Department of Biological Sciences
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Item Proteomics analysis in urinary bladder cancer patients identifies urinary SOD2 as a predictive marker of recurrence(2021-12) Dubey, Uma S.Early non-invasive detection of tumor is an urgent clinical need for managing urothelial bladder cancer. Cystoscopy and cytology are the current standards for diagnosis of recurrence, but are limited by low sensitivity. Quantitative proteomics tool was employed to identify important deregulated molecules in bladder cancer tissues and validated using Western blot and immunohistochemistry analysis. A set of 1137 proteins were identified in four paired bladder cancer patients. Among these, 64 proteins were deregulated in all cases among which 9 were commonly up-regulated. The Ingenuity Pathway Analysis (IPA) generated top 11 Networks in which three commonly upregulated (SERPING1, SOD2 and HSPB6) proteins were involved and selected for further validation. Tissue expression of SOD2, SERPING1 and HSPB6 monitored in an independent sample set (n=18) by immuno-histochemical analysis showed similar profile. Western blot analysis of these proteins in urine of bladder cancer (n=26) and healthy subjects (n=10) showed a specificity and sensitivity of >80% for SOD2 and so was selected for further validation in a separate set (n=150) by ELISA. Significant elevation in urinary SOD2 level was found in urothelial bladder cancer patients compared to healthy controls and in recurrent cases compared to primary (p-value<0.001). Kaplan Meier survival analysis showed urinary SOD2 concentration >2,100 pg/ml was significantly associated with poorer survival.Cumulative survival of patient with low SOD2 concentration was 34.4% compared to 18.9% in patient with high SOD2 at 24 months (p=0.025). The study identifies SOD2 as a non-invasive biomarker which may help to extend the period between cystoscopies during follow-up.Item Metal-free, visible-light-mediated synthesis of tetracyclic benzimidazole: regioselective c–h functionalization with in vitro and computational study of anti-breast cancer compounds(ACS, 2025-02) Murugesan, Sankaranarayanan; Mukherjee, SudeshnaGlobally, breast cancer is the leading cause of mortality. Within the field of antibreast cancer drug design by several compound docking studies, eight new N-containing nonsteroid tetracyclic derivatives have been synthesized via regioselective intramolecular C–H functionalization by visible light. The adopted methodology is highly efficient, green, and sustainable to unload a new pathway with excellent yield. It offers a rapid, low-cost, catalyst-free method for creating physiologically active molecules from easily accessible substrates. The synthesized substances were described using spectroscopic methods like HRMS, 1HNMR, 13CNMR, and XRD analysis. This study explores the cytotoxic potential of novel compounds against human MCF-7 breast cancer cells. This study includes in vitro experiments to assess the effect of our compounds on cells. These experiments include cytotoxicity assessment by cell cycle, apoptosis, MTT test analysis by flow cytometry, reactive oxygen species (ROS) production assessment, etc. Among the novel compounds, compound 2e exhibited the most potent cytotoxic activity, with an inhibitory concentration (IC50) of 40 nM, surpassing the efficacy of established drugs such as exemestane (IC50 24.97 micromolar) and tamoxifen (IC50 5.45 μM). Compound 2e also significantly induced apoptosis and cell cycle arrest in the G1 phase, increasing the apoptotic cell population to 65.97%. Additionally, the compound led to a marked rise in the level of ROS generation, implicating oxidative stress in its mechanism of action. Molecular docking and dynamic simulation further supported the vigorous anticancer activity of compound 2e, demonstrating its promise as an effective breast cancer treatment.Item Epigenetic adaptations in drug-tolerant tumor cells(Elsevier, 2023) Chowdhury, Rajdeep; Chowdhury, Shibasish; Mukherjee, SudeshnaTraditional chemotherapy against cancer is often severely hampered by acquired resistance to the drug. Epigenetic alterations and other mechanisms like drug efflux, drug metabolism, and engagement of survival pathways are crucial in evading drug pressure. Herein, growing evidence suggests that a subpopulation of tumor cells can often tolerate drug onslaught by entering a “persister” state with minimal proliferation. The molecular features of these persister cells are gradually unraveling. Notably, the “persisters” act as a cache of cells that can eventually re-populate the tumor post-withdrawal drug pressure and contribute to acquiring stable drug-resistant features. This underlines the clinical significance of the tolerant cells. Accumulating evidence highlights the importance of modulation of the epigenome as a critical adaptive strategy for evading drug pressure. Chromatin remodeling, altered DNA methylation, and de-regulation of non-coding RNA expression and function contribute significantly to this persister state. No wonder targeting adaptive epigenetic modifications is increasingly recognized as an appropriate therapeutic strategy to sensitize them and restore drug sensitivity. Furthermore, manipulating the tumor microenvironment and “drug holiday” is also explored to maneuver the epigenome. However, heterogeneity in adaptive strategies and lack of targeted therapies have significantly hindered the translation of epigenetic therapy to the clinics. In this review, we comprehensively analyze the epigenetic alterations adapted by the drug-tolerant cells, the therapeutic strategies employed to date, and their limitations and future prospects.Item THERAPEUTIC POTENTIAL OF CAMEL MILK(EJFA, 2016) Dubey, Uma S.; Kapur, SumanCamel milkis recognized for its therapeutic potential against many diseases. It is reported to have microbicidal and immuno stimulatory properties as it contains immunoactive proteins like lysozyme, lactoperoxidase and lactoferrin. Camelid antibodies have a unique structure. Theypossess the heavy chains but are devoid of the usual light chains. This special feature enhances theirpenetration. Camelid proteins have a very high degree of thermal stability and areresistant to acid hydrolysis. Camel milk components act like a ligand to the aryl hydrocarbon receptor.They significantly inhibit the induction of some cancer-activating genes and also induce tumor suppressor genes. Modulation of aryl hydrocarbon receptors is now recognized to have a vital role in cancer therapy. The present review deals with clinical significance of camel milk with special reference to cancer. It also encompasses its unique composition, relevance to otherdiseases and special properties as compared to human milk.Item Cytoplasmic Signaling Circuitry: An Important Trait of Cancer(Taylor & Francis, 2018) Mukherjee, SudeshnaItem Dual drug loaded vitamin D3 nanoparticle to target drug resistance in cancer(RSC, 2014) Chowdhury, RajdeepOvercoming drug resistance is one of the most challenging problems in cancer chemotherapy. Drug cocktails can overcome the drug resistance. However, multiple drug combinations lead to multifold increment of off-target toxicity, as well as the delivery of the required therapeutic amount of combined drugs remains problematic. To address these problems, we have developed a sub 200 nm vitamin D3 nanoparticle, which can contain a rational combination of dual drugs (PI103 and cisplatin or doxorubicin or proflavine). The size, shape and morphology of these dual drug containing vitamin D3 nanoparticles were characterized by DLS, FESEM, AFM and TEM. The nanoparticles released the dual drugs in high quantity at pH = 5.5 compared to pH = 7.4 in a slow and sustained manner over 72 h with stability over 15 days at 37 °C, as well as 4 °C. These dual drug loaded nanoparticles induced increased cell death in human hepatocellular carcinoma, Hep3B cells at 24 h compared to monotherapy; moreover, they were effective against cisplatin-resistant cells (Hep3B-R) as well. VitD3–PI103–CDDP-NP and vitD3–PI103–Dox-NP showed cytotoxicity by inducing apoptosis through DNA damage. Furthermore, vitD3–PI103–CDDP-NP showed considerably improved efficacy in 5-fluorouracil (5-FU) resistant Hep3B–5FU-R cells; its activity was even better compared to 5-FU. Finally, vitD3–PI103–proflavine-NP internalized into Hep3B-R cells considerably faster (within 3 minutes) compared to Hep3B cells, as visualized by fluorescent microscopy. Therefore, these dual drug loaded nanoparticles can successfully overcome the trauma of drug resistance and have the potential to be applied into the clinics for improved cancer therapeutics.Item Understanding cancer complexome using networks, spectral graph theory and multilayer framework(Springer Nature, 2017) Chowdhury, RajdeepCancer complexome comprises a heterogeneous and multifactorial milieu that varies in cytology, physiology, signaling mechanisms and response to therapy. The combined framework of network theory and spectral graph theory along with the multilayer analysis provides a comprehensive approach to analyze the proteomic data of seven different cancers, namely, breast, oral, ovarian, cervical, lung, colon and prostate. Our analysis demonstrates that the protein-protein interaction networks of the normal and the cancerous tissues associated with the seven cancers have overall similar structural and spectral properties. However, few of these properties implicate unsystematic changes from the normal to the disease networks depicting difference in the interactions and highlighting changes in the complexity of different cancers. Importantly, analysis of common proteins of all the cancer networks reveals few proteins namely the sensors, which not only occupy significant position in all the layers but also have direct involvement in causing cancer. The prediction and analysis of miRNAs targeting these sensor proteins hint towards the possible role of these proteins in tumorigenesis. This novel approach helps in understanding cancer at the fundamental level and provides a clue to develop promising and nascent concept of single drug therapy for multiple diseases as well as personalized medicine.Item Evaluation of novel platinum(ii) based AIE compound-encapsulated mesoporous silica nanoparticles for cancer theranostic application(RSC, 2018) Chowdhury, Rajdeep; Laskar, Inamur RahamanAdvanced biomedical research has established that cancer is a multifactorial disorder which is highly heterogeneous in nature and responds differently to different treatment modalities, due to which constant monitoring of therapy response is becoming extremely important. To accomplish this, different theranostic formulations have been evaluated. However, most of them are found to suffer from several limitations extending from poor resolution, radiation damage, to high costs. In order to develop a better theranostic modality, we have designed and synthesized a novel platinum(II)-based ‘aggregation induced emission’ (AIE) molecule (named BMPP-Pt) which showed strong intra-cellular fluorescence and also simultaneously exhibited potent cytotoxic activity. Due to this dual functionality, we wanted to explore the possibility of using this compound as a single molecule based theranostic modality. This compound was characterized using elemental analysis, NMR and IR spectroscopy, mass spectrometry and single crystal X-ray structure determination. BMPP-Pt was found to exhibit a high AIE property with emission maxima at 497 nm. For more efficient cancer cell targeting, BMPP-Pt was encapsulated into mesoporous silica nanoparticles (Pt-MSNPs) and the MSNPs were further surface modified with an anti-EpCAM aptamer (Pt-MSNP-E). Pt-MSNPs exhibited higher intracellular fluorescence compared to free BMPP-Pt, though both of them induced a similar degree of cell death via the apoptosis pathway, possibly via cell cycle arrest in the G1 phase. Anti-EpCAM aptamer modification was found to increase both cytotoxicity and intracellular fluorescence compared to unmodified MSNPs. Our study showed that EpCAM functionalized BMPP-Pt loaded MSNPs can efficiently internalize and induce apoptosis of cancer cells as well as show strong intracellular fluorescence. This study provides clues towards the development of a potential single compound based theranostic modality in future.Item Common and Unique microRNAs in Multiple Carcinomas Regulate Similar Network of Pathways to Mediate Cancer Progression(Springer Nature, 2020) Chowdhury, Rajdeep; Chowdhury, Shibasish; Majumder, Syamantak; Majumder, SyamantakCancer is a complex disease with a fatal outcome. Early detection of cancer, by monitoring appropriate molecular markers is very important for its therapeutic management. In this regard, the short non-coding RNA molecules, microRNAs (miRNAs) have shown great promise due to their availability in circulating fluids facilitating non-invasive detection of cancer. In this study, an in silico comparative analysis was performed to identify specific signature miRNAs dysregulated across multiple carcinomas and simultaneously identify unique miRNAs for each cancer type as well. The miRNA-seq data of cancer patient was obtained from GDC portal and their differential expressions along with the pathways regulated by both common and unique miRNAs were analyzed. Our studies show twelve miRNAs commonly dysregulated across seven different cancer types. Interestingly, four of those miRNAs (hsa-mir-210, hsa-mir-19a, hsa-mir-7 and hsa-mir-3662) are already reported as circulatory miRNAs (circRNAs); while, the miR-183 cluster along with hsa-mir-93 have been found to be incorporated in exosomes signifying the importance of the identified miRNAs for their use as prospective, non-invasive biomarkers. Further, the target mRNAs and pathways regulated by both common and unique miRNAs were analyzed, which interestingly had significant commonality. This suggests that miRNAs that are commonly de-regulated and specifically altered in multiple cancers might regulate similar pathways to promote cancer. Our data is of significance because we not only identify a set of common and unique miRNAs for multiple cancers but also highlight the pathways regulated by them, which might facilitate the development of future non-invasive biomarkers conducive for early detection of cancers.Item Endogenously produced nitric oxide mitigates sensitivity of melanoma cells to cisplatin(PNAS, 2012) Chowdhury, RajdeepMelanoma patients experience inferior survival after biochemotherapy when their tumors contain numerous cells expressing the inducible isoform of NO synthase (iNOS) and elevated levels of nitrotyrosine, a product derived from NO. Although several lines of evidence suggest that NO promotes tumor growth and increases resistance to chemotherapy, it is unclear how it shapes these outcomes. Here we demonstrate that modulation of NO-mediated S-nitrosation of cellular proteins is strongly associated with the pattern of response to the anticancer agent cisplatin in human melanoma cells in vitro. Cells were shown to express iNOS constitutively, and to generate sustained nanomolar levels of NO intracellularly. Inhibition of NO synthesis or scavenging of NO enhanced cisplatin-induced apoptotic cell death. Additionally, pharmacologic agents disrupting S-nitrosation markedly increased cisplatin toxicity, whereas treatments favoring stabilization of S-nitrosothiols (SNOs) decreased its cytotoxic potency. Activity of the proapoptotic enzyme caspase-3 was higher in cells treated with a combination of cisplatin and chemicals that decreased NO/SNOs, whereas lower activity resulted from cisplatin combined with stabilization of SNOs. Constitutive protein S-nitrosation in cells was detected by analysis with biotin switch and reduction/chemiluminescence techniques. Moreover, intracellular NO concentration increased significantly in cells that survived cisplatin treatment, resulting in augmented S-nitrosation of caspase-3 and prolyl-hydroxylase-2, the enzyme responsible for targeting the prosurvival transcription factor hypoxia-inducible factor-1α for proteasomal degradation. Because activities of these enzymes are inhibited by S-nitrosation, our data thus indicate that modulation of intrinsic intracellular NO levels substantially affects cisplatin toxicity in melanoma cells. The underlying mechanisms may thus represent potential targets for adjuvant strategies to improve the efficacy of chemotherapy.