Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma
<b>Background</b>: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of <sup>225</sup>Ac-labeled peptides in pancreatic cancer remains uninvestigated. <b>Methods</b>: In the cytotoxicity s...
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| author | Mitsuyoshi Yoshimoto Kohshin Washiyama Kazunobu Ohnuki Ayano Doi Miki Inokuchi Motohiro Kojima Brian W. Miller Yukie Yoshii Anri Inaki Hirofumi Fujii |
| author_facet | Mitsuyoshi Yoshimoto Kohshin Washiyama Kazunobu Ohnuki Ayano Doi Miki Inokuchi Motohiro Kojima Brian W. Miller Yukie Yoshii Anri Inaki Hirofumi Fujii |
| author_sort | Mitsuyoshi Yoshimoto |
| collection | DOAJ |
| description | <b>Background</b>: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of <sup>225</sup>Ac-labeled peptides in pancreatic cancer remains uninvestigated. <b>Methods</b>: In the cytotoxicity study, tumor cells were incubated with <sup>225</sup>Ac-DOTA-RGD<sub>2</sub>. DNA damage responses (γH2AX and 53BP1) were detected using flowcytometry or immunohistochemistry analysis. Biodistribution and therapeutic studies were carried out in BxPC-3-bearing mice. <b>Results</b>: <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> demonstrated potent cytotoxicity against cells expressing α<sub>v</sub>β<sub>3</sub> or α<sub>v</sub>β<sub>6</sub> integrins and induced G2/M arrest and γH2AX expression as a marker of double-stranded DNA breaks. <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> (20, 40, 65, or 90 kBq) showed favorable pharmacokinetics and remarkable tumor growth inhibition without severe side effects in the BxPC-3 mouse model. In vitro studies revealed that 5 and 10 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> swiftly induced G2/M arrest and elevated γH2AX expression. Furthermore, to clarify the mechanism of successful tumor growth inhibition for a long duration in vivo, we investigated whether short-term high radiation exposure enhances radiation sensitivity. Initially, a 4 h induction treatment with 5 and 10 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> enhanced both cytotoxicity and γH2AX expression with 0.5 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> compared to a treatment with only 0.5 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub>. Meanwhile, the γH2AX expression induced by 5 or 10 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> alone decreased over time. <b>Conclusions</b>: These findings highlight the potential of using <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> in the treatment of intractable pancreatic cancers, as its ability to induce G2/M cell cycle arrest enhances radiosensitization, resulting in notable growth inhibition. |
| format | Article |
| id | doaj-art-6f3a0cc3754c4d258a2f15e95186393f |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-6f3a0cc3754c4d258a2f15e95186393f2025-01-24T13:45:33ZengMDPI AGPharmaceutics1999-49232024-12-01171910.3390/pharmaceutics17010009Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal AdenocarcinomaMitsuyoshi Yoshimoto0Kohshin Washiyama1Kazunobu Ohnuki2Ayano Doi3Miki Inokuchi4Motohiro Kojima5Brian W. Miller6Yukie Yoshii7Anri Inaki8Hirofumi Fujii9Division of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, JapanAdvanced Clinical Research Center, Fukushima Global Medical Science Center, Fukushima Medical University, Fukushima 960-1295, JapanDivision of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, JapanDivision of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, JapanDivision of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, JapanDivision of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, JapanDepartment of Radiation Oncology, College of Medicine, University of Arizona, Tucson, AZ 85719, USANational Institute of Radiological Sciences, National Institutes for Quantum Science and Technology, Chiba 263-8555, JapanDivision of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, JapanDivision of Functional Imaging, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa 277-8577, Japan<b>Background</b>: Alpha radionuclide therapy has emerged as a promising novel strategy for cancer treatment; however, the therapeutic potential of <sup>225</sup>Ac-labeled peptides in pancreatic cancer remains uninvestigated. <b>Methods</b>: In the cytotoxicity study, tumor cells were incubated with <sup>225</sup>Ac-DOTA-RGD<sub>2</sub>. DNA damage responses (γH2AX and 53BP1) were detected using flowcytometry or immunohistochemistry analysis. Biodistribution and therapeutic studies were carried out in BxPC-3-bearing mice. <b>Results</b>: <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> demonstrated potent cytotoxicity against cells expressing α<sub>v</sub>β<sub>3</sub> or α<sub>v</sub>β<sub>6</sub> integrins and induced G2/M arrest and γH2AX expression as a marker of double-stranded DNA breaks. <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> (20, 40, 65, or 90 kBq) showed favorable pharmacokinetics and remarkable tumor growth inhibition without severe side effects in the BxPC-3 mouse model. In vitro studies revealed that 5 and 10 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> swiftly induced G2/M arrest and elevated γH2AX expression. Furthermore, to clarify the mechanism of successful tumor growth inhibition for a long duration in vivo, we investigated whether short-term high radiation exposure enhances radiation sensitivity. Initially, a 4 h induction treatment with 5 and 10 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> enhanced both cytotoxicity and γH2AX expression with 0.5 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> compared to a treatment with only 0.5 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub>. Meanwhile, the γH2AX expression induced by 5 or 10 kBq/mL of <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> alone decreased over time. <b>Conclusions</b>: These findings highlight the potential of using <sup>225</sup>Ac-DOTA-RGD<sub>2</sub> in the treatment of intractable pancreatic cancers, as its ability to induce G2/M cell cycle arrest enhances radiosensitization, resulting in notable growth inhibition.https://www.mdpi.com/1999-4923/17/1/9radionuclide therapy<sup>225</sup>AcRGD peptidepancreatic cancerintegrinDNA damage |
| spellingShingle | Mitsuyoshi Yoshimoto Kohshin Washiyama Kazunobu Ohnuki Ayano Doi Miki Inokuchi Motohiro Kojima Brian W. Miller Yukie Yoshii Anri Inaki Hirofumi Fujii Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma Pharmaceutics radionuclide therapy <sup>225</sup>Ac RGD peptide pancreatic cancer integrin DNA damage |
| title | Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma |
| title_full | Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma |
| title_fullStr | Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma |
| title_full_unstemmed | Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma |
| title_short | Long-Term Therapeutic Effects of <sup>225</sup>Ac-DOTA-E[c(RGDfK)]<sub>2</sub> Induced by Radiosensitization via G2/M Arrest in Pancreatic Ductal Adenocarcinoma |
| title_sort | long term therapeutic effects of sup 225 sup ac dota e c rgdfk sub 2 sub induced by radiosensitization via g2 m arrest in pancreatic ductal adenocarcinoma |
| topic | radionuclide therapy <sup>225</sup>Ac RGD peptide pancreatic cancer integrin DNA damage |
| url | https://www.mdpi.com/1999-4923/17/1/9 |
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