Research Fellow, CSIR-Central Drug Research Institute
Epithelial and mesenchymal transition targeting in the progression of breat cancer
I am a senior research fellow at CSIR- Central Drug Research Institute since 2011under the guidance of Dr. Rituraj Konwar. I have been working on "Identification and mechanism of action of molecule(s) targeting epithelial and mesenchymal transition in the breast cancer'. A part of my PhD work was also done at Barts Cancer Institute, Queen Mary University of London under the guidance of Prof John Marshall as a Newton-Bhabha research fellow supported and funded by DST and British Council. The fundamental aim of my PhD thesis is discovery of small molecule inhibitor(s) that could target the Epithelial Mesenchymal Transition (EMT), invasion and metastasis in breast cancer cells.
Abstract: Tinospora cordifolia is a widely distributed medicinal plant used in various traditional and commercial Ayurvedic formulations. Due to the wide use of this plant it is important to know the extent of variability in the metabolite profile resulting from geographical location, season and gender.To develop a statistical approach based on phytochemical markers for confident prediction of variations in metabolic profile and cytotoxicity due to geographical, seasonal and gender difference in T. cordifolia stem.A HPLC-ESI-QTOF-MS method was used for the metabolite profiling of T. cordifolia stem. The data were analysed using chemometric methods including Student's t-test, ANOVA, FA/PCA and ROC curve analysis and validated for the identification of chemical variations. The bioactivity of selected samples was also tested using a cell cytotoxicity assay to assess the functional aspect of the phytochemical variability.The chemometric approach applied here identified marker ions for geographical locations (m/z 294.1139 and 445.2136), seasons (m/z 344.1482, 359.1501, and 373.1305) and gender (m/z 257.1380) with 100% statistical sensitivity and specificity. An in vitro cytotoxicity evaluation revealed that male T. cordifolia stem was the most effective in inhibiting the growth of cancerous cell lines.The developed and validated chemometric approach identified the analytical markers for phytochemical variations in unknown T. cordifolia stem samples from male or female plants and samples collected from different geographical locations and seasons. The results are supported by comparative cytotoxic activity data. Copyright © 2017 John Wiley & Sons, Ltd.
Pub.: 24 Jan '17, Pinned: 30 Jun '17
Abstract: Tubulin is a well established target for anticancer drug development. Lignans and neolignans were synthesized as tubulin interacting agents. Neolignans 10 and 19 exhibited significant anticancer activity against MCF-7 and MDAMB-231 human breast cancer cell lines. Both the compounds effectively induced stabilization of microtubule at 4 and 20 μM concentrations respectively. Neolignan 10 induced G2/M phase arrest in MCF-7 cells. Docking experiments raveled that 10 and 19 occupied the same binding pocket of paclitaxel with some difference in active site amino acids and good bioavailability of both the compounds. In in vivo acute oral toxicity 10 was well tolerated up to 300 mg/kg dose in Swiss-albino mice.
Pub.: 25 Jan '14, Pinned: 30 Jun '17
Abstract: 2-Methoxyestradiol (2ME2) is an investigational anticancer drug. In the present study, 2-alkoxyesters/acid and 2-benzyloxy analogues of estradiol have been synthesized as analogues of 2ME2. Three of the derivatives exhibited significant anticancer activity against human breast cancer cell lines. The best analogue of the series i.e. 24 showed stabilization of tubulin polymerisation process. It was substantiated by confocal microscopy and molecular docking studies where 24 occupied 'paclitaxel binding pocket' to stabilize the polymerisation process. Compound 24 significantly inhibited MDA-MB-231 cells (IC50: 7 μM) and induced arrest of cell cycle and apoptosis in MDA-MB-231 cells. In acute oral toxicity, 24 was found to be non-toxic and well tolerated in Swiss albino mice up to 1000 mg/kg dose.
Pub.: 23 Sep '14, Pinned: 30 Jun '17
Abstract: This study reports the development of Vitamin B6 (VitB6) modified pH sensitive charge reversal nanoparticles for efficient intracellular delivery of Doxorubicin (DOX). Herein, VitB6 was conjugated to stearic acid and the nanoparticles of the lipid were formulated by solvent injection method (DOX-B6-SA-NP). Due to the pKa (5.6) of VitB6, DOX-B6-SA-NP showed positive charge and enhanced release of DOX at pH 5. Confocal microscopy illustrated that DOX-B6-SA-NP treatment keep higher DOX accumulation inside the cells that conventional pH insensitive lipid nanoparticles (DOX-SA-NP). The cationic charge of nanoparticles subsequently facilitated the endosomal escape and promoted the nuclear accumulation of DOX. Furthermore, in vitro cytotoxicity, apoptosis, cell cycle arrest and mitochondrial membrane depolarization studies supported the enhanced efficacy of DOX-B6-SA-NP in comparison to free DOX and DOX-SA-NP. Intravenous pharmacokinetics and bio-distribution investigations indicated that pH sensitive nanoparticles can significantly prolong the blood circulation time of DOX in biological system and increase the drug accumulation to tumor site. Consequent to this DOX-B6-SA-NP also exhibited much enhanced therapeutic efficacy and lower toxicity in tumor-bearing rats compared to free DOX. The reduction in toxicity was confirmed by histological and survival analysis. In conclusion, these results suggest that the VitB6 modified charge reversal nanoparticles can be a novel platform for the successful delivery of anticancer drugs.
Pub.: 16 Oct '16, Pinned: 30 Jun '17
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