Browsing by Author "Mukherjee, Sudeshna"

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Arsenic Toxicity: Remediation and Treatment
(Taylor & Francis, 2016) Chowdhury, Rajdeep; Verma, S.K.; Mukherjee, Sudeshna
Association of FANCC and PTCH1 with the Development of Early Dysplastic Lesions of the Head and Neck
(Springer, 2011-08-23) Mukherjee, Sudeshna
Alteration of chromosome 9q22.3 region is an early and frequent event in head and neck squamous cell carcinoma (HNSCC). The aim of this study was to understand the association of candidate tumor suppressor genes PHF2, FANCC, PTCH1, and XPA located in this region in the development of HNSCC.
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.
Autophagy Regulated by Gain of Function Mutant p53 Enhances Proteasomal Inhibitor-Mediated Cell Death through Induction of ROS and ERK in Lung Cancer Cells
(Hindawi, 2019) Chowdhury, Shibasish; Chowdhury, Rajdeep; Mukherjee, Sudeshna
Mutations in p53, especially gain of function (GOF) mutations, are highly frequent in lung cancers and are known to facilitate tumor aggressiveness. Yet, the links between mutant GOF-p53 and lung cancers are not well established. In the present study, we set to examine how we can better sensitize resistant GOF-p53 lung cancer cells through modulation of cellular protein degradation machineries, proteasome and autophagy. H1299 p53 null lung cancer cells were stably transfected with R273H mutant GOF-p53 or wild-type (wt) p53 or empty vectors. The presence of R273H-P53 conferred the cancer cells with drug resistance not only against the widely used chemotherapeutic agents like cisplatin (CDDP) or 5-flurouracil (5-FU) but also against potent alternative modes of therapy like proteasomal inhibition. Therefore, there is an urgent need for new strategies that can overcome GOF-p53 induced drug resistance and prolong patient survival following failure of standard therapies. We observed that the proteasomal inhibitor, peptide aldehyde N-acetyl-leu-leu-norleucinal (commonly termed as ALLN), caused an activation of cellular homeostatic machinery, autophagy in R273H-P53 cells. Interestingly, inhibition of autophagy by chloroquine (CQ) alone or in combination with ALLN failed to induce enhanced cell death in the R273H-P53 cells; however, in contrast, an activation of autophagy by serum starvation or rapamycin increased sensitivity of cells to ALLN-induced cytotoxicity. An activated autophagy was associated with increased ROS and ERK signaling and an inhibition of either ROS or ERK signaling resulted in reduced cytotoxicity. Furthermore, inhibition of GOF-p53 was found to enhance autophagy resulting in increased cell death. Our findings provide novel insights pertaining to mechanisms by which a GOF-p53 harboring lung cancer cell is better sensitized, which can lead to the development of advanced therapy against resistant lung cancer cells.
Black Tea Polyphenols Restrict Benzopyrene-induced Mouse Lung Cancer Progression through Inhibition of Cox-2 and Induction of Caspase-3 Expression
(APJCP, 2006) Mukherjee, Sudeshna
Lung cancer is one of the leading causes of cancer related death in most developed and many developing countriesof the world. Due to lack of validated screening methods and poor prognosis, treatment of lung cancer has notimproved significantly over the last two decades. Therefore the risk of the disease needs to be minimized by preventivemeasures. One approach for lung cancer prevention envisages reversal or restriction of precancerous lesions bychemopreventive intervention. It demands a deeper understanding of the pathogenesis of the disease and identificationof the ideal point of intervention. In the present investigation, tea components, epigallocatechin gallate (EGCG) andtheaflavins (TF) were assessed for their chemopreventive potential when administered in the post initiation phase oflung carcinogenesis in an experimental mouse model. Histopathological changes in lungs of mice administeredbenzo(a)pyrene (BP) were followed serially and correlated with the expression of Cox-2, caspase-3 and caspase-7,which play key roles in histopathogenesis of neoplasia. The observations strongly indicate that both EGCG and TFcan influence the expression of these genes to modulate the process of carcinogenesis, resulting in delayed onset andlowered incidence of pre-invasive lung lesions.
Cancer: an evolutionary perspective
(Sci Medical, 2015) Chowdhury, Rajdeep; Mukherjee, Sudeshna
Cancer is intricately linked to our evolutionary history. The origin and progression of cancer can hence be better understood when viewed from an evolutionary perspective. In this review, we portray the fundamental fact that within the complex ecosystem of the human body, the cancerous cells also evolve. Just like any organism, they face diverse selective pressure to adapt to the tumor environment. There exists a competitive struggle that eliminates the unfit, leaving the well-adapted to thrive. Sequential acquisition of “driver mutations”, chromosomal instability triggering macromutations and punctuated bursts of genetic changes can all hypothetically contribute to the origin and evolution of cancer. We further describe that like in any ecosystem, cancer evolution involves not just the cancerous cells but also its interaction with the environment. However, as cancer evolves, individual cells behave more like a unicellular organism focused on its own survival. We also discuss evidences where cancer has evolved through transmission between individuals. An evolutionary analogy can open up new vistas in the treatment of this dreadful disease
Chloroquine attenuates hypoxia-mediated autophagy to curb thrombosis- an ex vivo and in vivo study
(2024-04) Mukherjee, Sudeshna; Majumder, Syamantak; Chowdhury, Shibasish; Chowdhury, Rajdeep
Hypoxia can trigger the activation of blood platelets, leading to thrombosis. If not addressed clinically, it can cause severe complications and fatal consequences as well. The current treatment regime for thrombosis is often palliative and includes long-term administration of anticoagulants, which has the risk of over-bleeding in injury and other secondary effects as well. This demands a deeper understanding of the process and exploration of an alternative therapeutic avenue. Interestingly, recent studies demonstrate that platelets though atypical and enucleated, possess components of autophagy machinery. This cellular homeostatic process though well-studied in non-platelet cells, is under-explored in platelets.
Chloroquine induces transitory attenuation of proliferation of human lung cancer cells through regulation of mutant P53 and YAP
(Springer, 2022-11) Chowdhury, Shibasish; Chowdhury, Rajdeep; Mukherjee, Sudeshna
Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer-associated deaths worldwide. Though recent development in targeted therapy has improved NSCLC prognosis, yet there is an unmet need to identify novel causative factors and appropriate therapeutic regimen against NSCLCs.
Cisplatin-induced oxidative stress regulates YAP to modulate epigenome promoting survival of osteosarcoma cells
(2025-08) Chowdhury, Rajdeep; Chowdhury, Shibasish; Mukherjee, Sudeshna
The widely used chemotherapeutic drug cisplatin (CDDP) is an integral part of the pre-operative chemotherapy protocol for high-grade osteosarcoma (OS). However, despite an aggressive treatment regimen, drug refractoriness is a major hindrance to successful therapy. We previously identified key transcriptomic alterations essential for the survival of OS cells following CDDP exposure. In the present study, we further demonstrate that CDDP treatment resulted in a ROS-dependent enrichment of the repressive histone mark H3K27me3 at the upstream promoter regions of growth-promoting genes such as CCNA2, and on the promoter of the negative regulator of Yes-Associated Protein (YAP)-LATS1, thereby contributing to their transcriptional repression. This was associated with a growth arrest, and quenching of ROS with N-acetyl cysteine (NAC) reversed it. Importantly, repression of LATS1 led to an increased nuclear localization of YAP, while pharmacological or genetic ablation of YAP reduced CDDP-mediated induction of repressive marks. YAP was further found to co-localize and co-immunoprecipitate with the Polycomb Repressive Complex 2 (PRC2) catalytic member-the histone methyl transferase-EZH2, indicating its putative role in mediating transcriptional repression. In lieu of the above, inhibition of YAP or reversal of the repressive chromatin state using a histone deacetylase (HDAC) inhibitor sensitized OS cells to a low-dose CDDP treatment as well. Overall, the present study demonstrates an interplay between oxidative stress, epigenetics, and YAP in modulating OS cell fate post CDDP exposure.
Cytoplasmic Signaling Circuitry: An Important Trait of Cancer
(Taylor & Francis, 2018) Mukherjee, Sudeshna
Differential alterations in metabolic pattern of the spliceosomal uridylic acid-rich small nuclear RNAs (UsnRNAs) during malignant transformation of 20-methylcholanthrene-induced mouse CNCI-PM-20 embryonic fibroblasts
(Wiley, 2009-06-03) Mukherjee, Sudeshna
Differential alterations of the spliceosomal Uridylic acid rich small nuclear RNAs (UsnRNAs) (U1, U2, U4, U5, and U6) are reported to be associated with cellular proliferation and development, but definitive information is scarce and also elusive. An attempt is made in this study to analyze the metabolic patterns of major spliceosomal UsnRNAs, during tumor development, in an in vitro carcinogenesis model of 20-methylcholanthrene (MCA)-transformed Swiss Mouse Embryonic Fibroblast (MEF), designated as CNCI-PM-20. MEF cells, after treatment with 20-MCA, progressed through a sequence of passages with distinct and heritable changes, finally becoming neoplastic at passage-42 (P42). A differential expression pattern of major UsnRNAs was observed during this process. The abundance of U1 was 20% below control (P1) at passage-20 (P20), followed by a gradual increase up until P42 (∼12% above the P1 value). The abundance of U2 was more or less constant during the cellular transformation. U4 showed a trend of increase, with above 30% abundance than control at P20, followed by a significant increase at P36 and P42 (1.5- and 2-fold, respectively, P-value <0.01). U5 also followed an identical pattern, with an increase of 70% compared to control (P-value <0.05) at P42. Interestingly, U6 gradually decreased from P20 onwards up until P42, with 22% at P20 and 67% at P42 (P-value <0.01). An overall significant quantitative alteration in abundance of U4, U5, and U6, observed in our study, contributes to the understanding of the fact that, the metabolism of major spliceosomal UsnRNAs is differentially regulated during the process of neoplastic transformation.
DRP1-mediated mitochondrial dynamics orchestrate EMT in glioblastoma cells
(2025-12) Chowdhury, Shibasish; Chowdhury, Rajdeep; Mukherjee, Sudeshna
Epithelial to mesenchymal transition (EMT), a differentiation process, frequently imparts invasive properties in Glioblastoma Multiforme (GBM), which leads to a poor prognosis. Cells lose apical-basal polarity, cell-cell connections, and/or chemo-resistance during EMT, which can result in the spread of cancer and the acquisition of additional stem cell-like traits. It is unclear how organelle dynamics influence EMT in this respect. The interaction between cytoskeletal and mitochondrial regulators governing GBM cell EMT is explored in this article.
The dynamic role of autophagy and MAPK signaling in determining cell fate under cisplatin stress in osteosarcoma cell
(Plos One, 2017) Chowdhury, Rajdeep; Mukherjee, Sudeshna
Osteosarcoma (OS) is an aggressive bone malignancy commonly observed in children and adolescents. Sub-optimal therapy for years has irretrievably compromised the chances of OS patient survival; also, lack of extensive research on this rare disease has hindered therapeutic development. Cisplatin, a common anti-tumor drug, is currently an integral part of treatment regime for OS along with methotrexate and doxorubicin. However, toxicity issues associated with combination module impede OS therapy. Also, despite the proven benefits of cisplatin, acquisition of resistance remains a concern with cisplatin-based therapy. This prompted us to investigate the molecular effects of cisplatin exposure and changes associated with acquired resistance in OS cells. Cisplatin shock was found to activate MAPK signaling and autophagy in OS cells. An activation of JNK and autophagy acted as pro-survival strategy, while ERK1/2 triggered apoptotic signals upon cisplatin stress. A crosstalk between JNK and autophagy was observed. Maximal sensitivity to cisplatin was obtained with simultaneous inhibition of both autophagy and JNK pathway. Cisplatin resistant cells were further developed by repetitive drug exposure followed by clonal selection. The resistant cells showed an altered signaling circuitry upon cisplatin exposure. Our results provide valuable cues to possible molecular alterations that can be considered for development of improved therapeutic strategy against osteosarcoma
Epigallocatechin gallate induced apoptosis in Sarcoma180 cells in vivo: Mediated by p53 pathway and inhibition in U1B, U4-U6 UsnRNAs expression
(Springer, 2006-10-12) Mukherjee, Sudeshna
The aim of this study was to understand the mode of action of tea polyphenol epigallocatechin gallate (EGCG) in vivo. Swiss albino mice were treated i.p. with EGCG at two different doses i.e. 12-mg/kg body weight and 15-mg/kg body weight, for 7 days prior to inoculation of Sarcoma180 (S180) cells and continued for another 7 days. The growth of the S180, harvested 7 days after inoculation, was significantly reduced due to treatment with EGCG. The flowcytometric analysis of S180 cells, showed significant increase in apoptosis and reduction in the number of cells in G2/M phase of cell cycle due to treatment with EGCG. The induction of apoptosis has also been confirmed by the TUNEL and DNA fragmentation assays. Both RT-PCR and Western blot analysis showed significant up-regulation of p53 and bax, and down-regulation of bcl-2 and c-myc due to EGCG treatment. No changes in the expression pattern of p21, p27, bcl-xl, mdm2 and cyclin D1 were seen. Interestingly, there was significant down-regulation of spliceosomal uridylic acid rich small nuclear RNAs (UsnRNAs) U1B and U4-U6 due to EGCG treatment. This indicates that these UsnRNAs may be involved in the apoptosis process. Taken together, our study suggests that in vivo EGCG could induce apoptosis in S180 cells through alteration in G2/M phase of the cell cycle by up-regulation of p53, bax and down-regulation of c-myc, bcl-2 and U1B, U4-U6 UsnRNAs.
Epigenetic adaptations in drug-tolerant tumor cells
(Elsevier, 2023) Chowdhury, Rajdeep; Chowdhury, Shibasish; Mukherjee, Sudeshna
Traditional 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.
Eugenol restricts DMBA croton oil induced skin carcinogenesis in mice: downregulation of c-Myc and H-ras, and activation of p53 dependent apoptotic pathway.
(Elsiever, 2010-07-01) Mukherjee, Sudeshna
Eugenol is the active component of essential oil isolated from clove (Syzigium aromaticum). Eugenol has antimutagenic, antigenotoxic, anti-inflammatory properties. The anticarcinogenic effect of eugenol was evident in different types of cell lines. However, its anticarcinogenic effect in in vivo has not yet been fully explored.
Evaluation of Apoptosis and Autophagy Inducing Potential of Berberis aristata, Azadirachta indica, and Their Synergistic Combinations in Parental and Resistant Human Osteosarcoma Cells
(Frontiers, 2017) Chowdhury, Rajdeep; PAUL, Atish T.; Mukherjee, Sudeshna
Cancer is a multifactorial disease and hence can be effectively overcome by a multi-constituently therapeutic strategy. Medicinal plant extracts represent a perfect example of such stratagem. However, minimal studies have been done till date that portray the effect of extraction techniques on the phyto-constituent profile of plant extracts and its impact on anticancer activity. In the present study, we have evaluated the anticancer potential of methanolic extracts of Berberis aristata root and Azadirachta indica seeds prepared by various extraction techniques in human osteosarcoma (HOS) cells. Soxhlation extract of B. aristata (BAM-SX) and sonication extract of A. indica (AIM-SO) were most effective in inducing apoptosis in parental drug sensitive, as well as resistant cell type developed by repeated drug exposure. Generation of reactive oxygen species and cell cycle arrest preceded caspase-mediated apoptosis in HOS cells. Interestingly, inhibition of autophagy enhanced cell death suggesting the cytoprotective role of autophagy. Combination studies of different methanolic extracts of BAM and AIM were performed, among which, the combination of BAM-SO and AIM-SO (BAAISO) was found to show synergism (IC50 10.27 µg/ml) followed by combination of BAM-MC and AIM-MC (BAAIMC) with respect to other combinations in the ratio of 1:1. BAAISO also showed synergism when it was added to cisplatin-resistant HOS cells (HCR). Chromatographic profiling of BAM-SX and AIM-SO by high performance thin layer chromatography resulted in identification of berberine (Rf 0.55), palmitine (Rf 0.50) in BAM-SX and azadirachtin A (Rf 0.36), azadirachtin B (Rf 0.56), nimbin (Rf 0.80), and nimbolide (Rf 0.43) in AIM-SO. The cytotoxic sensitivity obtained can be attributed to the above compounds. Our results highlight the importance of extraction technique and subsequent mechanism of action of multi-constituential B. aristata and A. indica against both sensitive and drug refractory HOS cells.
Exploring the extensive crosstalk between the antagonistic cytokines- TGF-β and TNF-α in regulating cancer pathogenesis
(Elsiever, 2021) Chowdhury, Rajdeep; Mukherjee, Sudeshna
A plethora of cytokines are produced in the tumor microenvironment (TME) those play a vital role in cancer prognosis. Though it is completely contextual, cytokines produced from an inflammatory micro-environment can either modulate cancer progression at early stages of tumor development or in later stages cytokine derived cues can in turn control tumor cell invasion and metastasis. Therefore, understanding the crosstalk between the key cytokines regulating cancer prognosis is critical for the development of an effective therapy. In this regard, the role of transforming growth factor-beta (TGF-β) in cancer is controversially discussed in general inhibition of TGF-β promotes de novo tumorigenesis whereas paradoxically, TGF-β can promote malignancy in already established tumors. Another important cytokine, TNF-α have intense crosstalk with TGF-β from the fact that in a non-cancer context, TGF-β promotes fibrosis whereas TNF-α has anti-fibrotic activity. We have recently reported that TGF-β-induced differentiation of epithelial cells to mesenchymal type is suppressed by TNF-α through regulation of cellular homeostatic machinery- autophagy. Moreover, there are also rare reports of synergy between these two cytokines as well. The crosstalk between TGF-β and TNF-α is not only limited to regulating cancer cell differentiation and proliferation but also includes involvement in cell death. In this review, we hence summarize the molecular mechanisms by which these two important cytokines, TGF-β and TNF-α control cancer prognosis.
A genome wide expression profile of non-coding RNAs in human osteosarcoma cells as they acquire resistance to cisplatin
(Springer, 2021-10) Chowdhury, Rajdeep; Chowdhury, Shibasish; Mukherjee, Sudeshna
Recurrence after cisplatin therapy is one of the major hindrances in the management of cancer. This necessitates a deeper understanding of the molecular signatures marking the acquisition of resistance. We therefore modeled the response of osteosarcoma (OS) cells to the first-line chemotherapeutic drug cisplatin. A small population of nondividing cells survived acute cisplatin shock (persisters; OS-P). These cells regained proliferative potential over time re-instating the population again (extended persisters; OS-EP).
A global transcriptomic pipeline decoding core network of genes involved in stages leading to acquisition of drug-resistance to cisplatin in osteosarcoma cells
(OUP, 2019) Chowdhury, Rajdeep; Chowdhury, Shibasish; Majumder, Syamantak; Mukherjee, Sudeshna
Traditional cancer therapy is focused on eradicating fast proliferating population of tumor cells. However, existing evidences suggest survival of sub-population of cancer cells that can resist chemotherapy by entering a ‘persister’ state of minimal growth. These cells eventually survive to produce cells resistant to drugs. The identifying of appropriate targets that can eliminate the drug-tolerant ‘persisters’ remains a challenge. Hence, a deeper understanding of the distinctive genetic signatures that lead to resistance is of utmost importance to design an appropriate therapy.