Browsing by Author "Dhananjay Shukla"

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Counteracting Action of Curcumin on High Glucose-Induced Chemoresistance in Hepatic Carcinoma Cells
(Frontiers Media S.A., 2021) Vivek Kumar Soni; Arundhati Mehta; Yashwant Kumar Ratre; Vikas Chandra; Dhananjay Shukla; Ajay Kumar; Naveen Kumar Vishvakarma
Along with direct anticancer activity, curcumin hinders the onset of chemoresistance. Among many, high glucose condition is a key driving factor for chemoresistance. However, the ability of curcumin remains unexplored against high glucose-induced chemoresistance. Moreover, chemoresistance is major hindrance in effective clinical management of liver cancer. Using hepatic carcinoma HepG2 cells, the present investigation demonstrates that high glucose induces chemoresistance, which is averted by the simultaneous presence of curcumin. Curcumin obviated the hyperglycemia-induced modulations like elevated glucose consumption, lactate production, and extracellular acidification, and diminished nitric oxide and reactive oxygen species (ROS) production. Modulated molecular regulators are suggested to play a crucial role as curcumin pretreatment also prevented the onset of chemoresistance by high glucose. High glucose instigated suppression in the intracellular accumulation of anticancer drug doxorubicin and drug-induced chromatin compactness along with declined expression of drug efflux pump MDR-1 and transcription factors and signal transducers governing the survival, aggressiveness, and apoptotic cell death (p53, HIF-1α, mTOR, MYC, STAT3). Curcumin alleviated the suppression of drug retention and nuclear condensation along with hindering the high glucose-induced alterations in transcription factors and signal transducers. High glucose-driven resistance in cancer cells was associated with elevated expression of metabolic enzymes HKII, PFK1, GAPDH, PKM2, LDH-A, IDH3A, and FASN. Metabolite transporters and receptors (GLUT-1, MCT-1, MCT-4, and HCAR-1) were also found upregulated in high glucose exposed HepG2 cells. Curcumin inhibited the elevated expression of these enzymes, transporters, and receptors in cancer cells. Curcumin also uplifted the SDH expression, which was inhibited in high glucose condition. Taken together, the findings of the present investigation first time demonstrate the ability of curcumin against high glucose-induced chemoresistance, along with its molecular mechanism. This will have implication in therapeutic management of malignancies in diabetic conditions. © Copyright © 2021 Soni, Mehta, Ratre, Chandra, Shukla, Kumar and Vishvakarma.
Curcumin circumvent lactate-induced chemoresistance in hepatic cancer cells through modulation of hydroxycarboxylic acid receptor-1
(Elsevier Ltd, 2020) Vivek Kumar Soni; Dhananjay Shukla; Ajay Kumar; Naveen Kumar Vishvakarma
Curcumin has been demonstrated to affect the chemoresistance in cancer cells of various origins. However, its ability to modulate lactate-induced chemoresistance remains unclear. The Present investigation demonstrates that curcumin inhibits the survival of HepG2 and HuT78 cells and can modulate chemo-susceptibility of HepG2 cells. Experimental simulation of simultaneous and pre-treatment suggest cooperatively between curcumin and anticancer drugs as well as the modulation of molecular regulators. Inhibition of glucose consumption, lactate production, extracellular acidity and augmented level of Nitric oxide were observed. DAPI staining revealed hyper condensation of chromatin in curcumin-treated HepG2 cells. Curcumin also diminished the lactate-induced chemoresistance against doxorubicin in hepatic cancer cells along with down regulation of lactate receptor (hydroxycarboxylic acid receptor-1; HCAR-1/GPR81). Alteration of the extracellular milieu along with inhibited expression of genes (hif-1α, ldh-a, mct-1, mdr-1 and stat-3) and proteins (HIF-1α and HCAR-1) are indicated to be involved in curcumin-induced reversal of chemoresistance in HepG2 cells. Findings of present investigation contribute to knowledge of curcumin mediated chemosensitization and its mechanism. © 2020 Elsevier Ltd
Curcumin: a spice pigment against hepatic cancer
(Elsevier, 2022) Vivek Kumar Soni; Yashwant Kumar Ratre; Arundhati Mehta; Ashwini Kumar Dixit; Mrigendra Dwivedi; Dhananjay Shukla; Ajay Kumar; Naveen Kumar Vishvakarma
Hepatic cancer is one of the most deadly malignancies owing to the pivotal role of liver in physiological homeostasis. Various strategies are being implemented to combat the onset and progression of liver cancer that has achieved promising success. However, conventional therapeutic approaches have their own limitations, particularly nonspecific toxicity and the onset of the chemoresistance. Therefore alternative approaches, including bioactive components of natural origins are being explored for their antineoplastic activity. Curcumin, the yellow pigment of turmeric spice, has shown effective cytotoxic activity against numerous malignant cells, including hepatic cancer. The abilities of curcumin such as its antioxidant nature, antiinflammatory effects, immunostimulatory activity, and protective behavior against organ damage make this phytochemical as a better choice of therapeutic agent in various medical ailments including malignancies of hepatic origin. Mechanistic explorations on curcumin have identified various molecular targets for its therapeutic effects against liver cancer. Moreover, curcumin is devoid of any specific adverse effects and safe for consumption. Curcumin also exhibits chemosensitizing ability and makes liver cancer cells more susceptible to conventional chemotherapeutic drugs. Although few concerns, including bioavailability and its metabolism limit the optimal clinical exploitation of curcumin, its derivatives is found to overcome such obstacles. Collectively curcumin stands high in prospective therapeutic molecules against liver cancers with evident success in preclinical as well clinical investigations. © 2022 Elsevier Inc. All rights reserved.
Orchestral role of lipid metabolic reprogramming in T-cell malignancy
(Frontiers Media S.A., 2023) Arundhati Mehta; Yashwant Kumar Ratre; Vivek Kumar Soni; Dhananjay Shukla; Subhash C. Sonkar; Ajay Kumar; Naveen Kumar Vishvakarma
The immune function of normal T cells partially depends on the maneuvering of lipid metabolism through various stages and subsets. Interestingly, T-cell malignancies also reprogram their lipid metabolism to fulfill bioenergetic demand for rapid division. The rewiring of lipid metabolism in T-cell malignancies not only provides survival benefits but also contributes to their stemness, invasion, metastasis, and angiogenesis. Owing to distinctive lipid metabolic programming in T-cell cancer, quantitative, qualitative, and spatial enrichment of specific lipid molecules occur. The formation of lipid rafts rich in cholesterol confers physical strength and sustains survival signals. The accumulation of lipids through de novo synthesis and uptake of free lipids contribute to the bioenergetic reserve required for robust demand during migration and metastasis. Lipid storage in cells leads to the formation of specialized structures known as lipid droplets. The inimitable changes in fatty acid synthesis (FAS) and fatty acid oxidation (FAO) are in dynamic balance in T-cell malignancies. FAO fuels the molecular pumps causing chemoresistance, while FAS offers structural and signaling lipids for rapid division. Lipid metabolism in T-cell cancer provides molecules having immunosuppressive abilities. Moreover, the distinctive composition of membrane lipids has implications for immune evasion by malignant cells of T-cell origin. Lipid droplets and lipid rafts are contributors to maintaining hallmarks of cancer in malignancies of T cells. In preclinical settings, molecular targeting of lipid metabolism in T-cell cancer potentiates the antitumor immunity and chemotherapeutic response. Thus, the direct and adjunct benefit of lipid metabolic targeting is expected to improve the clinical management of T-cell malignancies. Copyright © 2023 Mehta, Ratre, Soni, Shukla, Sonkar, Kumar and Vishvakarma.
Tumor-associated macrophages in prostate cancer: role in progression and therapy
(Elsevier, 2022) Arundhati Mehta; Shiv Govind Rawat; Yashwant Ratre; Vivek Soni; Dhananjay Shukla; Ajay Kumar; Naveen Vishvakarma
Conventionally, tumor-infiltrating immune cells were only thought to exhibit anticancer response against neoplastic cells. Prostate cancer tissue is also highly infiltrated by the cells of the immune system. In an established prostate tumor, these immune cells, contrasting to their high number, are seized to perform their anticancer activity; they rather contribute to the maintenance of various hallmarks of cancer. Macrophages recruited at the tumor site, known as tumor-associated macrophages (TAMs), also play a dual role in the progression of tumor growth and metastasis. The unique physiological, biochemical, as well as physical constitution of the tumor microenvironment (TME) of prostate cancer have regulatory consequences on the functional activation of TAMs. Two distinct phenotypic activations of macrophages, that is, M1 and M2, exhibit contrasting consequences in the TME; the former exhibits antitumor properties, while the latter promotes the tumor growth. Diverse mechanisms underlying phenotypic polarization of TAMs in the TME, ranging from metabolic interventions triggered by reprogrammed tumor metabolism to cognate and non-cognate interactions with cellular residents of the TME, have been proposed. Recently, epigenetic modifications of macrophages in the TME have been linked with their pro-tumor behavior. TAMs also play a multifaceted role in carcinogenic events and the progression of prostate cancer. Significant contribution of TAMs in inflammatory sequences drives the progression of prostate cancer cell growth and aggressive behavior. Moreover, the vascularization of tumor tissues is also promoted by TAMs through the production of pro-angiogenic mediators. The cooperative maneuver of metabolism between cancer cells and TAMs serves as a maintaining force at the rear of unique tumor metabolism. Macrophages in the TME regulate the invasion and metastasis of prostate cancer. Nevertheless, TAMs have also demonstrated to prime premetastatic niches and precondition the distant sites for the homing of circulatory tumor cells. Nevertheless, the degree of macrophage infiltration into tumor tissue is mostly associated with a poor prognosis in prostate cancer. Various strategies to crack this proximate alliance of TAMs in favor of tumor progression have been proposed and evaluated. These approaches include refraining macrophage recruitment in tumor tissues, hindering their survival, or preventing their M2 polarization. Based on the available experimental pieces of evidence uncovering the crucial role of TAMs in cancer biology, this chapter will discuss the mechanisms of TAM polarization and its role in various stages of prostate cancer progression along with therapeutic approaches focused on TAMs and their prospects. © 2023 Elsevier Inc. All rights reserved.