Action of YM155 on clear cell renal cell carcinoma does not depend on survivin expression levels
| Autor: | Hung Huynh, Mei-Lin Go, Mei Yi Sim, John Shyi Peng Yuen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Inhibitor of Differentiation Protein 1 Male Survivin Protein Expression Cancer Treatment Gene Expression lcsh:Medicine Apoptosis Mice SCID urologic and male genital diseases Biochemistry Inhibitor of Apoptosis Proteins Mice 0302 clinical medicine Renal cell carcinoma Medicine and Health Sciences Small interfering RNAs lcsh:Science Multidisciplinary Cell Death Forkhead Box Protein O1 Messenger RNA Imidazoles Sorafenib Kidney Neoplasms female genital diseases and pregnancy complications Deubiquitinating Enzyme CYLD Nucleic acids Gene Expression Regulation Neoplastic Drug Combinations Oncology Cell Processes Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis medicine.drug Research Article Signal Transduction Niacinamide Cell Survival Primary Cell Culture Antineoplastic Agents Biology Research and Analysis Methods Carcinomas 03 medical and health sciences Cell Line Tumor medicine Genetics Gene Expression and Vector Techniques Animals Humans Molecular Biology Techniques Non-coding RNA Molecular Biology Carcinoma Renal Cell neoplasms Molecular Biology Assays and Analysis Techniques Dose-Response Relationship Drug Microarray analysis techniques Phenylurea Compounds Tumor Suppressor Proteins lcsh:R Renal Cell Carcinoma Biology and Life Sciences Cancers and Neoplasms Cell Biology medicine.disease Xenograft Model Antitumor Assays Gene regulation Clear cell renal cell carcinoma Genitourinary Tract Tumors 030104 developmental biology Cell culture Cancer research RNA lcsh:Q Clear cell Cloning Naphthoquinones |
| Zdroj: | PLoS ONE, Vol 12, Iss 6, p e0178168 (2017) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | The dioxonapthoimidazolium YM155 is a survivin suppressant which has been investigated as an anticancer agent in clinical trials. Here, we investigated its growth inhibitory properties on a panel of immortalized and patient derived renal cell carcinoma (RCC) cell lines which were either deficient in the tumour suppressor von Hippel-Lindau (VHL) protein or possessed a functional copy. Neither the VHL status nor the survivin expression levels of these cell lines influenced their susceptibility to growth inhibition by YM155. Of the various RCC lines, the papillary subtype was more resistant to YM155, suggesting that the therapeutic efficacy of YM155 may be restricted to clear cell subtypes. YM155 was equally potent in cells (RCC786.0) in which survivin expression had been stably silenced or overexpressed, implicating a limited reliance on survivin in the mode of action of YM155. A follow-up in-vitro high throughput RNA microarray identified possible targets of YM155 apart from survivin. Selected genes (ID1, FOXO1, CYLD) that were differentially expressed in YM155-sensitive RCC cells and relevant to RCC pathology were validated with real-time PCR and western immunoblotting analyses. Thus, there is corroboratory evidence that the growth inhibitory activity of YM155 in RCC cell lines is not exclusively mediated by its suppression of survivin. In view of the growing importance of combination therapy in oncology, we showed that a combination of YM155 and sorafenib at ½ x IC50 concentrations was synergistic on RCC786.0 cells. However, when tested intraperitoneally on a murine xenograft model derived from a nephrectomised patient with clear cell RCC, a combination of suboptimal doses of both drugs failed to arrest tumour progression. The absence of synergy in vivo highlighted the need to further optimize the dosing schedules of YM155 and sorafenib, as well as their routes of administration. It also implied that the expression of other oncogenic proteins which YM155 may target is either low or absent in this clear cell RCC. |
| Databáze: | OpenAIRE |
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