Tyrosine kinase receptor inhibitor-targeted combined chemotherapy for metastatic bladder cancer.
ABSTRACT Overexpression of hypoxia-inducible factor-1 alpha is noted during the invasive and metastatic process of transitional cell carcinoma. It will upregulate vascular endothelial growth factor (VEGF) and drive proliferation, invasiveness, metastasis, and antiapoptotic ability of cancer cells. We proposed that tyrosine kinase receptor inhibitor, sunitinib malate-(Sutent; Pfizer Inc., Taiwan), combined with chemotherapeutic drug may present synergistic cytotoxic enhancement to transitional cell carcinoma cells with subsequent inhibition of their cellular behaviors, including proliferation, invasiveness, and metastatic activity. The contents of VEGF-A in mouse bladder tumor cells (MBT-2) and culture medium were detected by quantification-polymerase chain reaction and Western blot individually. The inhibitory concentrations of various chemotherapeutic drugs, sunitinib, and their combination treatment in MBT-2 were determined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Microchamber transmembrane migration assay was applied in evaluation of the inhibitory effects of different dosages of sunitinib and combination treatment on tumor cells. The cell cycle and apoptosis were analyzed after combination therapy by flow cytometry. Variation in apoptotic pathway was elucidated by Western blot using specific antibodies with cleaved PARP and caspase-3. Metastatic animal model mimicked by tail vein injection of MBT-2 cells was used to evaluate the treatment efficiency in tumor weight and survival rate. The mRNA and protein level of VEGF-A in MBT-2 cells increased by 70% at 48 hours interval under hypoxia stress condition. In MTT assay, MBT-2 cells had shown the highest sensitivity to epirubicin. Sunitinib combined with epirubicin had shown a synergistic cytotoxic effect to MBT-2 cells. Sunitinib and its combination with epirubicin showed significant inhibition on MBT-2 cells migration in microchambers. G2/M phase arrest and increased subG1 in cell cycle was seen in the epirubicin and sunitinib combination treatment group. The activation of apoptosis pathway was confirmed by increased cleaved caspase-3 and cleaved PARP in MBT-2 cells. In tail vein tumor inoculation C3H mice model, epirubicin alone and sunitinib combination therapy decreased tumor growth in lungs with marginal effect. Sunitinib and epirubicin combination had shown a synergistic cytotoxic effect and inhibited cell migration ability in MBT-2 cells. The combination can induce cell cycle arrest at G2/M phase and increase subG1 cells. Metastatic animal study also showed that sunitinib combined with epirubicin has a marginal effect on inhibition of tumor growth of lungs. The tyrosine kinase receptor inhibitor-targeted combined chemotherapy regimen may provide as a new treatment modality for advanced bladder cancer in the future.
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ABSTRACT: This review describes the scientific background, current achievement and future perspective of combination therapy using polymer nanoparticle drug carriers in cancer treatment. Nanotechnology-based drug delivery is expected to dramatically change combination cancer therapy by controlling accumulation and distribution patterns of multiple drugs selectively in disease sites. Rationally designed polymer materials can produce functional nanoparticulate drug carriers that can be used in various biomedical applications. In comparison with conventional drug combination approaches, using polymer nanoparticle drug carriers appears to suppress tumor growth more efficiently, potentially overcoming multidrug resistance in many cancers. It also provides versatile combination options for a variety of therapeutic agents, molecular targeting agents and nucleotide drugs.Future Oncology 11/2012; 8(11):1471-1480. · 3.20 Impact Factor
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ABSTRACT: Introduction: Urothelial cancer (UC) is the fourth most common cancer in men, worldwide. After cystectomy, muscle invasive disease progresses up to 50%, either regionally or as distant metastases, and treatment of metastatic disease remains a challenge, with a median survival that not exceeded 14 months with current chemotherapy regimens. Angiogenesis has been shown to play a role in UC progression and targeting this pathway may improve treatment outcomes. Sunitinib , an anti-angiogenic tyrosine kinase inhibitor, has been tested in preclincal models and Phase II trials in UC. Areas covered: In this review, the authors discuss the rational for targeting angiogenesis pathway in UC with sunitinib. They also discuss its mechanisms of action, and the data from its preclinical and clinical data studies. Expert opinion: Sunitinib monotherapy has clinical activity in UC, identifying the potential role of the angiogenic pathway as a target for therapy in this tumor type. However, overlapping toxicity with chemotherapy has limited further development. Future research should be focused on improving patient selection which is based on the identification of validated predictive markers for sunitinib treated patients.Expert Opinion on Investigational Drugs 11/2013; · 4.74 Impact Factor
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ABSTRACT: Background:Tyrosine kinase inhibitors (TKI) such as sunitinib and pazopanib display their efficacy in a variety of solid tumours. However, their use in therapy is limited by the lack of evidence about the ability to induce cell death in cancer cells. Our aim was to evaluate cytotoxic effects induced by sunitinib and pazopanib in 5637 and J82 bladder cancer cell lines.Methods:Cell viability was tested by MTT assay. Autophagy was evaluated by western blot using anti-LC3 and anti-p62 antibodies, acridine orange staining and FACS analysis. Oxygen radical generation and necrosis were determined by FACS analysis using DCFDA and PI staining. Cathepsin B activation was evaluated by western blot and fluorogenic Z-Arg-Arg-AMC peptide. Finally, gene expression was performed using RT-PCR Profiler array.Results:We found that sunitinib treatment for 24 h triggers incomplete autophagy, impairs cathepsin B activation and stimulates a lysosomal-dependent necrosis. By contrast, treatment for 48 h with pazopanib induces cathepsin B activation and autophagic cell death, markedly reversed by CA074-Me and 3-MA, cathepsin B and autophagic inhibitors, respectively. Finally, pazopanib upregulates the α-glucosidase and downregulates the TP73 mRNA expression.Conclusion:Our results showing distinct cell death mechanisms activated by different TKIs, provide the biological basis for novel molecularly targeted approaches.British Journal of Cancer advance online publication, 25 July 2013; doi:10.1038/bjc.2013.420 www.bjcancer.com.British Journal of Cancer 07/2013; · 5.08 Impact Factor