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15. In Vivo Evaluation of the Combined Anticancer Effects of Cisplatin and SAHA in Nonsmall Cell Lung Carcinoma Using [18F]FAHA and [18F]FDG PET/CT Imaging

Author

Skye Hsin-Hsien Yeh, Ming Hsien Lin, I. I. Leo Garcia Flores, Uday Mukhopadhyay, Danial Young, Kazuma Ogawa, Jeong-Hwan Jeong, William Tong, Juri G. Gelovani, and Nobuyoshi Fukumitsu

Subjects
Biology (General), QH301-705.5, Medical technology, R855-855.5
Abstract

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy.

Published
2021
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21. Radioactivity Reduction of 2-Deoxy-2-[18F] Fluoro-D-Glucose by Milk and Ursodeoxycholic Acid in Preclinical Study

Author

Jeong, Hwan-Jeong, Bagalkot, Tarique Rajasaheb, Kim, Hyeon Soo, Han, Yeon-Hee, Kim, Minjoo, Lim, Seok Tae, and Sohn, Myung-Hee

Abstract

Purpose: 2-Deoxy-2-[18F] fluoro-d-glucose positron emission tomography (18F-FDG-PET) is a less-invasive and widely used diagnostic tool for detection of malignant tumors. However, prolonged retention of 18F-FDG in the body increases radiation exposure. This study evaluated the effect of oral administration of milk and ursodeoxycholic acid (UDCA) in terms of reducing radiation exposure by 18F-FDG. Methods: 18F-FDG radioactivity was measured using a digital γ counter in the whole body and in various organs of rats after oral administration of milk and milk plus UDCA (milk + UDCA). Western blotting was performed to measure the expression levels of G6Pase, HK 2, CREB, FoxO1, and PGC-1α in the brain, liver, small intestine, and large intestine to assess the mechanism underlying the reduction in radiation exposure from 18F-FDG by oral administration of milk and UDCA. Results: We found a significant reduction in 18F-FDG radioactivity in the whole body and in the brain, liver, and small and large intestines. Expression of G6Pase was significantly increased in the above-mentioned organs in the milk and milk + UDCA groups. Expression of HK 2 was significantly decreased in the brain and small intestine in the milk and milk + UDCA groups. CREB, FoxO1, and PGC-1α expression levels in the brain, liver, and small intestine were increased in the milk and milk + UDCA groups. However, expression of PGC-1α in the large intestine in the milk and milk + UDCA groups was significantly decreased compared with that in the control group. Conclusion: The present study demonstrated that administration of milk and UDCA increased G6Pase expression levels and 18F-FDG release from the tissue. These results suggest milk and UDCA could be used to reduce radiation exposure from 18F-FDG after image acquisition. The mechanisms underpinning this phenomenon should be explored in a human study.

Published
2024
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49. In Vivo Evaluation of the Combined Anticancer Effects of Cisplatin and SAHA in Nonsmall Cell Lung Carcinoma Using [18F]FAHA and [18F]FDG PET/CT Imaging

Author

Juri G. Gelovani, Jeong-Hwan Jeong, Ming Hsien Lin, Danial Young, Uday Mukhopadhyay, Skye Hsin Hsien Yeh, I. I. Leo Garcia Flores, William P. Tong, Kazuma Ogawa, and Nobuyoshi Fukumitsu

Subjects
Article Subject, medicine.drug_class, QH301-705.5, medicine.medical_treatment, Biomedical Engineering, medicine.disease_cause, 03 medical and health sciences, 0302 clinical medicine, In vivo, medicine, Medical technology, Radiology, Nuclear Medicine and imaging, Biology (General), R855-855.5, 030304 developmental biology, Cisplatin, 0303 health sciences, Chemotherapy, business.industry, Histone deacetylase inhibitor, Cancer, Condensed Matter Physics, medicine.disease, EGFR Exon 19 Deletion Mutation, 030220 oncology & carcinogenesis, Cancer research, Molecular Medicine, Histone deacetylase, KRAS, business, Biotechnology, medicine.drug, Research Article
Abstract

Combining standard drugs with low doses of histone deacetylase inhibitors (HDACIs) is a promising strategy to increase the efficacy of chemotherapy. The ability of well-tolerated doses of HDACIs that act as chemosensitizers for platinum-based chemotherapeutics has recently been proven in many types and stages of cancer in vitro and in vivo. Detection of changes in HDAC activity/expression may provide important prognostic and predictive information and influence treatment decision-making. Use of [18F] FAHA, a HDAC IIa-specific radionuclide, for molecular imaging may enable longitudinal, noninvasive assessment of HDAC activity/expression in metastatic cancer. We evaluated the synergistic anticancer effects of cisplatin and the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in xenograft models of nonsmall cell lung cancer (NSCLC) using [18F] FAHA and [18F] FDG PET/CT imaging. Cisplatin alone significantly increased [18F] FAHA accumulation and reduced [18F] FDG accumulation in H441 and PC14 xenografts; coadministration of cisplatin and SAHA resulted in the opposite effects. Immunochemical staining for acetyl-histone H3 confirmed the PET/CT imaging findings. Moreover, SAHA had a more significant effect on the acetylome in PC14 (EGFR exon 19 deletion mutation) xenografts than H441 (wild-type EGFR and KRAS codon 12 mutant) xenografts. In conclusion, [18F] FAHA enables quantitative visualization of HDAC activity/expression in vivo, thus, may represent a clinically useful, noninvasive tool for the management of patients who may benefit from synergistic anticancer therapy.

Published
2021

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