V. Vigneshwaran

BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation

Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl2-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.

A tumoural angiogenic gateway blocker, Benzophenone-1B represses the HIF-1α nuclear translocation and its target gene activation against neoplastic progression

Graphical abstract Figure. No Caption available. ABSTRACT Hypoxia is an important module in all solid tumours to promote angiogenesis, invasion and metastasis. Stabilization and subsequent nuclear localization of HIF‐1&agr; subunits result in the activation of tumour promoting target genes such as VEGF, MMPs, Flt‐1, Ang‐1 etc. which plays a pivotal role in adaptation of tumour cells to hypoxia. Increased HIF‐&agr; and its nuclear translocation have been correlated with pronounced angiogenesis, aggressive tumour growth and poor patient prognosis leading to current interest in HIF‐1&agr; as an anticancer drug target. Benzophenone‐1B ([4‐(1H‐benzimidazol‐2‐ylmethoxy)‐3,5‐dimethylphenyl]‐(4‐methoxyphenyl) methanone, or BP‐1B) is a new antineoplastic agent with potential angiopreventive effects. Current investigation reports the cellular biochemical modulation underlying BP‐1B cytotoxic/antiangiogenic effects. Experimental evidences postulate that BP‐1B exhibits the tumour specific cytotoxic actions against various cancer types with prolonged action. Moreover BP‐1B efficiently counteracts endothelial cell capillary formation in in‐vitro, in‐vivo non‐tumour and tumour angiogenic systems. Molecular signaling studies reveal that BP‐1B arrests nuclear translocation of HIF‐1&agr; devoid of p42/44 pathway under CoCl2 induced hypoxic conditions in various cancer cells thereby leading to abrogated HIF‐1&agr; dependent activation of VEGF‐A, Flt‐1, MMP‐2, MMP ‐9 and Ang‐1 angiogenic factors resulting in retarded cell migration and invasions. The in‐vitro results were reproducible in the reliable in‐vivo solid tumour model. Taken together, we conclude that BP‐1B impairs angiogenesis by blocking nuclear localization of HIF‐1&agr; which can be translated into a potent HIF‐1&agr; inhibitor.

The latex sap of the ‘Old World Plant’ Lagenaria siceraria with potent lectin activity mitigates neoplastic malignancy targeting neovasculature and cell death

Lifestyle and dietary modifications have contributed much to somatic genetic alteration which has concomitantly led to increase in malignant diseases. Henceforth, plant based and dietary interventions to mitigate and impede oncogenic transformation are in great demand. We investigated the latex sap (LSL) of the dietary Lagenaria siceraria vegetable, the first domesticated plant species with the potent lectin activity for its functional role against the tumor progression and its mechanism. LSL has markedly stimulated proliferation of lymphocytes and displayed strong cytotoxic activity against cancer both in-vitro and in-vivo. The tumor regression was paralleled with drastic reduction in tumoral neovasculature as evidenced from angiogenic parameters and abrogated related gene expressions. LSL has also triggered apoptotic signaling cascade in cancer cells through activation of caspase-3 mediated activation of endonuclease and inducing apoptotic cellular events. Collectively our study provides tangible evidences that latex sap from L. siceraria with immunopotentiating ability significantly regresses the tumor progression by targeting angiogenesis and inducing cell death.

Scutellarein antagonizes the tumorigenesis by modulating cytokine VEGF mediated neoangiogenesis and DFF-40 actuated nucleosomal degradation.

Neoplastic cells often reside in distinctive tumor hypoxia armed with a series of adaptive responses including oxidative stress, defective apoptotic machinery and neoangiogenesis, through that further confer cell survival improvement. Plants still acts as reservoir of natural chemicals to provide newer active pharmacophores. Scutellarein is flavones which has wide range of pharmacophoral effects. In our current research, scutellarein employed for targeting oxidative stress mediated tumor angiogenesis and apoptotic nuclear fragmentation. Experimental results revealed that scutellarein has antiproliferative index against multiple cancer cell lines and diminished the oxidative stress and tumor development of murine ascitic lymphoma & inflammatory hepatocellular carcinoma. Eventual consequences lead to reduced neovessel formation by abrogating angiogeneic factors cytokine-VEGF-A, Flt-1, HIF-1α, MMP-2 and MMP-9 and reversing of evading apoptosis by activating caspase-3 activated DNA fragmentation factor (DFF-40) mediated nucleosomal degradation. In summary, our experimental evidences suggest that scutellarein has strong potentiality to attenuate the tumor development by modulating sprouting neovasculature and DFF-40 mediated apoptosis.

Pharmacological Potential of Tetrahydrofurano/Pyrano Quinoline and Benzo[b]furoindolyl Derivatives in Acute Inflammation, Pain and Oxidative Stress

OBJECTIVEnInvestigation of the pharmacological potential of Tetrahydrofurano/pyrano quinoline and Benzo [b]furoindolyl derivatives in acute inflammation, pain and oxidative stress.nnnMETHODSnTetrahydrofurano/ pyrano quinoline and Benzo[b]furoindolyl were evaluated for anti-inflammatory activity by carrageenan-induced hind paw edema in rats. Analgesic activity in mice was assessed by both peripheral and central analgesic models. The free radical scavenging activity of the synthetic compound was analyzed by the in vivo antioxidant assays, by measuring the antioxidant enzymes such as Superoxide dismutase (SOD), Catalase and Peroxidase from the liver homogenate and the in vitro antioxidant activity was evaluated by DPPH photometric assay, Hydroxyl radical scavenging and Lipid Peroxidation assay.nnnRESULTSnThe compounds had substantially inhibited the inflammation induced by subcutaneous carrageenan injection. The same compounds had demonstrated remarkable central and peripheral analgesic activity with potent free radical scavenging activity as evident from both in vitro and in vivo antioxidant assays.nnnCONCLUSIONnTetrahydrofurano/pyrano quinoline and Benzo[b]furoindolyl derivatives exhibit varied pharmacological activities that include anti-inflammatory, analgesic and antioxidant activity.

Immunomodulatory glc/man-directed Dolichos lablab lectin (DLL) evokes anti-tumour response in vivo by counteracting angiogenic gene expressions: Immunomodulatory glc/man-directed DLL

Neovascularization and jeopardized immunity has been critically emphasized for the establishment of malignant progression. Lectins are the diverse class of carbohydrate interacting proteins, having great potential as immunopotentiating and anti‐cancer agents. The present investigation sought to demonstrate the anti‐proliferative activity of Dolichos lablab lectin (DLL) encompassing immunomodulatory attributes. DLL specific to glucose and mannose carbohydrate moieties has been purified to homogeneity from the common dietary legume D. lablab. Results elucidated that DLL agglutinated blood cells non‐specifically and displayed striking mitogenicity to human and murine lymphocytes in vitro with interleukin (IL)‐2 production. The DLL‐conditioned medium exerted cytotoxicity towards malignant cells and neoangiogenesis in vitro. Similarly, in‐vivo anti‐tumour investigation of DLL elucidated the regressed proliferation of ascitic and solid tumour cells, which was paralleled with blockade of tumour neovasculature. DLL‐treated mice showed an up‐regulated immunoregulatory cytokine IL‐2 in contrast to severely declined levels in control mice. Mechanistic validation revealed that DLL has abrogated the microvessel formation by weakening the proangiogenic signals, specifically nuclear factor kappa B (NF‐κB), hypoxia inducible factor 1α (HIF‐1 α), matrix metalloproteinase (MMP)‐2 and 9 and vascular endothelial growth factor (VEGF) in malignant cells leading to tumour regression. In summary, it is evident that the dietary lectin DLL potentially dampens the malignant establishment by mitigating neoangiogenesis and immune shutdown. For the first time, to our knowledge, this study illustrates the critical role of DLL as an immunostimulatory and anti‐angiogenic molecule in cancer therapeutics.

The tumor antagonistic steroidal alkaloid Solanidine prompts the intrinsic suicidal signal mediated DFF-40 nuclear import and nucleosomal disruption

Aim Deformity in the cellular homeostatic event associated with cell survival and apoptosis are committing factors for carcinogenesis. Interventions of these events by pharmacologically active agent gain predominance in cancer treatment. In current investigation Solanidine, a steroidal alkaloid was evaluated on tumorigenesis by targeting death signal using multiple tumor cells and model systems. Main methods: Anti‐proliferative effect was evaluated using cytotoxic studies. Prolonged cytotoxic effect of Solanidine was examined by colony formation assay. Exhibition of apoptotic hallmark induced by Solanidine was examined using FACS analysis, Annexin‐V staining, Acridine orange staining, TUNEL assay. Altered gene expression was evaluated using Immunoblot, Immunofluorescence and Immunohistochemistry technique. In‐vitro results were revalidated in EAC solid tumor and CAM xenograft model. Key findings: Solanidine exerts its potential effect in a target specific manner. The cytotoxic/anticlonogenic activity was due to induction of typical cellular apoptotic hallmarks and cell cycle blockage at S‐G2/M phase. The molecular events underlying this effect is through activation of intrinsic pathway via Bax, Bad and Cytochrome c activation by neutralizing Bcl‐2 expression, along with downregulated PI3K/Akt survival signal. As a consequence, downstream pro apoptogenic gene, active Caspase‐3 was over expressed by Solanidine to cleave its substrate PARP and promotes nuclear import of DFF‐40. Anti‐carcinogenic aptitude was further confirmed by murine solid tumors and in‐vivo CAM xenograft studies. Significance: Solanidine emerged as active molecule against tomorigenesis by activating nuclear import of DFF‐40 mediated nucleosomal disruption and cell demise. It can be developed as a potential apoptogenic small molecule for cancer therapy. Graphical abstract: Figure. No caption available.