Molecular Mechanism Underlying Hesperetin-induced Apoptosis by in silico Analysis and in Prostate Cancer PC-3 Cells

Abstract

Aim: To investigate the molecular mechanisms underlying triggering of apoptosis by hesperetin using in silico and in vitro methods. Methods: The mechanism of binding of hesperetin with NF-kB and other apoptotic proteins like BAX, BAD, BCL 2 and BCL XL was analysed in silico using Schrodinger suite 2009. In vitro studies were also carried out to evaluate the potency of hesperetin in inducing apoptosis using the human prostate cancer PC-3 cell line. Results: Hesperetin was found to exhibit high-affinity binding resulting from greater intermolecular forces between the ligand and its receptor NF-kB (-7.48 Glide score). In vitro analysis using MTT assay confirmed that hesperetin reduced cell proliferation (IC 50 values of 90 and 40µM at 24 and 48h respectively) in PC-3 cells. Hesperetin also downregulated expression of the anti-apoptotic gene BCL XL at both mRNA and protein levels and increased the expression of pro-apoptotic genes like BAD at mRNA level and BAX at mRNA as well as protein levels. Conclusion: The results suggest that hesperetin can induce apoptosis by inhibiting NF-kB.

Anti-Proliferation Effects and Molecular Mechanisms of Action of Tetramethypyrazine on Human SGC-7901 Gastric Carcinoma Cells

“…NF-kB regulates the expression of both antiapoptotic and proapoptotic genes. It is a family of closely related protein dimers that bind to a common sequence motif in DNA the kB site (Shanmugam et al, 2013). p50p65 dimer is the the most common active form of NF-κB.…”

Fungal Taxol Extracted from Cladosporium oxysporum Induces Apoptosis in T47D Human Breast Cancer Cell Line

“…Generally NF-ĸB is residing in the cytoplasm, once activated by various signals translocated into the nucleus and regulates the expression of both anti-apoptotic and pro-apoptotic genes. Recently some of the target genes activated by NF-ĸB (cyclin D1, Bcl-2, Bcl-XL, matrix metallo-proteinases (MMPs) and VEGF) which are very important for cellular transformation, cell proliferation, invasion, migration and metastasis (Sambantham et al, 2013). The other report explains either up-regulation of Bax or decrease in the Bcl-2 protein level after treatment with various cancer drugs resulting in mitochondrial mediated apoptosis (Wan et al, 2013).…”

Mangiferin inhibition of proliferation and induction of apoptosis in human prostate cancer cells is correlated with downregulation of B-cell lymphoma-2 and upregulation of microRNA-182

“…The primary anti-apoptotic and pro-apoptotic members of the Bcl-2 family regulate apoptosis by controlling mitochondrial function (19). Bcl-2 inhibits apoptosis by preventing an increase in cytoplasmic calcium concentration (6). In previous studies, Bcl-2 expression has been observed to be a notable feature in certain human malignant tumors; and Bcl-2 is now believed to be an anti-apoptotic gene that promotes tumor occurrence through inhibiting apoptosis and prolonging the survival of cells (20).…”

“…Reduced apoptosis and increased proliferation are thought to be the primary mechanisms underlying the formation of the majority of tumors. Inhibition of apoptosis may also possess a significant role in the progression of prostate cancer, and B-cell lymphoma-2 (Bcl-2) is thought to be one of the most significant genes required for apoptosis (6).…”