TAIPEI, TAIWAN (UroToday.com) - Introduction and Objectives: The deregulation of the NFjB signaling cascade has been associated with human cancers including RCC. YM155 is a known survivin inhibitor that possesses potent anti-RCC activity. The objective of this study is to investigate whether the anti-RCC activity of YM155 is mediated by the NFjB signaling pathway, in addition to survivin inhibition.
Methods: Paired isogenic human RCC cell lines: 786.0 EV and 786.0 VHL (VHL-mutant and VHL-wt), RCC786.0, primary RCC cell lines (NCC010, NCC035, P.RCC), and a human non- malignant cell line (IMR90) were used in this study. MTS cell proliferation assay was used to determine IC50 of YM155 on these cell lines. The activation of nuclear p65 was determined using a chemiluminescent-based NFjB p65 transcription factor kit. The transcription activity of un-induced and TNFa -induced NFjB in YM155 treated and untreated RCC786.0 cells was determined using a luciferase reporter assay.
Results: YM155 demonstrated potent nanomolar growth inhibitory activity, compared to pure NFjB inhibitor on various RCC cell lines. In addition to survivin inhibition, it reduced nuclear translocation of NFjB in RCC786.0 in a dose dependent manner. YM155 significantly inhibits the TNFa-induced transcriptional activity of NFjB in RCC786.0 cells. At 0.5X IC50 (20 nM), inhibitions by YM155 of both nuclear translocation and transcription activity of NFjB were comparable (20%, 36% respectively).
Conclusions: Our data suggests that the anti-survivin agent YM155 inhibits other oncogenic targets such as NFkB at con- centrations that are closely aligned to its growth inhibitory IC50. Co-targeting of NFjB and survivin by YM155 has the potential for clinical drug development.
Source of Funding: SingHealth Cluster Research Fund
|Listen to an interview with John S. Yuen, one of the authors of this study.|
Presented by John S Yuen,1 Mei Y Sim,1 Mei L Go1, 2 at the 32nd World Congress of Endourology & SWL - September 3 - 7, 2014 - Taipei, Taiwan
1Singapore General Hospital (Singapore); 2National University of Singapore (Singapore)