In situ allicin generation using targeted alliinase delivery for inhibition of MIA PaCa-2 cells via epigenetic changes, oxidative stress and cyclin-dependent kinase inhibitor (CDKI) expression

Abstract Allicin, an extremely active constituent of freshly crushed garlic, is produced upon reaction of substrate alliin with the enzyme alliinase (EC 4.4.1.4). Allicin has been shown to be toxic to several mammalian cells in vitro in a dose-dependent manner. In the present study this cytotoxicity was taken to advantage to develop a novel approach to cancer treatment, based on site directed generation of allicin. Alliinase was chemically conjugated to a monoclonal antibody (mAb) which was directed against a specific pancreatic cancer marker, CA19-9. After the CA19-9 mAb-alliinase conjugate was bound to targeted pancreatic cancer cells (MIA PaCa-2 cells), on addition of alliin, the cancer cell-localized alliinase produced allicin, which effectively induced apoptosis in MIA PaCa-2 cells. Specificity of anticancer activity of in situ generated allicin was demonstrated using a novel in vitro system—integrated discrete multiple organ co-culture technique. Further, allicin-induced caspase-3 expression, DNA fragmentation, cell cycle arrest, p21Waf1/Cip1 cyclin-dependent kinase inhibitor expression, ROS generation, GSH depletion, and led to various epigenetic modifications which resulted in stimulation of apoptosis. This approach offers a new therapeutic strategy, wherein alliin and alliinase-bound antibody work together to produce allicin at targeted locations which would reverse gene silencing and suppress cancer cell growth, suggesting that combination of these ta...
Source: Apoptosis - Category: Molecular Biology Source Type: research

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l Sumit Sahni Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid tumors in the world. Currently, there are no approved targeted therapies for PDAC. Mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are known to be a major driver of PDAC progression, but it was considered an undruggable target until recently. Moreover, PDAC also suffers from drug delivery issues due to the highly fibrotic tumor microenvironment. In this perspective, we provide an overview of recent developments in targeting mutant KRAS and strategies to overcome drug delivery issues (e.g., nanoparticle delivery). Over...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Perspective Source Type: research
Publication date: Available online 21 May 2020Source: Cancer CellAuthor(s): Zhentian Wang, Simone Hausmann, Ruitu Lyu, Tie-Mei Li, Shane M. Lofgren, Natasha M. Flores, Mary E. Fuentes, Marcello Caporicci, Ze Yang, Matthew Joseph Meiners, Marcus Adrian Cheek, Sarah Ann Howard, Lichao Zhang, Joshua Eric Elias, Michael P. Kim, Anirban Maitra, Huamin Wang, Michael Cory Bassik, Michael-Christopher Keogh, Julien Sage
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research
AbstractSmac/Diablo is a pro-apoptotic protein via interaction with inhibitors of apoptosis proteins (IAPs) to relieve their inhibition of caspases. Smac mimetic compounds (also known as antagonists of IAPs) mimic the function of Smac/Diablo and sensitize cancer cells to TNF-induced apoptosis. However, the majority of cancer cells are resistant to Smac mimetic alone. Doxorubicin is a widely used chemotherapeutic drug and causes adverse effect of cardiotoxicity in many patients. Therefore, it is important to find strategies of combined chemotherapy to increase chemosensitivity and reduce the adverse effects. Here, we report...
Source: Apoptosis - Category: Molecular Biology Source Type: research
In this study, a 3D tumor model was used to investigate the correlation between temperature and the effectiveness of standard clinical IRE and high frequency (H-FIRE) protocols. It was found for human glioblastoma cells that in the range of 2 to 37 °C the H-FIRE lethal electric field threshold value, which describes the minimum electric field to cause cell death, is highly dependent on temperature. Increasing the initial temperature from 2 to 37 °C resulted in a significant decrease in lethal electric field threshold from 1168 to 507 V/cm and a 139% increase in ablation size for H-FIRE burst treatmen...
Source: Annals of Biomedical Engineering - Category: Biomedical Engineering Authors: Tags: Ann Biomed Eng Source Type: research
Weight loss and anorexia are common symptoms in cancer patients that occur prior to initiation of cancer therapy. Inflammation in the brain is a driver of these symptoms, yet cellular sources of neuroinflammation during malignancy are unknown. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), we observed early and robust myeloid cell infiltration into the brain. Infiltrating immune cells were predominately neutrophils, which accumulated at a unique central nervous system entry portal called the velum interpositum, where they expressed CCR2. Pharmacologic CCR2 blockade and genetic deletion ofCcr2 both resulted in...
Source: eLife - Category: Biomedical Science Tags: Immunology and Inflammation Neuroscience Source Type: research
Patients who undergo radiation treatment with lutetium-177 DOTATATE for neuroendocrine...Read more on AuntMinnie.comRelated Reading: SNMMI: PSMA-PET helps guide prostate cancer therapy Health Canada OKs AAA's Lutathera agent Novel PET tracer shows promise for neuroendocrine tumors Theranostic approach could aid pancreatic cancer patients SNMMI: PET prostate image lands Image of the Year honors
Source: AuntMinnie.com Headlines - Category: Radiology Source Type: news
Among inflammatory mediators, a growing body of evidence emphasizes the contribution of the interleukin 17 (IL-17) cytokine family in malignant diseases. Besides IL-17A, the prototypic member of the IL-17 family, several experimental findings strongly support the role of the IL-17B/IL-17 receptor B (IL-17RB) pathway in tumorigenesis and resistance to anticancer therapies. In mouse models, IL-17B signaling through IL-17RB directly promotes cancer cell survival, proliferation, and migration, and induces resistance to conventional chemotherapeutic agents. Importantly, recent work by our and other laboratories showed that IL-1...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
ACS NanoDOI: 10.1021/acsnano.0c02197
Source: ACS Nano - Category: Nanotechnology Authors: Source Type: research
Source: Cancer Management and Research - Category: Cancer & Oncology Tags: Cancer Management and Research Source Type: research
Abstract Pancreatic cancer tends to be highly resistant to current therapy and remains one of the great challenges in biomedicine with very low 5-year survival rates. Here, we report that zalcitabine, an antiviral drug for human immunodeficiency virus infection, can suppress the growth of primary and immortalized human pancreatic cancer cells through the induction of ferroptosis, an iron-dependent form of regulated cell death. Mechanically, this effect relies on zalcitabine-induced mitochondrial DNA stress, which activates the STING1/TMEM173-mediated DNA sensing pathway, leading to macroautophagy/autophagy-depende...
Source: Autophagy - Category: Cytology Authors: Tags: Autophagy Source Type: research
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