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Selenium-Based Novel Epigenetic Regulators Offer Effective Chemotherapeutic Alternative with Wider Safety Margins in Experimental Colorectal Cancer

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Abstract

Colorectal cancer (CRC) is a major cause of morbidity and mortality worldwide. Despite the critical involvement of epigenetic modifications in CRC, the studies on the chemotherapeutic efficacy of various epigenetic regulators remain limited. Considering the key roles of histone deacetylases (HDACs) in the regulation of diverse cellular processes, several HDAC inhibitors are implied as effective therapeutic strategies. In this context, suberoylanilide hydroxamic acid (SAHA), a 2nd-generation HDAC inhibitor, showed limited efficacy in solid tumors. Also, side effects associated with SAHA limit its clinical application. Based on the redox-modulatory and HDAC inhbitiory activities of essential trace element selenium (Se), the anti-carcinogenic potential of Se substituted SAHA, namely, SelSA-1 (25 mg kg−1), was screened for it enhanced anti-tumorigenic role and wider safety profiles in DMH-induced CRC in Balb/c mice. A multipronged approach such as in silico, biochemical, and pharmacokinetics (PK) has been used to screen, characterize, and evaluate these novel compounds in comparison to existing HDAC inhibitor SAHA. This is the first in vivo study indicating the chemotherapeutic potential of Se-based novel epigenetic regulators such as SelSA-1 in any in vivo experimental model of carcinogenesis. Pharmcological and toxicity data indicated better safety margins, bioavailability, tolerance, and elimination rate of SelSA-1 compared to classical HDAC inhibitor SAHA. Further, histological and morphological evidence demonstrated enhanced chemotherapeutic potential of SelSA-1 even at lower pharmacological doses than SAHA. This is the first in vivo study suggesting Se-based novel epigenetic regulators as potential chemotherapeutic alternatives with wider safety margins and enhanced anticancer activities.

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Acknowledgements

Dr. Pulkit Rastogi (Assistant professor, Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), for histopathological analysis of the colon sections.

Data Availability Statement

The authors declare that all the data supporting the findings of this study are available within the article.

Funding

The work was supported by Senior Research Fellowship (SRF) Sanctioned to Ms. Preety by the Indian Council of Medical Research (ICMR) (45/21/2019-BIO/BMS). The work has been partially supported by DST-PURSE (58-60/RPC) and DST-FIST (SR/FST/LSI-425/2009) grants sanctioned to the Panjab University (PU) and Department of Biophysics, PU, Chandigarh (India).

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Authors and Affiliations

  1. Department of Biophysics, Panjab University, BMS Block II, Sector 25, Chandigarh, 160014, India

    Preety Ghanghas, Sankar Nath Sanyal & Naveen Kaushal

  2. Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER), Sector 81, Knowledge City, SAS, Nagar, Punjab, India

    Monika Sharma

  3. Department of Pharmacology, The Pennsylvania State University, Hershey, PA, USA

    Dhimant Desai & Shantu Amin

  4. Department of Pharmacy, Central University of Rajasthan, Ajmer, Rajasthan, India

    Kaisar Raza & Pramod Kumar

  5. Department of Chemistry, Panjab University, Chandigarh, India

    Aman Bhalla & Dipika Narula

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  1. Preety Ghanghas
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Contributions

Preety Ghanghas: methodology, software, validation, data curation, writing ± original draft, writing ± review and editing, and project administration. Dr Monika Sharma: validation, formal analysis, and investigation. Dr Dhimant Desai: formal analysis and investigation. Dr Kaisar Raza: validation and formal analysis. Dr Aman Bhalla: formal analysis. Dr Pramod Kumar: investigation. Dr Dipika Narula: investigation. Dr. Shantu Amin: investigation. Dr Sankar Nath Sanyal: formal analysis, visualization, and supervision. Dr. Naveen Kaushal: conceptualization, formal analysis, investigation, resources, writing ± original draft, writing ± review and editing, visualization, supervision, project administration, and funding acquisition.

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Ghanghas, P., Sharma, M., Desai, D. et al. Selenium-Based Novel Epigenetic Regulators Offer Effective Chemotherapeutic Alternative with Wider Safety Margins in Experimental Colorectal Cancer. Biol Trace Elem Res 200, 635–646 (2022). https://doi.org/10.1007/s12011-021-02659-5

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