Mechanism of Tumor Inhibitory Potential of Abrus Agglutinin in Oral Squamous Cell Carcinoma

Abrus agglutinin (AGG), isolated from Abrus precatorious, a medicinal plant induces antitumor activity in oral squamous cell carcinoma in vitro and in vivo. P53 being mutated in oral cancer, the focus of our study represented to p73, the sibling of p53 and its regulation in DNA damage mediated programed cell death in AGG treated FaDu cells. AGG effectively inhibited the cell viability of different oral squamous cell carcinoma with IC50 value 1-10 μg/ml. AGG selectively inhibited growth and, caused cell cycle arrest and mitochondrial apoptosis through reactive oxygen species (ROS) mediated ATM-p73 dependent pathway in FaDu cells. AGG-induced ROS accumulation was identified as chief mechanism of its effect on apoptosis, DNA damage and DNA-damage response which significantly reversed by ROS scavenger N-acetylcysteine (NAC). Moreover, AGG found to interact with mitochondrial manganese-dependent superoxide dismutase which might inhibit its activity and upshot ROS in FaDu cells. Further, AGG was found to inhibit epithelial-mesenchymal transition (EMT) in p73 dependent manner in epithelial growth factor (EGF) stimulated FaDu cells. Importantly, AGG induced Snail degradation through ubiqutination and Snail overexpression rescued suppression of EMT phenotypes. Confocal imaging and immunoprecipitation data elaborated about the Snail interaction with p73 in EGF stimulated FaDu cells and AGG found to inhibit the interaction of Snail and p73 through Snail degradation. In addition, our work demonstrated the efficiency of AGG on cancer stem-like cells which has high tumorigenic capacity in tumor population. We showed that AGG has a potential role as an integrative therapeutic approach for combating oral cancer by eliminating self-renewal capacity accompanied with apoptosis in orospheres of FaDu cells. Importantly, AGG induced ROS accumulation in orospheres and pretreatment of NAC inhibited AGG mediated caspase-3 activity and β-catenin expression. The present study provided deep insight into the mechanism of AGG-mediated tumor inhibition and elucidated the further scope for the development of cancer therapeutics against oral squamous cell carcinoma

Trust Enhanced Role Based Access Control Using Genetic Algorithm

Improvements in technological innovations have become a boon for business organizations, firms, institutions, etc. System applications are being developed for organizations whether small-scale or large-scale. Taking into consideration the hierarchical nature of large organizations, security is an important factor which needs to be taken into account. For any healthcare organization, maintaining the confidentiality and integrity of the patients’ records is of utmost importance while ensuring that they are only available to the authorized personnel. The paper discusses the technique of Role-Based Access Control (RBAC) and its different aspects. The paper also suggests a trust enhanced model of RBAC implemented with selection and mutation only ‘Genetic Algorithm’. A practical scenario involving healthcare organization has also been considered. A model has been developed to consider the policies of different health departments and how it affects the permissions of a particular role. The purpose of the algorithm is to allocate tasks for every employee in an automated manner and ensures that they are not over-burdened with the work assigned. In addition, the trust records of the employees ensure that malicious users do not gain access to confidential patient data

India\u27s Take on Legal Remedy of Passing Off: A Celebrity\u27s Perspective

The development of mass media led to the development of intrigue and curiosity around celebrities and their persona, and the profits hidden therein. Harping upon this intrigue, stakeholders realised the brand power behind celebrity personalities. However, problems arose when there was an increase in the unauthorised exploitation of celebrity personalities. While on the legal front, several remedies are resorted to, William Prosser narrowed down these into four, i.e., intrusion into one’s private space, disclosure of one’s personal and private facts, disclosure of incorrect facts that puts one under a false light and misappropriating one’s personality for commercial gain. Hinged on the brand value of a celebrity’s personality, the right to publicity emphasises the right of a celebrity to claim control over the commercial value of their identity. Remedy against the unauthorised commercial exploitation of a celebrity’s identity is commonly found in the tort of passing off. The article assesses the contours of the remedy of passing off as availed by celebrities and implemented by the Indian Courts. The article also draws a comparison with the approaches employed by American and English law in their understanding of celebrity personality, contrasting the same with the Indian approach

<i>Cissus quadrangularis</i> (Hadjod) Inhibits RANKL-Induced Osteoclastogenesis and Augments Bone Health in an Estrogen-Deficient Preclinical Model of Osteoporosis Via Modulating the Host Osteoimmune System

Osteoporosis is a systemic skeletal disease characterised by low bone mineral density (BMD), degeneration of bone micro-architecture, and impaired bone strength. Cissus quadrangularis (CQ), popularly known as Hadjod (bone setter) in Hindi, is a traditional medicinal herb exhibiting osteoprotective potential in various bone diseases, especially osteoporosis and fractures. However, the cellular mechanisms underpinning its direct effect on bone health through altering the host immune system have never been elucidated. In the present study, we interrogated the osteoprotective and immunoporotic (the osteoprotective potential of CQ via modulating the host immune system) potential of CQ in preventing inflammatory bone loss under oestrogen-deficient conditions. The current study outlines the CQ’s osteoprotective potential under both ex vivo and in vivo (ovariectomized) conditions. Our ex vivo data demonstrated that, in a dose-dependent manner CQ, suppresses the RANKL-induced osteoclastogenesis (p p p p p p p p < 0.05) (TNF-α, IL-6, and IL-17). In conclusion, our data for the first time delineates the novel cellular and immunological mechanism of the osteoprotective potential of CQ under postmenopausal osteoporotic conditions

Randomized phase II study of the Bruton tyrosine kinase inhibitor acalabrutinib, alone or with pembrolizumab in patients with advanced pancreatic cancer

BackgroundThe immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade.MethodsThis was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed.ResultsA total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1–6). Grade 3–4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway.ConclusionsThe combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue.Trial registration numberNCT02362048

Abrus Agglutinin, a type II ribosome inactivating protein inhibits Akt/PH domain to induce endoplasmic reticulum stress mediated autophagy-dependent cell death

Abrus agglutinin (AGG), a type II ribosome-inactivating protein has been found to induce mitochondrial apoptosis. In the present study, we documented that AGG-mediated Akt dephosphorylation led to ER stress resulting the induction of autophagy-dependent cell death through the canonical pathway in cervical cancer cells. Inhibition of autophagic death with 3-methyladenine (3-MA) and siRNA of Beclin-1 and ATG5 increased AGG-induced apoptosis. Further, inhibiting apoptosis by Z-DEVD-FMK and N-acetyl cysteine (NAC) increased autophagic cell death after AGG treatment, suggesting that AGG simultaneously induced autophagic and apoptotic death in HeLa cells. Additionally, it observed that AGG-induced autophagic cell death in Bax knock down (Bax-KD) and 5-FU resistant HeLa cells, confirming as an alternate cell killing pathway to apoptosis. At the molecular level, AGG-induced ER stress in PERK dependent pathway and inhibition of ER stress by salubrinal, eIF2 phosphatase inhibitor as well as siPERK reduced autophagic death in the presence of AGG. Further, our in silico and colocalization study showed that AGG interacted with pleckstrin homology (PH) domain of Akt to suppress its phosphorylation and consequent downstream mTOR dephosphorylation in HeLa cells. We showed that Akt overexpression could not augment GRP78 expression and reduced autophagic cell death by AGG as compared to pcDNA control, indicating Akt modulation was the upstream signal during AGG's ER stress mediated autophagic cell death. In conclusion, we established that AGG stimulated cell death by autophagy might be used as an alternative tumor suppressor mechanism in human cervical cancer. (c) 2016 Wiley Periodicals, Inc

Autophagy: cancer’s friend or foe?

The functional relevance of autophagy in tumor formation and progression remains controversial. Autophagy can promote tumor suppression during cancer initiation and protect tumors during progression. Autophagy-associated cell death may act as a tumor suppressor, with several autophagy-related genes deleted in cancers. Loss of autophagy induces genomic instability and necrosis with inflammation in mouse tumor models. Conversely, autophagy enhances survival of tumor cells subjected to metabolic stress and may promote metastasis by enhancing tumor cell survival under environmental stress. Unraveling the complex molecular regulation and multiple diverse roles of autophagy is pivotal in guiding development of rational and novel cancer therapies

Abrus agglutinin is a potent anti-proliferative and anti-angiogenic agent in human breast cancer

Abrus agglutinin (AGG), a plant lectin isolated from the seeds of Abrus precatorius, has documented antitumor and immunostimulatory effects in murine models. To examine possible antitumor activity against breast cancer, we established human breast tumor xenografts in athymic nude mice and intraperitoneally administered AGG. AGG inhibited tumor growth and angiogenesis as confirmed by monitoring the expression of Ki‐67 and CD‐31, respectively. In addition, TUNEL positive cells increased in breast tumors treated with AGG suggesting that AGG mediates anti‐tumorigenic activity through induction of apoptosis and inhibition of angiogenesis. On a molecular level, AGG caused extrinsic apoptosis through ROS generation that was AKT‐dependent in breast cancer cells, without affecting primary mammary epithelial cells, suggesting potential cancer specificity of this natural compound. In addition, using HUVECs, AGG inhibited expression of the pro‐angiogenic factor IGFBP‐2 in an AKT‐dependent manner, reducing angiogenic phenotypes both in vitro and in vivo. Overall, the present results establish that AGG promotes both apoptosis and anti‐angiogenic activities in human breast tumor cells, which might be exploited for treatment of breast and other cancers