The Citrus Flavanone Hesperetin Induces Apoptosis in CTCL Cells via STAT3/Notch1/NFκB-Mediated Signaling Axis

Author:

Kottaiswamy Amuthavalli1ORCID,Kizhakeyil Atish2ORCID,Padmanaban Abirami M.1ORCID,Mirza Fathima B.1,Vijay Venkatesh R.2ORCID,Lee Pin S.2ORCID,Verma Navin K.2ORCID,Kalaiselvan Parkavi3ORCID,Samuel Shila1ORCID

Affiliation:

1. VRR Institute of Biomedical Science, University of Madras, Chennai, India

2. Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Nanyang Ave, Singapore

3. Chettinad Hospital and Research Institute, Chennai, India

Abstract

Background: Hesperetin is a natural compound known for its cholesterol-lowering effect and a wide range of pharmacological activities. Objectives: Investigating the potential anticancer activities of Hesperetin in malignant hematolymphoid cell lines HuT78 and MJ, derived from patients with Cutaneous T-Cell Lymphomas (CTCL). Methods: The cytotoxic effect of Hesperetin on two different CTCL cell lines, HuT78 and MJ, was assessed by MTS-based colorimetric assay. Apoptosis, cell cycle, ROS (Reactive Oxygen Species) and molecular analysis were performed using flow-cytometry and immunoblotting. Results: Hesperetin-treated CTCL cells were arrested at the sub-G1 phase of cell cycle with the concomitant decrease in the expression of the cell cycle regulator protein cyclin B. In addition, the study found that the cellular treatment with Hesperetin caused an induction of apoptosis, which was independent of ROS generation. Hesperetin caused a significant decrease in the expression level of anti-apoptotic protein Bcl-xL and an increase in cleaved caspase-3 and PARP proteins in CTCL cells. Furthermore, Hesperetin treatment in CTCL cells down-regulated the expression of Notch1 and phosphorylation of STAT3 (Tyr705) and inhibited NFκBp65. Conclusion: This study highlights the anticancer properties of Hesperetin. Which induces apoptosis in CTCL cells via STAT3/Notch1/NFκB mediated signaling pathway, suggesting that further development of this novel class of flavonoid may contribute to new drug discovery for certain hematolymphoid malignancies.

Funder

National Research Foundation (NRF) Singapore

Singapore Ministry of Education

Lee Kong Chian School of Medicine, Nanyang Technological University Singapore

Publisher

Bentham Science Publishers Ltd.

Subject

Cancer Research,Pharmacology,Molecular Medicine

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