Ayyappan Nair, Ph.D.
Head, Business Development (Technologies, Discovery Biology), Anthem Biosciences & DavosPharma, New Jersey, USA
Inhibition of NF-κB 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 – 690 525, Kerala, India
- Anthem Biosciences, No 49, Canara Bank Road, Bommasandra Industrial Area, Phase 1, Hosur Road, Bangalore – 560 099, Karnataka, India
Abstract: A large number of effective cancer-preventing compounds inhibit the activation of nuclear factor-κ B (NF-κB). 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-κB pathway, and on the expression of MMP-9 and COX-2 (two NF-κB regulated genes involved in metastasis) in the highly invasive human breast cancer cell line MDA-MB-231. The findings suggest that not all the quercetin like flavone backbone compounds inhibit the NF-κB 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. This indicates a correlation between inhibition of NF-κB and subsequent suppression of these NF-κB regulated genes. Here, we also report the novel observation that the not so well characterized methoxylated flavone chrysoeriol inhibited the NF-κB pathway, and was most potent in reducing the expression of MMP-9 and COX-2. Based on these observations, the cellular effects of chrysoeriol were evaluated in MDA-MB-231. 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. These effects of chrysoeriol make it a potential therapeutic candidate for breast cancer metastasis.
Lalitha Subramanian, Ph.D.
Chief Scientific Officer & VP, Services at Scienomics, USA
Nanoscale Simulations – Tackling Form and Formulation Challenges in Drug Development and Drug Delivery
Lalitha Subramanian, Dora Spyriouni, Andreas Bick, Sabine Schweizer, and Xenophon Krokidis Scienomics
The discovery of a compound which is potent in activity against a target is a major milestone in Pharmaceutical and Biotech industry. However, a potent compound is only effective as a therapeutic agent when it can be administered such that the optimal quantity is transported to the site of action at an optimal rate. The active pharmaceutical ingredient (API) has to be tested for its physicochemical properties before the appropriate dosage form and formulation can be designed. Some of the commonly evaluated parameters are crystal forms and polymorphs, solubility, dissolution behavior, stability, partition coefficient, water sorption behavior, surface properties, particle size and shape, etc. Pharmaceutical development teams face the challenge of quickly and efficiently determining a number of properties with small quantities of the expensive candidate compounds. Recently the trend has been to screen these properties as early as possible and often the candidate compounds are not available in sufficient quantities. Increasingly, these teams are leveraging nanoscale simulations similar to those employed by drug discovery teams for several decades. Nanoscale simulations are used to predict the behavior using very little experimental data and only if this is promising further experiments are done. Another aspect where nanoscale simulations are being used in drug development and drug delivery is to get insights into the behavior of the system so that process failures can be remediated and formulation performance can be improved. Thus, the predictive screening and the in-depth understanding leads to experimental efficiency resulting in far-reaching business impacts.
With specific examples, this talk will focus on the different types of nanoscale simulations used to predict properties of the API in excipients and also provide insight into system behavior as a function of shelf life, temperature, mechanical stress, etc.
Tejaswini Subbannayya, Nandini A. Sahasrabuddhe, Arivusudar Marimuthu, Santosh Renuse, Gajanan Sathe, Srinivas M. Srikanth, Mustafa A. Barbhuiya, Bipin Nair, Juan Carlos Roa, Rafael Guerrero-Preston, H. C. Harsha, David Sidransky, Akhilesh Pandey, T. S. Keshava Prasad and Aditi Chatterjee
Proteomic profiling of gallbladder cancer secretome – a source for circulatory biomarker discovery
Gallbladder cancer (GBC) is the fifth most common cancer of the gastrointestinal tract and one of the common malignancies that occur in the biliary tract (Misra et al. 2006; Lazcano-Ponce et al. 2001). It has a poor prognosis with survival of less than 5 years in 90% of the cases (Misra et al. 2003). The etiology is ill-defined. Several risk factors have been reported including cholelithiasis, obesity, female gender and exposure to carcinogens (Eslick 2010; Kumar et al. 2006). Poor prognosis in GBC is mainly due to late presentation of the disease and lack of reliable biomarkers for early diagnosis. This emphasizes the need to identify and characterize cancer biomarkers to aid in the diagnosis and prognosis of GBC. Secreted proteins are an important class of molecules which can be detected in body fluids and has been targeted for biomarker discovery. There are challenges faced in the proteomic interrogation of body fluids especially plasma such as low abundance of tumor secreted proteins, high complexity and high abundance of other proteins that are not released by the tumor cells (Tonack et al. 2009). Profiling of conditioned media from the cancer cell lines can be used as an alternate means to identify secreted proteins from tumor cells (Kashyap et al. 2010; Marimuthu et al. 2012). We analyzed the invasive property of 7 GBC cell lines (SNU-308, G-415, GB-d1, TGBC2TKB, TGBC24TKB, OCUG-1 and NOZ). Four cell lines were selected for analysis of the cancer secretome based on the invasive property of the cells. We employed isobaric tags for relative and absolute quantitation (iTRAQ) labeling technology coupled with high resolution mass spectrometry to identify and characterize secretome from the panel of 4GBC cancer cells mentioned above. In total, we have identified around 2,000 proteins of which 175 were secreted at differential abundance across all the four cell lines. This secretome analysis will act as a reservoir of candidate biomarkers. Currently, we are investigating and validating these candidate markers from GBC cell secretome. Through this study, we have shown mass spectrometry-based quantitative proteomic analysis as a robust approach to investigate secreted proteins in cancer cells.