Eppley Institute for Research in Cancer and Allied Diseases

About: Eppley Institute for Research in Cancer and Allied Diseases is a based out in . It is known for research contribution in the topics: Pancreatic cancer & Cancer. The organization has 965 authors who have published 1396 publications receiving 58994 citations.

Structure–Activity Relationship Studies with Tetrahydroquinoline Analogs as EPAC Inhibitors

Abstract: EPAC proteins are therapeutic targets for the potential treatment of cardiac hypertrophy and cancer metastasis. Several laboratories use a tetrahydroquinoline analog, CE3F4, to dissect the role of EPAC1 in various disease states. Here, we report SAR studies with tetrahydroquinoline analogs that explore various functional groups. The most potent EPAC inhibitor 12a exists as a mixture of inseparable E (major) and Z (minor) rotamers. The rotation about the N-formyl group indeed impacts the activity against EPAC.

Aging of tissue-resident adult stem/progenitor cells and their pathological consequences.

Abstract: The fascinating discovery of tissue-resident adult stem/progenitor cells in recent years led to an explosion of interest in the development of novel stem cell-based therapies for improving the regenerative capacity of these endogenous immature cells or transplanted cells for the repair of damaged and diseased tissues. In counterbalance, a growing body of evidence has revealed that the changes in phenotypic and functional properties of human adult stem/progenitor cells may occur during chronological aging and have severe pathological consequences. Especially, intense oxidative and metabolic stress and chronic inflammation, enhanced telomere attrition and defects in DNA repair mechanisms may lead to severe DNA damages and genomic instability in adult stem/progenitor cells with advancing age that may in turn trigger their replicative senescence and/or programmed cell death. Moreover, the changes in the intrinsic and extrinsic factors involved in the stringent control of self-renewal and multilineage differentiation capacities of these regenerative cells, including deregulated signals from the aged niche, may also contribute to their dysfunctions or loss during chronological aging. This age-associated decline in the regenerative capacity and number of functional adult stem/progenitor cells may increase the risk to develop certain diseases. At opposed end, the telomerase reactivation and accumulation of genetic alterations leading to a down-regulation of numerous tumor suppressor genes concomitant with the enhanced expression of diverse oncogenic products may result in their malignant transformation into cancer-initiating cells. Therefore, the rescue or replacement of aged and dysfunctional endogenous adult stem/progenitor cells or molecular targeting of their malignant counterpart, cancer stem/progenitor cells may constitute potential anti-aging and cancer therapies. These therapeutic strategies could be used for treating diverse devastating premature aging and age-related disorders including hematopoietic and immune disorders, heart failure and cardiovascular diseases, neurodegenerative, muscular and gastrointestinal diseases, atherosclerosis and aggressive and lethal cancers.

Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β.

Abstract: Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.

Monoclonal Antibodies Recognizing the Non-Tandem Repeat Regions of the Human Mucin MUC4 in Pancreatic Cancer

Abstract: The MUC4 mucin is a high molecular weight, membrane-bound, and highly glycosylated protein It is a multi-domain protein that is putatively cleaved into a large mucin-like subunit (MUC4α) and a C-terminal growth-factor like subunit (MUC4β) MUC4 plays critical roles in physiological and pathological conditions and is aberrantly overexpressed in several cancers, including those of the pancreas, cervix, breast and lung It is also a potential biomarker for the diagnosis, prognosis and progression of several malignancies Further, MUC4 plays diverse functional roles in cancer initiation and progression as evident from its involvement in oncogenic transformation, proliferation, inhibition of apoptosis, motility and invasion, and resistance to chemotherapy in human cancer cells We have previously generated a monoclonal antibody 8G7, which is directed against the TR region of MUC4, and has been extensively used to study the expression of MUC4 in several malignancies Here, we describe the generation of anti-MUC4 antibodies directed against the non-TR regions of MUC4 Recombinant glutathione-S-transferase (GST)-fused MUC4α fragments, both upstream (MUC4α-N-Ter) and downstream (MUC4α-C-Ter) of the TR domain, were used as immunogens to immunize BALB/c mice Following cell fusion, hybridomas were screened using the aforementioned recombinant proteins ad lysates from human pancreatic cell lines Three anti MUC4α-N-Ter and one anti-MUC4α-C-Ter antibodies were characterized by several inmmunoassays including enzyme-linked immunosorbent assay (ELISA), immunoblotting, immunofluorescene, flow cytometry and immunoprecipitation using MUC4 expressing human pancreatic cancer cell lines The antibodies also reacted with the MUC4 in human pancreatic tumor sections in immunohistochemical analysis The new domain-specific anti-MUC4 antibodies will serve as important reagents to study the structure-function relationship of MUC4 domains and for the development of MUC4-based diagnostics and therapeutics