Ayyappan Nair, Ph.D.
Head, Business Development (Technologies, Discovery Biology), Anthem Biosciences & DavosPharma, New Jersey, USA
Inhibition of NF-ÎșB regulated gene expression by chrysoeriol suppresses tumorigenesis in breast cancer cells
Amrutha K1, Pandurangan Nanjan1, Sanu K Shaji1, Damu Sunilkumar1, Subhalakshmi K1, Rashmi U Nair1, Lakshmi Rajakrishna2, Asoke Banerji1, Ayyappan Ramesh Nair1*,2
- School of Biotechnology, Amrita Vishwa Vidyapeetham, Amritapuri Campus, Clappana P.O., Kollam â 690 525, Kerala, India
- Anthem Biosciences, No 49, Canara Bank Road, Bommasandra Industrial Area, Phase 1, Hosur Road, Bangalore – 560 099, Karnataka, India
Abstract: Â A large number of effective cancer-preventing compounds inhibit the activation of nuclear factor-Îș B (NF-ÎșB). Â It has been previously demonstrated that some flavonoids that are a vital component of our diet inhibits this pathway. As a consequence, many flavonoids inhibit genes involved in various aspects of tumorigenesis and have thus emerged as potential chemopreventive candidates for cancer treatment. We studied the effect of 17 different flavonoids, including the highly evaluated quercetin on the NF-ÎșB pathway, and on the expression of MMP-9 and COX-2 (two NF-ÎșB regulated genes involved in metastasis) in the highly invasive human breast cancer cell line MDA-MB-231. Â The findings suggest that not all the quercetin like flavone backbone compounds inhibit the NF-ÎșB pathway, and that the highly hydoxylated flavonols quercetagetin and gossypetin did not inhibit this pathway, nor did it inhibit the expression of MMP-9 and COX-2. Â This indicates a correlation between inhibition of NF-ÎșB and subsequent suppression of these NF-ÎșB regulated genes. Here, we also report the novel observation that the not so well characterized methoxylated flavone chrysoeriol inhibited the NF-ÎșB pathway, and was most potent in reducing the expression of MMP-9 and COX-2. Â Based on these observations, the cellular effects of chrysoeriol were evaluated in MDA-MB-231. Â Chrysoeriol caused cell cycle arrest at G2/M, inhibited migration and invasion, and caused cell death of macrophages that contributed to migration of these cancer cells. Â These effects of chrysoeriol make it a potential therapeutic candidate for breast cancer metastasis.
Shigeki Miyamoto, Ph.D.
Professor, McArdle Laboratory for Cancer Research – UW Carbone Cancer Center
Department of Oncology, School of Medicine and Public Health
University of Wisconsin-Madison
âInside-outâ NF-ÎșB signaling in cancer and other pathologies
The NF-ÎșB/Rel family of transcription factors contributes to critical cellular processes, including immune, inflammatory and cell survival responses. As such, NF-ÎșB is implicated in immunity-related diseases, as well as multiple types of human malignancies. Indeed, genetic alterations in the NF-ÎșB signaling pathway are frequently observed in multiple human malignancies. NF-ÎșB is normally kept inactive in the cytoplasm by inhibitor proteins. Extracellular ligands can induce the release of NF-ÎșB from the inhibitors to allow its migration into the nucleus to regulate a variety of target genes. Â NF-ÎșB activation is also induced in response to multiple stress conditions, including those induced by DNA-damaging anticancer agents. Although precise mechanisms are still unclear, research from our group has revealed a unique nuclear-to-cytoplasmic signaling pathway. In collaboration with bioengineers, clinicians and pharmaceutical industry, our lab has developed new methods to analyze primary cancer patient samples and identified several compounds with different mechanisms that mitigate this cell survival pathway. Â Further contributions from other labs have also revealed additional mechanisms and molecular players in this âinside-outâ signaling pathway and expanded its role in other physiological and pathological processes, including B cell development, premature aging and therapy resistance of certain cancers. Our own new findings, along with these recent developments in the field, will be highlighted.
Rajasekhar Chekkara, Venkata Reddy Gorla and Sobha Rani Tenkayala
Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies on Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK 1 inhibitors
Polo-like kinase 1 (PLK1) is a significant enzyme with diverse biological actions in cell cycle progression, specifically mitosis. Suppression of PLK1 activity by small molecule inhibitors has been shown to inhibit cancer, being BI 2536 one of the most potent active inhibitor of PLK1 mechanism. Pharmacophore modeling, atom-based 3D-QSAR and molecular docking studies were carried out for a set of 54 compounds belonging to Pyrimido[5,4-e][1,2,4]triazine derivatives as PLK1 inhibitors. A six-point pharmacophoremodel AAADDR, with three hydrogen bond acceptors (A), two hydrogen bond donors (D) and one aromatic ring (R) was developed by Phase module of Schrdinger suite Maestro 9. The generated pharmacophore model was used to derive a predictive atom-based 3D quantitative structure-activity relationship analysis (3D-QSAR) model for the training set (r2 = 0.88, SD = 0.21, F = 57.7, N = 44) and for test set (Q2 = 0.51, RMSE = 0.41, PearsonR = 0.79, N = 10). The original set of compounds were docked into the binding site of PLK1 using Glide and the active residues of the binding site were analyzed. The most active compound H18 interacted with active residues Leu 59, Cys133 (glide score = ĂąËâ10.07) and in comparison of BI 2536, which interacted with active residues Leu 59, Cys133 (glide score = ĂąËâ10.02). The 3D-QSAR model suggests that hydrophobic and electron-withdrawing groups are essential for PLK1 inhibitory activity. The docking results describes the hydrogen bond interactions with active residues of these compounds. These results which may support in the design and development of novel PLK1 inhibitors.