BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways
(1) Destabilization of microtubule dynamics is a primary strategy to inhibit fast growing tumor cells. The low cytotoxic derivative of microtubule inhibitor D-24851, named BPR0C261 exhibits antitumor activity via oral administration. In this study, we investigated if BPR0C261 could modulate the radi...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/22/14083 |
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| author | Jyh-Der Leu Shih-Ting Lin Chiung-Tong Chen C.-Allen Chang Yi-Jang Lee |
| author_facet | Jyh-Der Leu Shih-Ting Lin Chiung-Tong Chen C.-Allen Chang Yi-Jang Lee |
| author_sort | Jyh-Der Leu |
| collection | DOAJ |
| description | (1) Destabilization of microtubule dynamics is a primary strategy to inhibit fast growing tumor cells. The low cytotoxic derivative of microtubule inhibitor D-24851, named BPR0C261 exhibits antitumor activity via oral administration. In this study, we investigated if BPR0C261 could modulate the radiation response of human non-small cell lung cancer (NSCLC) cells with or without p53 expression. (2) Different doses of BPR0C261 was used to treat human NSCLC A549 (p53+/+) cells and H1299 (p53−/−) cells. The cytotoxicity, radiosensitivity, cell cycle distribution, DNA damage, and protein expression were evaluated using an MTT assay, a colony formation assay, flow cytometry, a comet assay, and an immunoblotting analysis, respectively. (3) BPR0C261 showed a dose-dependent cytotoxicity on A549 cells and H1299 cells with IC<sub>50</sub> at 0.38 μM and 0.86 μM, respectively. BPR0C261 also induced maximum G<sub>2</sub>/M phase arrest and apoptosis in both cell lines after 24 h of treatment with a dose-dependent manner. The colony formation analysis demonstrated that a combination of low concentration of BPR0C261 and X-rays caused a synergistic radiosensitizing effect on NSCLC cells. Additionally, we found that a low concentration of BPR0C261 was sufficient to induce DNA damage in these cells, and it increased the level of DNA damage induced by a fractionation radiation dose (2 Gy) of conventional radiotherapy. Furthermore, the p53 protein level of A549 cell line was upregulated by BPR0C261. On the other hand, the expression of PTEN tumor suppressor was found to be upregulated in H1299 cells but not in A549 cells under the same treatment. Although radiation could not induce PTEN in H1299 cells, a combination of low concentration of BPR0C261 and radiation could reverse this situation. (4) BPR0C261 exhibits specific anticancer effects on NSCLC cells by the enhancement of DNA damage and radiosensitivity with p53-dependent and p53-independent/PTEN-dependent manners. The combination of radiation and BPR0C261 may provide an important strategy for the improvement of radiotherapeutic treatment. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T18:16:42Z |
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| spelling | doaj.art-74b6ac0669a744188183675ebd7bbbf62023-11-24T08:38:17ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123221408310.3390/ijms232214083BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent PathwaysJyh-Der Leu0Shih-Ting Lin1Chiung-Tong Chen2C.-Allen Chang3Yi-Jang Lee4Division of Radiation Oncology, Taipei City Hospital RenAi Branch, Taipei 106, TaiwanDepartment of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 11221, TaiwanInstitute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan 350, TaiwanDepartment of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 11221, TaiwanDepartment of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan(1) Destabilization of microtubule dynamics is a primary strategy to inhibit fast growing tumor cells. The low cytotoxic derivative of microtubule inhibitor D-24851, named BPR0C261 exhibits antitumor activity via oral administration. In this study, we investigated if BPR0C261 could modulate the radiation response of human non-small cell lung cancer (NSCLC) cells with or without p53 expression. (2) Different doses of BPR0C261 was used to treat human NSCLC A549 (p53+/+) cells and H1299 (p53−/−) cells. The cytotoxicity, radiosensitivity, cell cycle distribution, DNA damage, and protein expression were evaluated using an MTT assay, a colony formation assay, flow cytometry, a comet assay, and an immunoblotting analysis, respectively. (3) BPR0C261 showed a dose-dependent cytotoxicity on A549 cells and H1299 cells with IC<sub>50</sub> at 0.38 μM and 0.86 μM, respectively. BPR0C261 also induced maximum G<sub>2</sub>/M phase arrest and apoptosis in both cell lines after 24 h of treatment with a dose-dependent manner. The colony formation analysis demonstrated that a combination of low concentration of BPR0C261 and X-rays caused a synergistic radiosensitizing effect on NSCLC cells. Additionally, we found that a low concentration of BPR0C261 was sufficient to induce DNA damage in these cells, and it increased the level of DNA damage induced by a fractionation radiation dose (2 Gy) of conventional radiotherapy. Furthermore, the p53 protein level of A549 cell line was upregulated by BPR0C261. On the other hand, the expression of PTEN tumor suppressor was found to be upregulated in H1299 cells but not in A549 cells under the same treatment. Although radiation could not induce PTEN in H1299 cells, a combination of low concentration of BPR0C261 and radiation could reverse this situation. (4) BPR0C261 exhibits specific anticancer effects on NSCLC cells by the enhancement of DNA damage and radiosensitivity with p53-dependent and p53-independent/PTEN-dependent manners. The combination of radiation and BPR0C261 may provide an important strategy for the improvement of radiotherapeutic treatment.https://www.mdpi.com/1422-0067/23/22/14083NSCLCBPR0C261radiosensitivityDNA damagemicrotubule inhibitorp53 |
| spellingShingle | Jyh-Der Leu Shih-Ting Lin Chiung-Tong Chen C.-Allen Chang Yi-Jang Lee BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways International Journal of Molecular Sciences NSCLC BPR0C261 radiosensitivity DNA damage microtubule inhibitor p53 |
| title | BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways |
| title_full | BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways |
| title_fullStr | BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways |
| title_full_unstemmed | BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways |
| title_short | BPR0C261, An Analogous of Microtubule Disrupting Agent D-24851 Enhances the Radiosensitivity of Human Non-Small Cell Lung Cancer Cells via p53-Dependent and p53-Independent Pathways |
| title_sort | bpr0c261 an analogous of microtubule disrupting agent d 24851 enhances the radiosensitivity of human non small cell lung cancer cells via p53 dependent and p53 independent pathways |
| topic | NSCLC BPR0C261 radiosensitivity DNA damage microtubule inhibitor p53 |
| url | https://www.mdpi.com/1422-0067/23/22/14083 |
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