Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects
We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide an...
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MDPI AG
2022-01-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/2/730 |
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| author | Marina Filimonova Anna Shitova Olga Soldatova Ljudmila Shevchenko Alina Saburova Tatjana Podosinnikova Valentina Surinova Petr Shegay Andrey Kaprin Sergey Ivanov Alexander Filimonov |
| author_facet | Marina Filimonova Anna Shitova Olga Soldatova Ljudmila Shevchenko Alina Saburova Tatjana Podosinnikova Valentina Surinova Petr Shegay Andrey Kaprin Sergey Ivanov Alexander Filimonov |
| author_sort | Marina Filimonova |
| collection | DOAJ |
| description | We have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents. |
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| format | Article |
| id | doaj.art-3191a5f3b6114b3594dfad7f5f7746fa |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T01:18:47Z |
| publishDate | 2022-01-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3191a5f3b6114b3594dfad7f5f7746fa2023-11-23T14:03:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-01-0123273010.3390/ijms23020730Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor EffectsMarina Filimonova0Anna Shitova1Olga Soldatova2Ljudmila Shevchenko3Alina Saburova4Tatjana Podosinnikova5Valentina Surinova6Petr Shegay7Andrey Kaprin8Sergey Ivanov9Alexander Filimonov10Personalized Medicine Centre, Almazov National Medical Research Centre, 197341 Saint Petersburg, RussiaPersonalized Medicine Centre, Almazov National Medical Research Centre, 197341 Saint Petersburg, RussiaPersonalized Medicine Centre, Almazov National Medical Research Centre, 197341 Saint Petersburg, RussiaPersonalized Medicine Centre, Almazov National Medical Research Centre, 197341 Saint Petersburg, RussiaA. Tsyb Medical Radiological Research Center—Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, RussiaA. Tsyb Medical Radiological Research Center—Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, RussiaPersonalized Medicine Centre, Almazov National Medical Research Centre, 197341 Saint Petersburg, RussiaNational Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, RussiaNational Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, RussiaA. Tsyb Medical Radiological Research Center—Branch of the National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, 249036 Obninsk, RussiaPersonalized Medicine Centre, Almazov National Medical Research Centre, 197341 Saint Petersburg, RussiaWe have previously demonstrated a high antitumor potential of NOS inhibitor T1023 (1-isobutanoyl-2-isopropylisothiourea hydrobromide): antitumor antiangiogenic activity in several animal tumor models and its ability to synergistically enhance the antitumor effects of bevacizumab, cyclophosphamide and γ-radiation. At the same time, rather rapid adaptation of experimental neoplasias to T1023 treatment was often observed. We attempted to enhance the antitumor activity of this NOS inhibitor by supplementing its molecular structure with a PDK-inhibiting fragment, dichloroacetate (DCA), which is capable of hypoxia-oriented toxic effects. We synthesized compound T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). Its toxic properties, NOS-inhibiting and PDK-inhibiting activity in vivo, and antitumor activity on the mouse Ehrlich carcinoma model (SEC) were investigated in compare with T1023 and Na-DCA. We found that the change of the salt-forming acid from HBr to DCA does not increase the toxicity of 1-isobutanoyl-2-isopropylisothiourea salts, but significantly expands the biochemical and anti-tumor activity. New compound T1084 realizes in vivo NOS-inhibiting and PDK-inhibiting activity, quantitatively, at the level of the previous compounds, T1023 and Na-DCA. In two independent experiments on SEC model, a pronounced synergistic antitumor effect of T1084 was observed in compare with T1023 and Na-DCA at equimolar doses. There were no signs of SEC adaptation to T1084 treatment, while experimental neoplasia rapidly desensitized to the separate treatment of both T1023 and Na-DCA. The totality of the data obtained indicates that the combination of antiangiogenic and hypoxia-oriented toxic effects (in this case, within the molecular structure of the active substance) can increase the antitumor effect and suppress the development of hypoxic resistance of neoplasias. In general, the proposed approach can be used for the design of new anticancer agents.https://www.mdpi.com/1422-0067/23/2/730NOS-inhibitorPDK-inhibitorantitumor effecthypoxic resistanceErlich carcinoma |
| spellingShingle | Marina Filimonova Anna Shitova Olga Soldatova Ljudmila Shevchenko Alina Saburova Tatjana Podosinnikova Valentina Surinova Petr Shegay Andrey Kaprin Sergey Ivanov Alexander Filimonov Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects International Journal of Molecular Sciences NOS-inhibitor PDK-inhibitor antitumor effect hypoxic resistance Erlich carcinoma |
| title | Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects |
| title_full | Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects |
| title_fullStr | Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects |
| title_full_unstemmed | Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects |
| title_short | Combination of NOS- and PDK-Inhibitory Activity: Possible Way to Enhance Antitumor Effects |
| title_sort | combination of nos and pdk inhibitory activity possible way to enhance antitumor effects |
| topic | NOS-inhibitor PDK-inhibitor antitumor effect hypoxic resistance Erlich carcinoma |
| url | https://www.mdpi.com/1422-0067/23/2/730 |
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