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Ethiraj P.,SRM University | Veerappan K.,VRR Institute of Biomedical Science | Doraisami B.,SRM University | Sivapatham S.,SRM University
International Immunopharmacology | Year: 2014

Cisplatin is one of the most commonly used chemotherapeutic agents for breast cancer treatment. However, its efficacy is greatly limited by its toxic side effects. The present study investigated the synergistic effect of interferon β with cisplatin on MDA MB231 cells. The antiproliferative effect was measured by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The combination index (CI) was calculated using the method of Chou and Talalay. Cytotoxicity was determined by trypan blue and clonogenic assay. Genotoxic and cytostatic effects were studied using micronucleus assay and nuclear division index (NDI). Protein expression was analyzed using immunoblotting. Interferon β (100-2500 IU/mL) and Cisplatin (0.01-100 μM) had an inhibitory effect on the proliferation of cancer cells in a dose-dependent manner, with the IC50values at 1500 IU/mL and 20 μM for interferon β and cisplatin, respectively. Western blot analysis revealed expression of interferon β binding receptor in MDA MB231 cells. More interestingly, synergistic, cytotoxic and genotoxic effects were observed after treatment with a combination of interferon β with reduced dosage of cisplatin. Decreased expression of Bcl-2 and increased expression of Bax stimulated the cytochrome c release, which triggers caspase-9 and -3 activation significantly increased in the combinational group. In conclusion the combination of interferon β with reduced dose of cisplatin results synergistically improved growth-inhibition and apoptosis-inducing effect on MDA MB231 cells. © 2014 Elsevier B.V.

Sathishkumar N.,Kyung Hee University | Karpagam V.,Kyung Hee University | Karpagam V.,VRR Institute of Biomedical Science | Sathiyamoorthy S.,Kyung Hee University | And 3 more authors.
Computers in Biology and Medicine | Year: 2013

Natural products have served as structural resources in the history of drug discovery for cancer therapy. Among these natural products, Korean Panax ginseng serves as a potential anti-cancer medicinal plant. To determine the anti-cancer activities of Korean P. ginseng active compounds, we performed pharmacophore-based virtual screening and molecular docking studies on EGFR (epidermal growth factor receptor) tyrosine kinase domain. The EGFR family tyrosine kinase receptor is a cell surface receptor that regulates diverse biological processes including cell proliferation, differentiation, survival, and apoptosis. Over expression of EGFR tyrosine kinase domain associated with the development and progression of numerous human cancers. In our study, we developed the best pharmacophore model (Hypo1) using a diverse training set and validated by Fischer's randomization, a test set, and a decoy set. The best validated model was employed in the virtual screening of P. ginseng compound database. Further, chosen molecules were evaluated by applying ADMET screening and molecular docking studies. Finally, 14 compounds were obtained based on binding affinity scores and interactions with protein active site residues. These final lead compounds from P. ginseng can be used in the designing of new EGFR tyrosine kinase inhibitors. © 2013 Elsevier Ltd.

Ethiraj P.,SRM University | Veerappan K.,VRR Institute of Biomedical Science | Samuel S.,VRR Institute of Biomedical Science | Sivapatham S.,SRM University
Fundamental and Clinical Pharmacology | Year: 2015

Conventional chemotherapy fails to cure metastatic hepatoma mainly due to its high hepatotoxicity. Currently, doxorubicin is the most widely used drug against liver cancer either as single agent or in combination with other chemotherapeutics such as cisplatin. It is limited due to their severe toxicity on normal hepatocytes. Therefore, alternative therapeutic agents without or with low hepatotoxicity are highly desirable. Interferons are a family of cytokines that potently demonstrate antiviral, immunomodulatory, and antiproliferative activities. It also exerts direct cytotoxic effects on tumor cells. The purpose of this study was to examine the in vitro cytotoxicity of interferon-β on HepG2 cells. We revealed the presence of binding receptor of interferon-β in HepG2 cells. The dose-dependent inhibition on cell proliferation was observed. We demonstrated that IFN-β exhibited significant cytotoxicity in HepG2 cells mainly through phosphorylation of signal transducers and activators of transcription 2. The activation of Akt was suppressed. The stimulation of pro-apoptotic protein expression of Bax, inhibition of anti-apoptotic protein expression of Bcl-2, activation of cleaved caspases 9 and 3 was found at increasing concentrations. In conclusion, our results suggest that interferon-β has potential to inhibit cell proliferation dose dependently. Increased concentrations of interferon-β influenced apoptosis via mitochondrial pathway through inhibition of p-Akt. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Karpagam V.,VRR Institute of Biomedical Science | Sathishkumar N.,Kyung Hee University | Sathiyamoorthy S.,Kyung Hee University | Rasappan P.,VRR Institute of Biomedical Science | And 3 more authors.
Computers in Biology and Medicine | Year: 2013

BACE1, a β secretase candidate enzyme, initiates the Alzheimer's disease (AD) pathogenesis via amyloid β (Aβ) peptide production serving as a potential therapeutic target. Previous experimental evidence suggested that ginsenosides, a key component of Panax ginseng, are effective against AD. In this study, we implemented a molecular modeling method to reveal the inhibitory action of ginsenosides on BACE1 activity. We selected 12 ginsenosides and performed molecular docking studies to evaluate its interaction with the BACE1 active site, which is essential for inhibition. Further ADMET filtration was applied to find drug-like molecules with a specific ability to cross blood brain barrier (BBB), and to determine toxicity. The BACE1-ginsenosides complex was further subjected to a molecular dynamics simulation to study the stability of the complex and its hydrogen bond interactions. In summary, our findings show ginsenosides CK, F1, Rh1 and Rh2 are potential BACE1 inhibitors from Panax ginseng. © 2013 Elsevier Ltd.

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