Browsing by Author "Sumit S. Verma"

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Anti-cancer activities of Bharangin against breast cancer: Evidence for the role of NF-κB and lncRNAs
(Elsevier B.V., 2018) Nikee Awasthee; Vipin Rai; Sumit S. Verma; K. Sajin Francis; Mangalam S. Nair; Subash C. Gupta
Breast cancer remains one of the leading causes of cancer related deaths in women worldwide. Bharangin is a diterpenoid quinonemethide that has demonstrated therapeutic potential against leukemia, lymphoma, and multiple myeloma cells. Whether this diterpenoid exhibit activities against breast cancer cells and the underlying mechanism is largely unknown. Herein, we provide evidence that bharangin suppresses the proliferation of MCF-7, MDA-MB-231, MDA-MB-453, MDA-MB-468 and T-47D breast cancer cells. As examined by AO/PI staining, DAPI staining, sub-G1 analysis, phosphatidylserine externalization, caspase activation, DNA laddering, and poly-ADP ribose polymerase cleavage, the diterpenoid induced apoptosis in breast cancer cells. The growth inhibitory effect of bharangin on breast cancer cells was further confirmed from colony-formation assay. Furthermore, the cancer cell migration was also suppressed by the diterpenoid. Mechanistically, bharangin was found to modulate multiple cancer related cell signalling pathways in breast cancer cells. Bharangin suppressed the expression of cell survival and invasive proteins, and induced Bax and mitochondrial depolarization in breast cancer cells. The diterpenoid also suppressed the activation of pro-inflammatory transcription factor, nuclear factor (NF)-κB induced by okadaic acid. Finally, the diterpenoid induced the expression of tumor suppressor lncRNAs (MEG-3, GAS-5), while down-regulating oncogenic H19 expression. Overall, these results suggest that bharangin exhibits anti-carcinogenic, anti-proliferative and anti-inflammatory activities against breast cancer cells. The modulation of lncRNA expression and inhibition of NF-κB activation by bharangin may contribute to its anti-carcinogenic activities. © 2018 Elsevier B.V.
Isodeoxyelephantopin, a Sesquiterpene Lactone Induces ROS Generation, Suppresses NF-κB Activation, Modulates LncRNA Expression and Exhibit Activities Against Breast Cancer
(Nature Research, 2019) Sumit S. Verma; Vipin Rai; Nikee Awasthee; Anupam Dhasmana; Dhanya S Rajalaksmi; Mangalam S. Nair; Subash C. Gupta
The sesquiterpene lactones, Isodeoxyelephantopin (IDET) and Deoxyelephantopin (DET) are known to exhibit activities against some cancer types. The activities of these lactones against breast cancer and the molecular bases is not known. We examined the efficacy of lactones in breast cancer preclinical model. Although both lactones exhibited drug like properties, IDET was relatively effective in comparison to DET. IDET suppressed the proliferation of both invasive and non-invasive breast cancer cell lines. IDET also suppressed the colony formation and migration of breast cancer cells. The assays for Acridine Orange (AO)/Propidium Iodide (PI) staining, cell cycle distribution, phosphatidylserine externalization and DNA laddering suggested the apoptosis inducing potential of IDET. The treatment with IDET also induced an accumulation of cells in the sub-G1 and G2/M phases. The exposure of breast cancer cells to the lactone was associated with a depolarization in mitochondrial membrane potential, and cleavage of caspase and PARP. The lactone induced reactive oxygen species (ROS) generation in breast cancer cells. Further, the use of N-acetyl cysteine (NAC) suppressed IDET induced ROS generation and apoptosis. The NF-κB-p65 nuclear translocation induced by okadaic acid (OA) was suppressed by the sesquiterpene. IDET also suppressed the expression of NF-κB regulated tumorigenic proteins, and induced the expression of proapoptotic gene (Bax) in cancer cells. While the expression of oncogenic lncRNAs was suppressed, the tumor suppressor lncRNAs were induced by the sesquiterpene. Collectively, the modulation of multiple cell signaling molecules by IDET may contribute to its activities in breast cancer cells. © 2019, The Author(s).
Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases
(Springer Science and Business Media Deutschland GmbH, 2019) Shruti Mishra; Sumit S. Verma; Vipin Rai; Nikee Awasthee; Srinivas Chava; Kam Man Hui; Alan Prem Kumar; Kishore B. Challagundla; Gautam Sethi; Subash C. Gupta
The long non-coding RNAs (lncRNAs) are the crucial regulators of human chronic diseases. Therefore, approaches such as antisense oligonucleotides, RNAi technology, and small molecule inhibitors have been used for the therapeutic targeting of lncRNAs. During the last decade, phytochemicals and nutraceuticals have been explored for their potential against lncRNAs. The common lncRNAs known to be modulated by phytochemicals include ROR, PVT1, HOTAIR, MALAT1, H19, MEG3, PCAT29, PANDAR, NEAT1, and GAS5. The phytochemicals such as curcumin, resveratrol, sulforaphane, berberine, EGCG, and gambogic acid have been examined against lncRNAs. In some cases, formulation of phytochemicals has also been used. The disease models where phytochemicals have been demonstrated to modulate lncRNAs expression include cancer, rheumatoid arthritis, osteoarthritis, and nonalcoholic fatty liver disease. The regulation of lncRNAs by phytochemicals can affect multi-steps of tumor development. When administered in combination with the conventional drugs, phytochemicals can also produce synergistic effects on lncRNAs leading to the sensitization of cancer cells. Phytochemicals target lncRNAs either directly or indirectly by affecting a wide variety of upstream molecules. However, the potential of phytochemicals against lncRNAs has been demonstrated mostly by preclinical studies in cancer models. How the modulation of lncRNAs by phytochemicals produce therapeutic effects on cancer and other chronic diseases is discussed in this review. © Springer Nature Switzerland AG 2019.
PD-L1, inflammation, non-coding RNAs, and neuroblastoma: Immuno-oncology perspective
(Academic Press, 2018) Palanisamy Nallasamy; Srinivas Chava; Sumit S. Verma; Shruti Mishra; Santhi Gorantla; Don W. Coulter; Siddappa N. Byrareddy; Surinder K. Batra; Subash C. Gupta; Kishore B. Challagundla
Neuroblastoma is the most common pediatric solid tumor of neural crest origin. The current treatment options for neuroblastoma produce severe side effects. Programmed death-ligand 1 (PD-L1), chronic inflammation, and non-coding RNAs are known to play a significant role in the pathogenesis of neuroblastoma. Cancer cells and the surrounding cells in the tumor microenvironment express PD-L1. Programmed death-1 (PD-1) is a co-receptor expressed predominantly by T cells. The binding of PD-1 to its ligands, PD-L1 or PD-L2, is vital for the physiologic regulation of the immune system. Chronic inflammation is involved in the recruitment of leukocytes, production of cytokines and chemokines that in turn, lead to survival, metastasis, and angiogenesis in neuroblastoma tumors. The miRNAs and long non-coding (lnc) RNAs have emerged as a novel class of non-coding RNAs that can regulate neuroblastoma associated cell-signaling pathways. The dysregulation of PD-1/PD-L1, inflammatory pathways, lncRNAs, and miRNAs have been reported in clinical and experimental samples of neuroblastoma. These signaling molecules are currently being evaluated for their potential as the biomarker and therapeutic targets in the management of neuroblastoma. A monoclonal antibody called dinutuximab (Unituxin) that attaches to a carbohydrate molecule GD2, on the surface of many neuroblastoma cells, is being used as an immunotherapy drug for neuroblastoma treatment. Atezolizumab (Tecentriq), an engineered monoclonal antibody against PD-L1, are currently in clinical trial for neuroblastoma patients. The lncRNA/miRNA-based therapeutics is being developed to deliver tumor suppressor lncRNAs/miRNAs or silencing of oncogenic lncRNAs/miRNAs. The focus of this review is to discuss the current knowledge on the immune checkpoint molecules, PD-1/PD-L1 signaling, inflammation, and non-coding RNAs in neuroblastoma. © 2017 Elsevier Ltd
Piperlongumine, a piper alkaloid, enhances the efficacy of doxorubicin in breast cancer: involvement of glucose import, ROS, NF-κB and lncRNAs
(Springer, 2022) Nikee Awasthee; Anusmita Shekher; Vipin Rai; Sumit S. Verma; Shruti Mishra; Anupam Dhasmana; Subash C. Gupta
Piperlongumine (PL, piplartine) is an alkaloid derived from the Piper longum L. (long pepper) roots. Originally discovered in 1961, the biological activities of this molecule against some cancer types was reported during the last decade. Whether PL can synergize with doxorubicin and the underlying mechanism in breast cancer remains elusive. Herein, we report the activities of PL in numerous breast cancer cell lines. PL reduced the migration and colony formation by cancer cells. An enhancement in the sub-G1 population, reduction in the mitochondrial membrane potential, chromatin condensation, DNA laddering and suppression in the cell survival proteins was observed by the alkaloid. Further, PL induced ROS generation in breast cancer cells. While TNF-α induced p65 nuclear translocation, PL suppressed the translocation in cancer cells. The expression of lncRNAs such as MEG3, GAS5 and H19 were also modulated by the alkaloid. The molecular docking studies revealed that PL can interact with both p65 and p50 subunits. PL reduced the glucose import and altered the pH of the medium towards the alkaline side. PL also suppressed the expression of glucose and lactate transporter in breast cancer cells. In tumor bearing mouse model, PL was found to synergize with doxorubicin and reduced the size, volume and weight of the tumor. Overall, the effects of doxorubicin in cancer cells are enhanced by PL. The modulation of glucose import, NF-κB activation and lncRNAs expression may have contributory role for the activities of PL in breast cancer. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Regulation of non-coding RNAs by phytochemicals for cancer therapy
(Elsevier, 2019) Sumit S. Verma; Vipin Rai; Kamla Kant Shukla; Subash C. Gupta
Micro RNAs (miRNAs) and long non-coding RNAs (lncRNAs) are the major non-coding RNAs with potential to modulate multiple steps of tumor development. Phytochemicals and nutraceuticals are reported to be safe, affordable, and multi-targeted. Accumulating evidence provides a solid basis for their potential as cancer therapeutics. Phytochemicals have been reported to suppress oncogenic non-coding RNAs while upregulating tumor suppressor non-coding RNAs in several cancer types. The most common phytochemicals known to modulate non-coding RNAs include curcumin, resveratrol, genistein, honokiol, silibinin, bharangin and sulforaphane that are shown to regulate miRNAs and lncRNAs such as miR-15a, miR-16, miR-19, miR-181b, GAS-5, H19, HOTAIR, MALAT1, MEG-3, and NEAT1 among others. In addition to cancer prevention and treatment, phytochemicals can regulate non-coding RNAs and therefore sensitize cancer cells to traditional cancer therapeutics. In some cases, phytochemicals have been modified to improve their bioavailability as well as efficacy for non-coding RNA based therapy. Lastly, phytochemicals target non-coding RNAs either directly or indirectly through modulation of other signaling molecules. How phytochemicals target non-coding RNAs for cancer prevention and treatment is the focus of this chapter. © 2019 Elsevier Inc. All rights reserved.