Spermidine/Spermine N1-Acetyltransferase 1 (SAT1)—A Potential Gene Target for Selective Sensitization of Glioblastoma Cells Using an Ionizable Lipid Nanoparticle to Deliver siRNA
(This article belongs to the Special Issue Novel Techniques and Technology for Treatment of Brain Tumors)
Published on October 22, 2022
Abstract: Spermidine/spermine N1-acetyltransferase 1 (SAT1) responsible for cell polyamine catabolism is overexpressed in glioblastoma multiforme (GB). Its role in tumor survival and promoting resistance towards radiation therapy has made it an interesting target for therapy. In this study, we prepared a lipid nanoparticle-based siRNA delivery system (LNP-siSAT1) to selectively knockdown (KD) SAT1 enzyme in a human glioblastoma cell line. The LNP-siSAT1 containing ionizable DODAP lipid was prepared following a microfluidics mixing method and the resulting nanoparticles had a hydrodynamic size of around 80 nm and a neutral surface charge. The LNP-siSAT1 effectively knocked down the SAT1 expression in U251, LN229, and 42MGBA GB cells, and other brain-relevant endothelial (hCMEC/D3), astrocyte (HA) and macrophage (ANA-1) cells at the mRNA and protein levels. SAT1 KD in U251 cells resulted in a 40% loss in cell viability. Furthermore, SAT1 KD in U251, LN229 and 42MGBA cells sensitized them towards radiation and chemotherapy treatments. In contrast, despite similar SAT1 KD in other brain-relevant cells no significant effect on cytotoxic response, either alone or in combination, was observed. A major roadblock for brain therapeutics is their ability to cross the highly restrictive blood–brain barrier (BBB) presented by the brain microcapillary endothelial cells. Here, we used the BBB circumventing approach to enhance the delivery of LNP-siSAT1 across a BBB cell culture model. A cadherin binding peptide (ADTC5) was used to transiently open the BBB tight junctions to promote paracellular diffusion of LNP-siSAT1. These results suggest LNP-siSAT1 may provide a safe and effective method for reducing SAT1 and sensitizing GB cells to radiation and chemotherapeutic agents.
Metabolomic Profiling for the Early Detection of Lung Cancer
Journal: Annals of Oncology
Background: Currently, the five-year survival rate of lung cancer patients is very low, largely attributed to newly diagnosed patients presenting with locally advanced or metastatic disease. The lung cancer five-year survival rate (18.6%) is lower than many other leading cancer sites, such as colorectal (64.5%), breast (89.6%) and prostate (98.2%). The five-year survival rate for lung cancer is 56% for cases detected when the disease is still localized (within the lungs). However, only 16% of lung cancer cases are diagnosed at an early stage. For distant tumors (spread to other organs) the five-year survival rate is only 5%. More than 50% of lung cancer cases die within one year of being diagnosed. Accordingly, early diagnosis is key to the successful treatment, management and care of lung cancer.
Versatility of Amantadine and Rimantadine for Detection of Cancer
Journal: Novel Approaches in Cancer Study;
Published on April 21, 2021
Our Approach: We have developed a simple test that evaluates SSAT- 1 activity by measuring acetylated products in the urine. On this basis, we believe that SSAT-1 activity can predict the presence of cancer and possibly disease progression.
A High-Performing Plasma Metabolite Panel for Early-Stage Lung Cancer Detection
Published on March 7, 2020
Abstract: The objective of this research is to use metabolomic techniques to discover and validate plasma metabolite biomarkers for the diagnosis of early-stage non-small cell lung cancer (NSCLC).The study included plasma samples from 156 patients with biopsy-confirmed NSCLC along with age and gender-matched plasma samples from 60 healthy controls. A fully quantitative targeted mass spectrometry (MS) analysis (targeting 138 metabolites) was performed on all samples. The sample set was split into a discovery set and validation set. Metabolite concentration data, clinical data, and smoking history were used to determine optimal sets of biomarkers and optimal regression models for identifying different stages of NSCLC using the discovery sets. The same biomarkers and regression models were used and assessed on the validation models. Univariate and multivariate statistical analysis identified β-hydroxybutyric acid, LysoPC 20:3, PC ae C40:6, citric acid, and fumaric acid as being significantly different between healthy controls and stage I/II NSCLC. Robust predictive models with areas under the curve (AUC) > 0.9 were developed and validated using these metabolites and other, easily measured clinical data for detecting different stages of NSCLC. This study successfully identified and validated a simple, high-performing, metabolite-based test for detecting early stage (I/II) NSCLC patients in plasma. While promising, further validation on larger and more diverse cohorts is still required.
Liquid Biopsy in Lung Cancer Screening: The Contribution of Metabolomics. Results of A Pilot Study
Published on July 29, 2019
Abstract: Background: Lung cancer is the most common cause of cancer-related deaths worldwide. Early diagnosis is crucial to increase the curability chance of the patients. Low dose CT screening can reduce lung cancer mortality, but it is associated with several limitations. Metabolomics is a promising technique for cancer diagnosis due to its ability to provide chemical phenotyping data. The intent of our study was to explore metabolomic effects and profiles of lung cancer patients to determine if metabolic perturbations in the SSAT-1/polyamine pathway can distinguish between healthy participants and lung cancer patients as a diagnostic and treatment monitoring tool. Patients and Methods: Plasma samples were collected as part of the SSAT1 Amantadine Cancer Study. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to identify and quantify metabolite concentrations in lung cancer patient and control samples. Standard statistical analyses were performed to determine whether metabolite concentrations could differentiate between healthy subjects and lung cancer patients, as well as risk prediction modeling applied to determine whether metabolic profiles could provide an indication of cancer progression in later stage patients. Results: A panel consisting of 14 metabolites, which included 6 metabolites in the polyamine pathway, was identified that correctly discriminated lung cancer patients from controls with an area under the curve of 0.97 (95% CI: 0.875-1.0). Conclusion: When used in conjunction with the SSAT-1/polyamine pathway, these metabolites may provide the specificity required for diagnosing lung cancer from other cancer types and could be used as a diagnostic and treatment monitoring tool.
Predictive value and clinical significance of increased SSAT-1 activity in healthy adults
Journal: Future Science OA;
Published on July 1, 2019
Abstract: This study describes the potential of a novel noninvasive urine test for screening of cancer using a safe and approved drug, amantadine. We have previously measured high urinary concentration of the acetylated form of amantadine in patients diagnosed with cancer. However, higher than expected acetylated amantadine concentration was also measured in some of the healthy adult volunteers. Subsequent clinical assessments revealed that these healthy individuals could have early clinical signs of cancer. This is a simple test, which may serve as a useful tool for routine screening in populations considered at high risk for cancer.
Follow-up evaluation of outliers with elevated spermine-spermidine acetyltransferase-1 activity
The 2019 American Society of Clinical Oncology (ASCO) Annual Meeting
Released on May 15, 2019
Use of amantadine as substrate for SSAT-1 activity as a reliable clinical diagnostic assay for breast and lung cancer
Journal: Future Science OA;
Published on December 11, 2018
Abstract: This study describes a novel noninvasive urine test for detecting and screening of breast and lung cancer using a safe and approved drug called amantadine. Higher concentration of the acetylated form of amantadine in the urine are detectable in the urine of both breast and lung cancer patients as compared with healthy adult volunteers. This test is simple and may serve as a useful tool for determining the presence of breast and lung cancer.
Spermidine/spermine N1-acetyltransferase-1 as a diagnostic biomarker in human cancer
Journal: Future Science OA;
Published on September 10, 2018
Abstract: In response to cancer, cells tend to overproduce specific enzymes as a self-defense mechanism. By using a safe and reliable method to capture and measure the excess enzyme spermidine/spermine N1-acetyltransferase-1, the presence of cancer can be established. This study describes a novel approach of detecting and screening cancer noninvasively in the urine of cancer patients using a safe and approved drug called amantadine that acts as a smart-tracking agent. Higher levels of the acetylated form of amantadine are detectable in the urine of cancer patients, which may serve as a detection tool. In addition, increases in the amount of spermidine/spermine N1-acetyltransferase-1 in tumor tissue may provide a tool for determining the presence of cancer during pathology assessment.