adaptive responses to tumor hypoxia, this follow-up study aimed to determine whether the tumor kinase activity signatures might also correlate to systemic disease dissemination. Immunomagnetic detection of tumor cells in bone marrow aspirates was undertaken at the time of diagnosis, and bone marrow micrometastases (BMM) were observed in 33 of 55 (60%) of the patients from whom tumor kinase activity signatures had been obtained. In this new analysis, association between ex vivo sunitinib inhibition of the kinase activity and BMM status was studied, and phosphorylation of 31 tyrosine kinase substrates was significantly more strongly inhibited by sunitinib in the BMM negative patients than in the BMM positive individuals. Interestingly, discriminating phosphopeptides represented proteins derived from signaling pathways implicated in angiogenesis; e.g., signaling mediated by PDGFR, VEGFR, and EPOR, which is a central response to tumor hypoxia and fundamental for metastasis formation. At present, this patient cohort has a median follow-up of 41 months (range 13-58) and has demonstrated significantly poorer metastasis-free survival for the BMM-positive group than for the BMM-negative group (p = 0.008). In conclusion, in this cohort of rectal cancer patients, a tumor phenotype defined by a subset of tyrosine kinase activities insusceptible to the ex vivo inhibitory effect of sunitinib was associated with early systemic dissemination. This project was supported by the EU FP7 grant number 222741 (METOXIA). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 351. doi:10.1158/1538-7445.AM2011-351

ABSTRACT WINNER: BASIC SCIENCE CATEGORY

Background: The prognoses of patients with bone metastases, a common type of metastasis for renal cell carcinoma (RCC), is poor when treated with cytokines; average life expectancy is 8 to 16 months. Sunitinib is a newly approved, multitargeted, small-molecule tyrosine kinase inhibitor for the treatment of metastatic RCC (mRCC). In this study, we show that sunitinib has anticancer activity as well as inhibitory activity against osteolysis in an experimental mouse model of bone metastasis of RCC cells. Methods: In vitro cell proliferation was determined using the MTS assay. Mice, which had RCC cells transplanted into the left ventricle for the establishment of bone metastases, were treated orally with sunitinib (40 mg/kg/day) or placebo for 3 weeks. Growth of the cancer cells was monitored using an in vivo imaging system. In addition, a total of 16 patients with mRCC were treated with sunitinib; serum and urine levels of amino-terminal telopeptide (NTx) were measured as markers of bone resorption. Results: Sunitinib did not inhibit the growth of RCC cells in vitro at clinically or experimentally achievable serum levels (100 nM – 1 mM). To investigate the inhibitory effect of sunitinib in vivo, we established luciferase-labeled human RCC cells (ACHN Luc ). Metastatic bone lesions of ACHN Luc cells in the control group progressed during the 3 weeks. On the other hand, photon emissions were significantly suppressed in the sunitinib treatment group (P ,.001). The mean body weights of mice did not differ significantly between the 2 groups. The mean number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in mice treated with sunitinib was significantly lower than that in mice treated with vehicle control (23.1+ 4.7 versus 33.2+ 7.9 osteoclasts/100 high-power fields, respectively; P ¼ .0137). In addition, serum and urine levels of NTx in patients with mRCC declined significantly during the first 4 weeks of sunitinib treatment (P ¼ .027). Conclusion: In an animal model, we demonstrated that oral administration of a clinically achievable dose of sunitinib prevented the growth of RCC bone metastases in vivo. Because RCC cell lines are resistant to clinically and preclinically achievable plasma concentrations of sunitinib in vitro, prevention of osteoclast activity and/or maturation are possible mechanisms of sunitinib mediated growth inhibition in metastatic bone lesions in vivo. Our study supports the use of sunitinib as an initial treatment for RCC patients with bone metastasis.

Pharmacological interaction with sunitinib is abolished by a germ‐line mutation (1291T>C) of BCRP/ABCG2 gene

Sunitinib malate (Sutent, SU11248) is a small-molecule multitargeted tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumors. Some TKIs can overcome multidrug resistance conferred by ATP-binding cassette transporter, P-glycoprotein (P-gp)/ABCB1, multidrug resistance-associated protein 1 (MRP1)/ABCC1, and breast cancer resistance protein (BCRP)/ABCG2. Here, we analyzed the effects of sunitinib on P-gp and on wild-type and germ-line mutant BCRPs. Sunitinib remarkably reversed BCRP-mediated and partially reversed P-gp-mediated drug resistance in the respective transfectants. The in vitro vesicle transport assay indicated that sunitinib competitively inhibited BCRP-mediated estrone 3-sulfate transport and P-gp-mediated vincristine transport. These inhibitory effects of sunitinib were further analyzed in Q141K-, R482G-, R482S-, and F431L-variant BCRPs. Intriguingly, the F431L-variant BCRP, which is expressed by a germ-line mutant allele 1291T>C, was almost insensitive to both sunitinib- and fumitremorgin C (FTC)-mediated inhibition in a cell proliferation assay. Sunitinib and FTC did not inhibit (125)I-iodoarylazidoprazosin-binding to F431L-BCRP. Thus, residue Phe-431 of BCRP is important for the pharmacological interaction with sunitinib and FTC. Collectively, this is the first report showing a differential effect of a germ-line variation of the BCRP/ABCG2 gene on the pharmacological interaction between small-molecule TKIs and BCRP. These findings would be useful for improving our understanding of the pharmaceutical effects of sunitinib in personalized chemotherapy.