Browse > Article
http://dx.doi.org/10.7314/APJCP.2012.13.5.1957

Cytostatic in vitro Effects of DTCM-Glutarimide on Bladder Carcinoma Cells  

Brassesco, Maria S. (Division of Pediatric Oncology, Department of Pediatrics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
Pezuk, Julia A. (Department of Genetics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
Morales, Andressa G. (Department of Genetics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
De Oliveira, Jaqueline C. (Department of Genetics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
Valera, Elvis T. (Division of Pediatric Oncology, Department of Pediatrics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
Da Silva, Glenda N. (Faculty of Medicine of Botucatu, Sao Paulo State University - UNESP)
De Oliveira, Harley F. (Division of Radiotherapy, Clinics Department, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
Scrideli, Carlos A. (Division of Pediatric Oncology, Department of Pediatrics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
Umezawa, Kazuo (Faculty of Science and Technology, Keio University)
Tone, Luiz G. (Division of Pediatric Oncology, Department of Pediatrics, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo - USP)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.13, no.5, 2012 , pp. 1957-1962 More about this Journal
Abstract
Bladder cancer is a common malignancy worldwide. Despite the increased use of cisplatin-based combination therapy, the outcomes for patients with advanced disease remain poor. Recently, altered activation of the PI3K/Akt/mTOR pathway has been associated with reduced patient survival and advanced stage of bladder cancer, making its upstream or downstream components attractive targets for therapeutic intervention. In the present study, we showed that treatment with DTCM-glutaramide, a piperidine that targets PDK1, results in reduced proliferation, diminished cell migration and G1 arrest in 5637 and T24 bladder carcinoma cells. Conversely, no apoptosis, necrosis or autophagy were detected after treatment, suggesting that reduced cell numbers in vitro are a result of diminished proliferation rather than cell death. Furthermore previous exposure to 10 ${\mu}g/ml$ DTCM-glutarimide sensitized both cell lines to ionizing radiation. Although more studies are needed to corroborate our findings, our results indicate that PDK1 may be useful as a therapeutic target to prevent progression and abnormal tissue dissemination of urothelial carcinomas.
Keywords
Urothelial cancer; PI3K/Akt/mTOR pathway; molecular target; therapy;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Andersen JN, Sathyanarayanan S, Di Bacco A, et al. (2010). Pathway-based identification of biomarkers for targeted therapeutics: personalized oncology with PI3K pathway inhibitors. Sci Transl Med, 2, 43-55.
2 Baryawno N, Sveinbjornsson B, Eksborg S, et al. (2010). Smallmolecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. Cancer Res, 70, 266-76.   DOI
3 Ching CB, Hansel DE (2010). Expanding therapeutic targets in bladder cancer: the PI3K/Akt/mTOR pathway. Lab Invest, 90, 1406-14.   DOI
4 Choi JH, Yang YR, Lee SK, et al (2008). Potential inhibition of PDK1/Akt signaling by phenothiazines suppresses cancer cell proliferation and survival. Ann N Y Acad Sci, 1138, 393-403.   DOI
5 Cully M, You H, Levine AJ, Mak TW (2006). Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer, 6, 184-92.   DOI
6 De Santis M, Bellmunt J, Mead G, et al (2009). Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. J Clin Oncol, 27, 5634-9   DOI
7 Duronio V (2008). The life of a cell: apoptosis regulation by the PI3K/PKB pathway. Biochem J, 415, 333-44.   DOI   ScienceOn
8 Fan QW, Knight ZA, Goldenberg DD, et al (2006). A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma. Cancer Cell, 9, 341-9.   DOI
9 Feldman RI, Wu JM, Polokoff MA, et al (2005). Novel small molecule inhibitors of 3-phosphoinositide-dependent kinase-1. J Biol Chem, 280, 19867-74.   DOI
10 Franken NA, Rodermond HM, Stap J, et al. (2006). Clonogenic assay of cells in vitro. Nat Protoc, 1, 2315-9.   DOI
11 Gupta AK, Cerniglia GJ, Mick R, et al (2003). Radiation sensitization of human cancer cells in vivo by inhibiting the activity of PI3K using LY294002. Int J Radiat Oncol Biol Phys, 56, 846-53.   DOI
12 Hansel DE, Platt E, Orloff M, et al (2010). Mammalian target of rapamycin (mTOR) regulates cellular proliferation and tumor growth in urothelial carcinoma. Am J Pathol, 176, 3062-72.   DOI
13 Ito A, Kaneda A, Takeiri M, Umezawa K (2011). Indcution of apoptosis in adult T-cell leucemia by the novel PDK1 inhibitor DTCM-glutarimide. Int J Molecular Med, 28, 11.
14 Ikeda M, Matsumoto K, Niibe Y, et al (2011). The radiotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin treatment is an effective therapeutic option in patients with advanced or metastatic bladder cancer. J Radiat Res, 52, 674-9.   DOI
15 Ishikawa Y, Tachibana M, Matsui C, et al (2009). Synthesis and biological evaluation on novel analogs of 9-methylstreptimidone, an inhibitor of NF-kappaB. Bioorg Med Chem Lett, 19, 1726-8.   DOI
16 Ismaili N, Amzerin M, Flechon A (2011). Chemotherapy in advanced bladder cancer: current status and future. J Hematol Oncol, 4, 35.   DOI
17 Jemal A, Siegel R, Ward E, et al (2008). Cancer statistics, 2008. CA Cancer J Clin, 58, 71-96.   DOI   ScienceOn
18 Kaufman DS (2006). Challenges in the treatment of bladder cancer. Ann Oncol, 17, 106-12.   DOI
19 Kim IA, Bae SS, Fernandes A, et al (2005). Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res, 65, 7902-10.   DOI
20 Klionsky DJ, Abeliovich H, Agostinis P, et al (2008). Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy, 4, 151-75.   DOI
21 Lee YJ, Shacter E (1999). Oxidative stress inhibits apoptosis in human lymphoma cells. J Biol Chem, 274, 19792-8.   DOI
22 Liang CC, Park AY, Guan JL (2007). In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc, 2, 329-33.   DOI
23 Peifer C, Alessi DR. (2009) New anti-cancer role for PDK1 inhibitors: preventing resistance to tamoxifen. Biochem J, 417, 5-7.   DOI
24 Liu Y, Wang J, Wu M, et al (2009). Down-regulation of 3-phosphoinositide-dependent protein kinase-1 levels inhibits migration and experimental metastasis of human breast cancer cells. Mol Cancer Res, 7, 944-54.   DOI
25 Marta GN, Hanna SA, Gadia R, et al (2012). The role of radiotherapy in urinary bladder cancer: current status. Int Braz J Urol, 38, 144-54.   DOI
26 Pauwels B, Korst AE, de Pooter CM, et al (2003). Comparison of the sulforhodamine B assay and the clonogenic assay for in vitro chemoradiation studies. Cancer Chemother Pharmacol, 51, 221-6.
27 Qian Y, Deng J, Xie H, et al (2009). Regulation of TLR4-induced IL-6 response in bladder cancer cells by opposing actions of MAPK and PI3K signaling. J Cancer Res Clin Oncol, 135, 379-86.   DOI
28 Rieger-Christ KM, Lee P, Zagha R, et al (2004). Novel expression of N-cadherin elicits in vitro bladder cell invasion via the Akt signaling pathway. Oncogene, 23, 4745-53.   DOI
29 Sargeant AM, Klein RD, Rengel RC, et al (2007). Chemopreventive and bioenergetic signaling effects of PDK1/Akt pathway inhibition in a transgenic mouse model of prostate cancer. Toxicol Pathol, 35, 549-61.   DOI
30 Sato S, Fujita N, Tsuruo T (2002). Interference with PDK1-Akt survival signaling pathway by UCN-01 (7-hydroxystaurosporine). Oncogene, 21, 1727-38.   DOI
31 Segerstrom L, Baryawno N, Sveinbjornsson B, et al (2011). Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo. Int J Cancer, 129, 2958-65   DOI
32 Tao Y, Zhang P, Frascogna V, et al (2007). Enhancement of radiation response by inhibition of Aurora-A kinase using siRNA or a selective Aurora kinase inhibitor PHA680632 in p53-deficient cancer cells. Br J Cancer, 97, 1664-72.   DOI
33 Sellers WR, Fisher DE (1999). Apoptosis and cancer drug targeting. J Clin Invest, 104, 1655-61.   DOI   ScienceOn
34 Sun CH, Chang YH, Pan CC (2011). Activation of the PI3K/ Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. Histopathology, 58, 1054-63.   DOI
35 Takeiri M, Tachibana M, Kaneda A, et al (2011). Inhibition of macrophage activation and suppression of graft rejection by DTCM-glutarimide, a novel piperidine derived from the antibiotic 9-methylstreptimidone. Inflamm Res, 60, 879-88.   DOI
36 Wang, Z. Igarashi, M. Ikeda, et al (2006). Inhibition of NF kappa B activation by 9-methylstreptimidone isolated from Streptomyces. Heterocycles, 69, 377-383.   DOI
37 Wu X, Obata T, Khan Q, Highshaw RA, et al (2004). The phosphatidylinositol-3 kinase pathway regulates bladder cancer cell invasion. BJU Int, 93, 143-50.   DOI