Publications by authors named "Roopesh Krishnankutty"

14 Publications

  • Page 1 of 1

Dysregulated Phosphorylation of p53, Autophagy and Stemness Attributes the Mutant p53 Harboring Colon Cancer Cells Impaired Sensitivity to Oxaliplatin.

Front Oncol 2020 28;10:1744. Epub 2020 Aug 28.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

Colorectal cancer (CRC) forms one of the highest ranked cancer types in the world with its increasing incidence and mortality rates despite the advancement in cancer therapeutics. About 50% of human CRCs are reported to have defective p53 expression resultant of gene mutation often contributing to drug resistance. The current study was aimed to investigate the response of wild-type harboring HCT 116 and mutant harboring HT 29 colon cancer cells to chemotherapeutic drug oxaliplatin (OX) and to elucidate the underlying molecular mechanisms of sensitivity/resistance in correlation to their p53 status. OX inhibited growth of wild-type p53-harboring colon cancer cells via p53/p21-Bax mediated apoptosis. Our study revealed that dysregulated phosphorylation of p53, autophagy as well as cancer stemness attributes the mutant p53-harboring colon cancer cells impaired sensitivity to OX.
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http://dx.doi.org/10.3389/fonc.2020.01744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485421PMC
August 2020

Therapeutic Effects of Curcumol in Several Diseases; An Overview.

Nutr Cancer 2021 14;73(2):181-195. Epub 2020 Apr 14.

Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.

also known as is a traditional Chinese medicine that has been used for many centuries against several diseases. The rhizome of the plant is composed of curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), and essential volatile oils including curcumol, curdione, and germacrone. While curcuminoids have been extensively studied for their antimicrobial, antioxidant, anti-inflammatory and anticancer properties, the therapeutic efficacy of curcumol is still emerging. Recent studies have shown anticancer properties of curcumol against multiple solid tumors such as breast, colorectal, head and neck, and lung adenocarcinomas. The underlying anti-tumor mechanisms revealed inhibition of several signaling pathways (NF-κB, MAPK, PI-3K/AKT, and GSK-3β) associated with cell proliferation, survival, anti-apoptosis, invasion and metastasis. Besides curcumol, extracts from the roots possess many other terpenoids such as β-elemene, δ-elemene, germacrone, furanodiene and furanodienone with known anticancer properties. In this review, we comprehensively focused on the composition of essential oils, their structure, isolation and therapeutic uses of curcumol to aid in the improvement and development of novel drugs with minimal cytotoxicity, enhanced efficacy, and less cost.
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http://dx.doi.org/10.1080/01635581.2020.1749676DOI Listing
April 2020

Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy.

J Transl Med 2020 03 27;18(1):140. Epub 2020 Mar 27.

National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Introduction: Cancer Immunotherapy has recently emerged as a promising and effective modality to treat different malignancies. Antigenic profiling of cancer tissues and determination of any pre-existing immune responses to cancer antigens may help predict responses to immune intervention in cancer. NY-ESO-1, a cancer testis antigen is the most immunogenic antigen to date. The promise of NY-ESO-1 as a candidate for specific immune recognition of cancer comes from its restricted expression in normal adult tissue but frequent occurrence in multiple tumors including melanoma and carcinomas of lung, esophageal, liver, gastric, prostrate, ovarian, and bladder.

Main Body: This review summarizes current knowledge of NY-ESO-1 as efficient biomarker and target of immunotherapy. It also addresses limitations and challenges preventing a robust immune response to NY-ESO-1 expressing cancers, and describes pre-clinical and clinical observations relevant to NY-ESO-1 immunity, holding potential therapeutic relevance for cancer treatment.

Conclusion: NY-ESO-1 induces strong immune responses in cancer patients but has limited objective clinical responses to NY-ESO-1 expressing tumors due to effect of competitive negative signaling from immune-checkpoints and immune-suppressive tumor microenvironment. We propose that combination therapy to increase the efficacy of NY-ESO-1 specific immunotherapeutic interventions should be explored to unleash the immune response against NY-ESO-1 expressing tumors.
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http://dx.doi.org/10.1186/s12967-020-02306-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102435PMC
March 2020

Claudin-1, A Double-Edged Sword in Cancer.

Int J Mol Sci 2020 Jan 15;21(2). Epub 2020 Jan 15.

Division of Translational Medicine, Research Branch, Sidra Medicine, Doha 26999, Qatar.

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target.
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http://dx.doi.org/10.3390/ijms21020569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013445PMC
January 2020

Anticancer Activity of Camel Milk via Induction of Autophagic Death in Human Colorectal and Breast Cancer Cells

Asian Pac J Cancer Prev 2018 Dec 25;19(12):3501-3509. Epub 2018 Dec 25.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, State of Qatar. Email:

Background/ Objective: Camel milk is traditionally known for its human health benefits and believed to be a remedy for various human ailments including cancer. The study was aimed to evaluate the inhibitory effects of commercially available camel milk on cancer cells and its underlying mechanism(s). Materials and Methods: Two cell lines: colorectal cancer HCT 116 and breast cancer MCF-7 were cultured with different doses of camel milk. The effects of camel milk on cell death were determined by MTT assay, viability by trypan blue exclusion assay and migration by in vitro scratch assay. The mechanism was elucidated by western blotting and confocal microscopy was used to confirm autophagy. Results: Camel milk significantly reduced proliferation, viability as well as migration of both the cells. The accumulation of LC3-II protein along with reduction in expression of p62 and Atg 5-12, the autophagy proteins implied induction of autophagy. The (GFP)-LC3 puncta detected by confocal microscopy confirmed the autophagosome formation in response to camel milk treatment. Conclusion: Camel milk exerted antiproliferative effects on human colorectal HCT 116 and breast MCF-7 cancer cells by inducing autophagy.
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http://dx.doi.org/10.31557/APJCP.2018.19.12.3501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428541PMC
December 2018

Squamous Cell Carcinomas of the Head and Neck Cancer Response to Programmed Cell Death Protein-1 Targeting and Differential Expression of Immunological Markers: A Case Report.

Front Immunol 2018 30;9:1769. Epub 2018 Jul 30.

National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.

Targeting the programmed cell death protein-1 (PD-1)/PD-1 ligand (PD-L1) pathway has been shown to enhance T cell-mediated antitumor immunity. Clinical responses are limited to subgroups of patients. The search for biomarkers of response is a strategy to predict response and outcome of PD-1/PD-L1 checkpoint intervention. The NY-ESO-1 cancer testis antigen has been considered as a biomarker in head and neck squamous cell carcinoma (HNSCC) patients and can induce both specific NY-ESO-1 antibody and T cells responses. Here, we correlated clinical responsiveness to anti-PD-1 (nivolumab) treatment with immunity to NY-ESO-1 in a patient with recurrent HNSCC. The patient was treated with second-line treatment of nivolumab and had a stable disease for over 7 months. His NY-ESO-1 antibody was found to be lower after the third (**** < 0.0001) and the fifth (**** < 0.0001) cycles of treatment compared to base line, and this was in line with the stability of the disease. The NY-ESO-1-specific T cells response of the patient was found to be increased after the third and the fifth (** = 0.002) cycles of treatment but had a significant decline after progression (** = 0.0028). The PD-1 expression by the patient's T cells was reduced 15-folds after nivolumab treatment and was uniquely restricted to the CD8 T cells population. Several cytokines/chemokines involved in immune activation were upregulated after nivolumab treatment; two biomarkers were reduced at progression [interleukin (IL)-10: **** < 0.0001 and CX3CL1: **** < 0.0001]. On the other hand, some cytokines/chemokines contributing to immune inhibition were downregulated after nivolumab treatment; two biomarkers were increased at progression (IL-6: **** < 0.0001 and IL-8: **** < 0.0001). This data support the notion that the presence of anti-NY-ESO-1 integrated immunity and some cytokines/chemokines profile may potentially identify a response to PD-1 blockade in HNSCC patients.
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http://dx.doi.org/10.3389/fimmu.2018.01769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079623PMC
September 2019

Targeting of X-linked inhibitor of apoptosis protein and PI3-kinase/AKT signaling by embelin suppresses growth of leukemic cells.

PLoS One 2017 13;12(7):e0180895. Epub 2017 Jul 13.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, State of Qatar.

The X-linked inhibitor of apoptosis (XIAP) is a viable molecular target for anticancer drugs that overcome apoptosis-resistance of malignant cells. XIAP is an inhibitor of apoptosis, mediating through its association with BIR3 domain of caspase 9. Embelin, a quinone derivative isolated from the Embelia ribes plant, has been shown to exhibit chemopreventive, anti-inflammatory, and apoptotic activities via inhibiting XIAP activity. In this study, we found that embelin causes a dose-dependent suppression of proliferation in leukemic cell lines K562 and U937. Embelin mediated inhibition of proliferation correlates with induction of apoptosis. Furthermore, embelin treatment causes loss of mitochondrial membrane potential and release of cytochrome c, resulting in subsequent activation of caspase-3 followed by polyadenosin-5'-diphosphate-ribose polymerase (PARP) cleavage. In addition, embelin treatment of leukemic cells results in a decrease of constitutive phosphorylations/activation level of AKT and downregulation of XIAP. Gene silencing of XIAP and AKT expression showed a link between XIAP expression and activated AKT in leukemic cells. Interestingly, targeting of XIAP and PI3-kinase/AKT signaling augmented inhibition of proliferation and induction of apoptosis in leukemic cells. Altogether these findings raise the possibility that embelin alone or in combination with inhibitors of PI3-kinase/AKT pathway may have therapeutic usage in leukemia and possibly other malignancies with up-regulated XIAP pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0180895PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509148PMC
September 2017

Multiple DNA Interactions Contribute to the Initiation of Telomerase Elongation.

J Mol Biol 2017 07 12;429(14):2109-2123. Epub 2017 May 12.

Department of Biology, Genetics group, Lund University, Lund, 223 62, Sweden. Electronic address:

Telomerase maintains telomere length and chromosome integrity by adding short tandem repeats of single-stranded DNA to the 3' ends, via reverse transcription of a defined template region of its RNA subunit. To further understand the telomerase elongation mechanism, we studied the primer utilization and extension activity of the telomerase from the budding yeast Naumovozyma castellii (Saccharomyces castellii), which displays a processive nucleotide and repeat addition polymerization. For the efficient initiation of canonical elongation, telomerase required 4-nt primer 3' end complementarity to the template RNA. This DNA-RNA hybrid formation was highly important for the stabilization of an initiation-competent telomerase-DNA complex. Anchor site interactions with the DNA provided additional stabilization to the complex. Our studies indicate three additional separate interactions along the length of the DNA primer, each providing different and distinct contributions to the initiation event. A sequence-independent anchor site interaction acts immediately adjacent to the base-pairing 3' end, indicating a protein anchor site positioned very close to the catalytic site. Two additional anchor regions further 5' on the DNA provide sequence-specific contributions to the initiation of elongation. Remarkably, a non-telomeric sequence in the distal 25- to 32-nt region negatively influences the initiation of telomerase elongation, suggesting an anchor site with a regulatory role in the telomerase elongation decision.
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http://dx.doi.org/10.1016/j.jmb.2017.04.023DOI Listing
July 2017

Potential therapeutic targets of Guggulsterone in cancer.

Nutr Metab (Lond) 2017 28;14:23. Epub 2017 Feb 28.

Translational Research Institute, Hamad Medical Corporation, PO Box 3050, Doha, Qatar.

Natural compounds capable of inducing apoptosis in cancer cells have always been of considerable interest as potential anti-cancer agents. Many such compounds are under screening and development with their potential evolution as a clinical drug benefiting many of the cancer patients. Guggulsterone (GS), a phytosterol isolated gum resin of the tree has been widely used in Indian traditional medicine as a remedy for various diseses. GS has been shown to possess cancer chemopreventive and therapeutic potential as established by in vitro and in vivo studies. GS has been shown to target constitutively activated survival pathways such as PI3-kinase/AKT, JAK/STAT, and NFκB signaling pathways that are involved in the regulation of growth and inflammatory responses regulation of antiapoptotic and inflammatory genes. The current review focuses on the molecular targets of GS, cellular responses, and the animal model studies in various cancers. The mechanistic action of GS in different types of cancers also forms a part of this review. The perspective of translating this natural compound into a clinically approved drug with its pros and cons is also discussed.
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http://dx.doi.org/10.1186/s12986-017-0180-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331628PMC
February 2017

Vascular Endothelial Growth Factor (VEGF) Signaling in Tumour Vascularization: Potential and Challenges.

Curr Vasc Pharmacol 2017 ;15(4):339-351

Translational Research Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha. Qatar.

Angiogenesis is defined as the physiological process by which new blood vessels develop from pre-existing vessels; either by sprouting or intussusception. Inhibition of angiogenesis is one of the most encouraging strategies to manage the growth and metastasis of cancers. The functional and proliferative status of blood vessels is regulated by the balance between various key molecules that either stimulate or inhibit angiogenesis. During quiescence, the "angiogenic switch" is "off". However, during tumour development pro-angiogenic factors such as vascular endothelial growth factor (VEGF), basic and acidic fibroblast growth factor, tumour necrosis factor-α and interleukin-1 are pathologically enhanced. Persistent growth of tumour directed capillary networks creates a favourable microenvironment, promoting cancer growth, progression and metastasis. VEGF, particularly VEGF-A, is a key angiogenic factor. Targeting VEGF, its receptors and the downstream signaling cascade, is a viable strategy to prevent tumour growth and metastasis. The present review discusses the role of VEGF in tumour angiogenesis and the current understanding of anti-VEGF therapies as well as refractoriness of anti-angiogenesis cancer therapy.
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http://dx.doi.org/10.2174/1570161115666170105124038DOI Listing
April 2018

Therapeutic Potential of Resveratrol in Lymphoid Malignancies.

Nutr Cancer 2016 30;68(3):365-73. Epub 2016 Mar 30.

b Translational Research Institute, Academic Health System, Hamad Medical Corporation , Doha , Qatar.

Natural products have always been sought as a dependable source for the cure of many fatal diseases including cancer. Resveratrol (RSV), a naturally occurring plant polyphenol, has been of recent research interest and is being investigated for its beneficial biological properties that include antioxidant, anti-inflammatory, proapoptotic, and growth inhibitory activities. These effects are mainly mediated by cell cycle arrest, upregulation of proapoptotic proteins, loss of mitochondrial potential, and generation of reactive oxygen species. Among the beneficial properties of RSV, the anticancer property has been of the prime focus and extensively explored during the last few years. Although reports exist on the chemopreventive role of RSV in many solid tumors, limited information is available on the antiproliferative activity of RSV in human lymphoma cells and experimental models. Potential mechanisms for its antiproliferative effect include induction of cell differentiation, apoptosis, and inhibition of DNA synthesis. In this review, the different kinds of lymphoid malignancies and the main mechanisms of cell death induced by resveratrol are discussed. The challenges are limiting in vivo experimental studies involving resveratrol. An attempt for the translation of this compound into a clinical drug also forms a part of this review.
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http://dx.doi.org/10.1080/01635581.2016.1152386DOI Listing
January 2017

Bortezomib-mediated downregulation of S-phase kinase protein-2 (SKP2) causes apoptotic cell death in chronic myelogenous leukemia cells.

J Transl Med 2016 Mar 9;14:69. Epub 2016 Mar 9.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, PO Box 3050, Doha, State of Qatar.

Background: Proteasome inhibitors are attractive cancer therapeutic agents because they can regulate apoptosis-related proteins. Bortezomib also known as Velcade(®), a proteasome inhibitor that has been approved by the food and drug administration for treatment of patients with multiple myeloma, and many clinical trials are ongoing to examine to the efficacy of bortezomib for the treatment of other malignancies. Bortezomib has been shown to induce apoptosis and inhibit cell growth of many cancer cells. In current study, we determine whether bortezomib induces cell death/apoptosis in CML.

Methods: Cell viability was measured using MTT assays. Apoptosis was measured by annexin V/PI dual staining and DNA fragmentation assays. Immunoblotting was performed to examine the expression of proteins. Colony assays were performed using methylcellulose.

Results: Treatment of CML cells with bortezomib results in downregulation of S-phase kinase protein 2 (SKP2) and concomitant stabilization of the expression of p27Kip1. Furthermore, knockdown of SKP2 with small interference RNA specific for SKP2 caused accumulation of p27Kip1. CML cells exposed to bortezomib leads to conformational changes in Bax protein, resulting in loss of mitochondrial membrane potential and leakage of cytochrome c to the cytosol. In the cytosol, cytochrome c causes sequential activation of caspase-9, caspase-3, PARP cleavage and apoptosis. Pretreatment of CML cells with a universal inhibitor of caspases, z-VAD-fmk, prevents bortezomib-mediated apoptosis. Our data also demonstrated that bortezomib treatment of CML downregulates the expression of inhibitor of apoptosis proteins. Finally, inhibition of proteasome pathways by bortezomib suppresses colony formation ability of CML cells.

Conclusions: Altogether, these findings suggest that bortezomib suppresses the cell proliferation via induction of apoptosis in CML cells by downregulation of SKP2 with concomitant accumulation of p27Kip1, suggesting that proteasomal pathway may form novel therapeutic targets for better management of CML.
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http://dx.doi.org/10.1186/s12967-016-0823-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784454PMC
March 2016

Involvement of F-BOX proteins in progression and development of human malignancies.

Semin Cancer Biol 2016 Feb 26;36:18-32. Epub 2015 Sep 26.

Academic Health System, Translational Research Institute, Hamad Medical Corporation, Doha, Qatar. Electronic address:

The Ubiquitin Proteasome System (UPS) is a core regulator with various protein components (ubiquitin-activating E1 enzymes, ubiquitin-conjugating E2 enzymes, ubiquitin-protein E3 ligases, and the 26S proteasome) which work together in a coordinated fashion to ensure the appropriate and efficient proteolysis of target substrates. E3 ubiquitin ligases are essential components of the UPS machinery, working with E1 and E2 enzymes to bind substrates and assist the transport of ubiquitin molecules onto the target protein. As the UPS controls the degradation of several oncogenes and tumor suppressors, dysregulation of this pathway leads to several human malignancies. A major category of E3 Ub ligases, the SCF (Skp-Cullin-F-box) complex, is composed of four principal components: Skp1, Cul1/Cdc53, Roc1/Rbx1/Hrt1, and an F-box protein (FBP). FBPs are the substrate recognition components of SCF complexes and function as adaptors that bring substrates into physical proximity with the rest of the SCF. Besides acting as a component of SCF complexes, FBPs are involved in DNA replication, transcription, cell differentiation and cell death. This review will highlight the recent literature on three well characterized FBPs SKP2, Fbw7, and beta-TRCP. In particular, we will focus on the involvement of these deregulated FBPs in the progression and development of various human cancers. We will also highlight some novel substrates recently identified for these FBPs.
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http://dx.doi.org/10.1016/j.semcancer.2015.09.008DOI Listing
February 2016

Adaptation of a commonly used, chemically defined medium for human embryonic stem cells to stable isotope labeling with amino acids in cell culture.

J Proteome Res 2013 Jul 25;12(7):3233-45. Epub 2013 Jun 25.

Weill Cornell Medical College in Qatar, Doha, Qatar.

Metabolic labeling with stable isotopes is a prominent technique for comparative quantitative proteomics, and stable isotope labeling with amino acids in cell culture (SILAC) is the most commonly used approach. SILAC is, however, traditionally limited to simple tissue culture regimens and only rarely employed in the context of complex culturing conditions as those required for human embryonic stem cells (hESCs). Classic hESC culture is based on the use of mouse embryonic fibroblasts (MEFs) as a feeder layer, and as a result, possible xenogeneic contamination, contribution of unlabeled amino acids by the feeders, interlaboratory variability of MEF preparation, and the overall complexity of the culture system are all of concern in conjunction with SILAC. We demonstrate a feeder-free SILAC culture system based on a customized version of a commonly used, chemically defined hESC medium developed by Ludwig et al. and commercially available as mTeSR1 [mTeSR1 is a trade mark of WiCell (Madison, WI) licensed to STEMCELL Technologies (Vancouver, Canada)]. This medium, together with adjustments to the culturing protocol, facilitates reproducible labeling that is easily scalable to the protein amounts required by proteomic work flows. It greatly enhances the usability of quantitative proteomics as a tool for the study of mechanisms underlying hESCs differentiation and self-renewal. Associated data have been deposited to the ProteomeXchange with the identifier PXD000151.
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http://dx.doi.org/10.1021/pr400099jDOI Listing
July 2013