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Article

Striking at Survivin: YM-155 Inhibits High-Risk Neuroblastoma Growth and Enhances Chemosensitivity

by
Danielle C. Rouse
,
Rameswari Chilamakuri
and
Saurabh Agarwal
*
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(19), 3221; https://doi.org/10.3390/cancers17193221
Submission received: 8 September 2025 / Revised: 27 September 2025 / Accepted: 30 September 2025 / Published: 2 October 2025
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Malignant Nervous System Cancers)

Simple Summary

Neuroblastoma (NB) remains one of the most aggressive pediatric cancers, with high-risk disease showing poor prognosis and limited therapeutic options. Survivin (BIRC5), an anti-apoptotic protein frequently overexpressed in NB, is associated with resistance and adverse clinical outcomes. Analysis of NB patient datasets confirmed that high BIRC5 expression correlates with reduced survival. To investigate survivin targeting, we evaluated YM-155, a small-molecule inhibitor, in NB models. YM-155 demonstrated potent cytotoxicity, suppressed colony formation and 3D spheroid growth, downregulated survivin, induced apoptosis, and caused G0/G1 cell cycle arrest. Combination of YM-155 with etoposide produced synergistic activity, and in vivo YM-155 significantly reduced tumor burden without observed toxicity. These findings establish YM-155 as a promising therapeutic candidate and support survivin inhibition as a rational strategy in NB.

Abstract

Background/Objectives: Neuroblastoma (NB) is an aggressive pediatric malignancy that accounts for nearly 15% of all childhood cancer-related deaths, with high-risk cases showing a poor 20% prognosis and limited response to current therapies. Survivin, encoded by the BIRC5 gene, is an anti-apoptotic protein frequently overexpressed in NB and linked to treatment resistance and unfavorable clinical outcomes. Methods and Results: An analysis of 1235 NB patient datasets revealed a significant association between elevated BIRC5 expression and reduced overall and event-free survival, highlighting survivin as an important therapeutic target in NB. To explore this strategy, we evaluated the efficacy of YM-155, a small-molecule survivin inhibitor, across multiple NB cell lines. YM-155 displayed potent cytotoxic activity in six NB cell lines with IC50 values ranging from 8 to 212 nM and significantly inhibited colony formation and 3D spheroid growth in a dose-dependent manner. Mechanistic analyses revealed that YM-155 downregulated survivin at both mRNA and protein levels, induced apoptosis by about 2–7-fold, and caused G0/G1 phase cell cycle arrest. Moreover, YM-155 treatment enhanced p53 expression, suggesting reactivation of tumor suppressor pathways. Notably, combining YM-155 and the chemotherapeutic agent etoposide resulted in synergistic inhibition of NB growth with ED75 values ranging from 0.17 to 1, compared to either agent alone. In the xenograft mouse model, YM-155 inhibited tumor burden in contrast to controls by about 3-fold, and without any notable toxic effects in vivo. Conclusion: Overall, our findings identify YM-155 as a promising therapeutic agent for high-risk NB by directly targeting survivin and enhancing chemosensitivity. These results support continued preclinical development of survivin inhibitors as part of rational combination strategies in pediatric cancer treatment.
Keywords: Neuroblastoma; YM-155; Survivin; Pediatric Cancer; MYCN Neuroblastoma; YM-155; Survivin; Pediatric Cancer; MYCN

Share and Cite

MDPI and ACS Style

Rouse, D.C.; Chilamakuri, R.; Agarwal, S. Striking at Survivin: YM-155 Inhibits High-Risk Neuroblastoma Growth and Enhances Chemosensitivity. Cancers 2025, 17, 3221. https://doi.org/10.3390/cancers17193221

AMA Style

Rouse DC, Chilamakuri R, Agarwal S. Striking at Survivin: YM-155 Inhibits High-Risk Neuroblastoma Growth and Enhances Chemosensitivity. Cancers. 2025; 17(19):3221. https://doi.org/10.3390/cancers17193221

Chicago/Turabian Style

Rouse, Danielle C., Rameswari Chilamakuri, and Saurabh Agarwal. 2025. "Striking at Survivin: YM-155 Inhibits High-Risk Neuroblastoma Growth and Enhances Chemosensitivity" Cancers 17, no. 19: 3221. https://doi.org/10.3390/cancers17193221

APA Style

Rouse, D. C., Chilamakuri, R., & Agarwal, S. (2025). Striking at Survivin: YM-155 Inhibits High-Risk Neuroblastoma Growth and Enhances Chemosensitivity. Cancers, 17(19), 3221. https://doi.org/10.3390/cancers17193221

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