Department of Biological Sciences

Permanent URI for this collectionhttp://localhost:4000/handle/123456789/1922

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Author: search.filters.author.Roy, AniruddhaSubject: search.filters.subject.Biology

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    Repurposing of CNS accumulating drugs Gemfibrozil and Doxylamine for enhanced sensitization of glioblastoma cells through modulation of autophagy
    (Springer Nature, 2025-07) Mukherjee, Sudeshna; Chowdhury, Rajdeep; Majumder, Syamantak; Chowdhury, Shibasish; Roy, Aniruddha
    GBM is one of the most aggressive malignancies, having the greatest fatality rate and average life years lost. The current standard medicine, temozolomide (TMZ), is ineffective, requiring the development of new treatments. However, identifying and introducing a novel medicine takes time and money. In this context, repurposing FDA-approved drugs can be a novel yet efficient alternative method. Here, we, therefore, investigated the differential expression signatures of genes of patients suffering from GBM from publicly available GEO datasets and constructed a connectivity map. Functional annotation and KEGG pathway analysis showed dysregulated molecular activities and pathways. Based on their gene ontologies, putative key genes and hub genes linked with the disease were identified, and the C-MAP database was scanned for FDA-approved medicinal compounds that could alter hub gene expression or associated pathways. Our in-silico investigation showed that Gemfibrozil (Gem) and Doxylamine (Doxy) might reverse GBM disease patterns by deregulating GBM-related genes. Evaluation of the GBM inhibitory potential of these drugs through in-vitro and three-dimensional spheroid assay showed promising results. These drugs were more cytotoxic than TMZ; however, they synergised with TMZ as well. Interestingly, the cellular homeostatic process autophagy which has been implicated significantly in GBM pathogenesis and therapy resistance, was found to be inhibited by the drugs Gemfibrozil and Doxylamine, signifying their prospective potential. Therefore, in this study, we, for the first time, identify drugs with the ability to cross the blood brain barrier (BBB), with potential cytotoxic effects beyond TMZ, and with autophagy inhibitory potential, which can be further explored for repurposing against GBM.
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    Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria
    (Spandidos, 2018) Chowdhury, Rajdeep; Roy, Aniruddha; Mukherjee, Sudeshna
    Glioblastoma multiforme (GBM), often referred to as a grade IV astrocytoma, is the most invasive type of tumor arising from glial cells. The main treatment options for GBM include surgery, radiation and chemotherapy. However, these treatments tend to be only palliative rather than curative. Poor prognosis of GBM is due to its marked resistance to standard therapy. Currently, temozolomide (TMZ), an alkylating agent is used for treatment of GBM. However, GBM cells can repair TMZ‑induced DNA damage and therefore diminish the therapeutic efficacy of TMZ. The potential to evade apoptosis by GBM cells accentuates the need to target the non‑apoptotic pathway and/or inhibition of pro‑survival strategies that contribute to its high resistance to conventional therapies. In recent studies, it has been demonstrated that HDAC inhibitors, such as vorinostat (suberoyl anilide hydroxamic acid; SAHA) can induce autophagy in cancer cells, thereby stimulating autophagosome formation. In addition, a lysosomotropic agent such as chloroquine (CQ) can result in hyper‑accumulation of autophagic vacuoles by inhibiting autophagosome‑lysosome fusion, which can drive the cell towards apoptosis. Hence, we postulated that combination treatment with SAHA and CQ may lead to increased formation of autophagosomes, resulting in its hyper‑accumulation and ultimately inducing cell death in GBM cells. In the present study, we demonstrated that CQ co‑treatment enhanced SAHA‑mediated GBM cell apoptosis. Inhibition of the early stage of autophagy by 3‑methyladenine pre‑treatment reduced cell death confirming that apoptosis induced by CQ and SAHA was dependent on autophagosome accumulation. We also demonstrated that autophagy inhibition led to enhanced ROS, mitochondria accumulation and reduced mitochondrial membrane potential resulting in cell death. The present study provides cellular and molecular evidence concerning the combined effect of SAHA and CQ which can be developed as a therapeutic strategy for the treatment of glioblastoma in the future.
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    Disulfiram potentiates docetaxel cytotoxicity in breast cancer cells through enhanced ROS and autophagy
    (Springer, 2020) Chowdhury, Rajdeep; Roy, Aniruddha
    Recent studies have demonstrated that autophagy plays a critical role in reducing the drug sensitivity of docetaxel (DTX) therapy. Disulfiram (DSF) has exhibited potent autophagy inducing activity in multiple studies. We hypothesized that DSF co-treatment could sensitize breast cancer cells to DTX therapy via autophagy modulation.
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    Development of a tumor extracellular pH-responsive nanocarrier by terminal histidine conjugation in a star shaped poly(lactic-co-glycolic acid)
    (Elsiever, 2021) Chowdhury, Rajdeep; Roy, Aniruddha
    After reaching the tumor site, nanoparticles (NPs) mostly accumulate in the periphery of the tumor, as their intra-tumoral penetration is prevented due to the low perfusion, high interstitial fluid pressure, and dense matrix present in the tumor. A pH-responsive carrier can improve tumor permeation by releasing the drug quickly in the acidic tumor pH, helping its uniform tumor distribution through diffusion. In the current study, we have developed a histidine modified star-shaped PLGA (sPLGA-His) for the tumor-targeted delivery of the drug combination of docetaxel and disulfiram. The sPLGA-His NPs exhibited a rapid pH-responsive drug release behavior, with significantly increased drug release at pH 6.5 compared to pH 7.4 in 12 h. In-vitro cytotoxicity analysis showed that the pH-sensitive sPLGA-His NPs had enhanced efficacy in both 2D and 3D cell culture models. In the cell uptake study, the sPLGA-His NPs exhibited endosomal escape and uniform cellular distribution, whereas sPLGA NPs were found to be accumulated in the endosomes. In the tumor spheroid model, deep penetration was observed with the sPLGA-His NPs, while sPLGA NPs were found to be accumulated in the periphery. Using fluorescent colocalization as well as FRET analysis, increased release of the encapsulated cargo was noticed with the sPLGA-His NPs, compared to sPLGA NPs. Altogether, the sPLGA-His NPs can be used as a tumor extracellular pH-responsive nanocarrier for efficient drug delivery to the tumor.