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Decitabine augments cytotoxicity of cisplatin and doxorubicin to bladder cancer cells by activating hippo pathway through RASSF1A

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Abstract

Genetic abnormalities and epigenetic alterations both play vital role in initiation as well as progression of cancer. Whereas genetic mutations cannot be reversed, epigenetic alterations such as DNA methylation can be reversed by the application of DNA methyltransferase inhibitor decitabine. Epigenetic silencing of RASSF1A and involvement of hippo pathway both have been shown to involve in chemo-resistance. Purpose of this study was to observe the effect of combination treatment of decitabine with cisplatin or doxorubicin on bladder cancer cells involving hippo pathway through RASSF1A. Bladder cancer cells (HT1376 & T24) were treated with decitabine and its effect on RASSF1A expression, hippo pathway molecules (MST & YAP), and its downstream targets (CTGF, CYR61 & CTGF) was observed. Effect of decitabine pretreatment on sensitivity of bladder cancer cells towards chemotherapeutic drugs was also studied. Decitabine treatment leads to restoration of RASSF1A, activation of hippo pathway followed by decreased expression of its oncogenic downstream targets (CTGF & CYR61). Further pretreatment of decitabine enhanced cytotoxicity of cisplatin and doxorubicin to bladder cancer cells.

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Acknowledgements

Fellowship to M. Khandelwal from Council of Scientific and Industrial Research, India. We acknowledge Dr. P. P. Chattopadhyay (Department of Biochemistry, AIIMS) for providing HeLa cells.

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Authors and Affiliations

  1. Department of Biochemistry, AIIMS, New Delhi, India

    Madhuram Khandelwal, Vivek Anand, Sandeep Appunni & Alpana Sharma

  2. Department of Urology, AIIMS, New Delhi, India

    Amlesh Seth & Prabhjot Singh

  3. Department of Pathology, Aiims, New Delhi, India

    Sandeep Mathur

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  1. Madhuram Khandelwal
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Correspondence to Alpana Sharma.

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Khandelwal, M., Anand, V., Appunni, S. et al. Decitabine augments cytotoxicity of cisplatin and doxorubicin to bladder cancer cells by activating hippo pathway through RASSF1A. Mol Cell Biochem 446, 105–114 (2018). https://doi.org/10.1007/s11010-018-3278-z

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  • DOI: https://doi.org/10.1007/s11010-018-3278-z

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