Oncotarget

Research Papers:

Adaptation to chronic exposure to sepantronium bromide (YM155), a prototypical survivin suppressant is due to persistent DNA damage-response in breast cancer cells

Tasaduq H. Wani, Sreeraj Surendran, Vishnu S. Mishra, Jaya Chaturvedi, Goutam Chowdhury and Anindita Chakrabarty _

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Oncotarget. 2018; 9:33589-33600. https://doi.org/10.18632/oncotarget.26096

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Abstract

Tasaduq H. Wani1,*, Sreeraj Surendran1,*, Vishnu S. Mishra1, Jaya Chaturvedi1, Goutam Chowdhury2 and Anindita Chakrabarty1

1Department of Life Sciences, Shiv Nadar University, Greater Noida, UP 201314, India

2Department of Chemistry, Shiv Nadar University, Greater Noida, UP 201314, India

*These authors contributed equally and should be considered as joint first authors

Correspondence to:

Anindita Chakrabarty, email: [email protected]

Keywords: breast cancer; survivin; YM155; drug-adaptation; DNA damage

Abbreviations: BC: breast cancer; YMR: YM155-resistant; P: parental

Received: April 26, 2018     Accepted: August 23, 2018     Published: September 11, 2018

ABSTRACT

Sepantronium bromide (YM155), originally developed against the anti-apoptotic protein survivin, performed exceptionally well in pre-clinical and phase I clinical trials. However, in phase II trials of several cancer types including breast cancer it performed poorly. Additionally, no definitive correlation between survivin level and response to therapy was found. In an attempt to understand the true reason of the late-stage failure of this promising drug, we developed YM155-resistant MCF-7 breast cancer cell line and characterized side-by-side with the drug-naïve parental cell line. Chronic YM155 treatment resulted in downregulation of survivin expression yet triggered cellular responses typical of adaptation to persistent DNA damage. Lowering endogenous antioxidant glutathione level and activity of cell cycle check-point kinase restored YM155 activity. Thus, contrary to its development as a survivin suppressant, YM155 primarily acts as a chemotherapeutic drug causing oxidative stress-mediated DNA damage. Adaptation to long-term exposure to YM155 can be prevented and/or overcome by interfering with detoxification and DNA damage-response pathways. Finally, proteins associated with DNA damage-response pathway will be more appropriate as predictive biomarkers of YM155 in breast tumor cells.


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