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Title: Action of YM155 on clear cell renal cell carcinoma does not depend on surviving expression levels
Authors: Sim M.Y.
Huynh H. 
Go M.L. 
Yuen J.S.P. 
Keywords: inhibitor of differentiation 1
messenger RNA
sepantronium bromide
transcription factor FKHR
von Hippel Lindau protein
antineoplastic agent
BIRC5 protein, human
carbanilamide derivative
CYLD protein, human
drug combination
FOXO1 protein, human
ID1 protein, human
imidazole derivative
inhibitor of apoptosis protein
inhibitor of differentiation 1
sepantronium bromide
transcription factor FKHR
tumor suppressor protein
VHL protein, human
von Hippel Lindau protein
animal experiment
animal model
animal tissue
BIRC5 gene
cancer inhibition
cell viability
controlled study
CYLD gene
drug dose comparison
drug potentiation
FOXO1 gene
gene expression
human cell
ID1 gene
in vivo study
kidney carcinoma
microarray analysis
protein expression
real time polymerase chain reaction
renal cell carcinoma cell line
tumor regression
tumor xenograft
Western blotting
analogs and derivatives
antagonists and inhibitors
Carcinoma, Renal Cell
cell survival
dose response
drug combination
drug effects
drug screening
gene expression regulation
Kidney Neoplasms
primary cell culture
SCID mouse
signal transduction
tumor cell line
Antineoplastic Agents
Carcinoma, Renal Cell
Cell Line, Tumor
Cell Survival
Dose-Response Relationship, Drug
Drug Combinations
Forkhead Box Protein O1
Gene Expression Regulation, Neoplastic
Inhibitor of Apoptosis Proteins
Inhibitor of Differentiation Protein 1
Kidney Neoplasms
Mice, SCID
Phenylurea Compounds
Primary Cell Culture
Signal Transduction
Tumor Suppressor Proteins
Von Hippel-Lindau Tumor Suppressor Protein
Xenograft Model Antitumor Assays
Issue Date: 2017
Citation: Sim M.Y., Huynh H., Go M.L., Yuen J.S.P. (2017). Action of YM155 on clear cell renal cell carcinoma does not depend on surviving expression levels. PLoS ONE 12 (6) : e0178168. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: 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 1/2 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. © 2017 Sim et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Source Title: PLoS ONE
ISSN: 19326203
DOI: 10.1371/journal.pone.0178168
Rights: Attribution 4.0 International
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