The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice
Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an im...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/1/98 |
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| author | Sylvain Lamoine Mélissa Cumenal David A. Barriere Vanessa Pereira Mathilde Fereyrolles Laëtitia Prival Julie Barbier Ludivine Boudieu Emilie Brasset Benjamin Bertin Yoan Renaud Elisabeth Miot-Noirault Marie-Ange Civiale David Balayssac Youssef Aissouni Alain Eschalier Jérôme Busserolles |
| author_facet | Sylvain Lamoine Mélissa Cumenal David A. Barriere Vanessa Pereira Mathilde Fereyrolles Laëtitia Prival Julie Barbier Ludivine Boudieu Emilie Brasset Benjamin Bertin Yoan Renaud Elisabeth Miot-Noirault Marie-Ange Civiale David Balayssac Youssef Aissouni Alain Eschalier Jérôme Busserolles |
| author_sort | Sylvain Lamoine |
| collection | DOAJ |
| description | Oxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on <i>APC<sup>Min/+</sup></i> mice and on cancer progression when combined with oxaliplatin, both in vivo on <i>APC<sup>Min/+</sup></i> mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in <i>APC<sup>Min/+</sup></i> mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect. |
| first_indexed | 2024-03-10T03:40:19Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:40:19Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-338d3ed82f0e411298c13db584c94ca12023-11-23T11:34:42ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-012319810.3390/ijms23010098The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in MiceSylvain Lamoine0Mélissa Cumenal1David A. Barriere2Vanessa Pereira3Mathilde Fereyrolles4Laëtitia Prival5Julie Barbier6Ludivine Boudieu7Emilie Brasset8Benjamin Bertin9Yoan Renaud10Elisabeth Miot-Noirault11Marie-Ange Civiale12David Balayssac13Youssef Aissouni14Alain Eschalier15Jérôme Busserolles16UMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceiGReD, CNRS, INSERM, Faculté de Médecine, Université Clermont Auvergne, 63000 Clermont-Ferrand, FranceiGReD, CNRS, INSERM, Faculté de Médecine, Université Clermont Auvergne, 63000 Clermont-Ferrand, FranceiGReD, CNRS, INSERM, Faculté de Médecine, Université Clermont Auvergne, 63000 Clermont-Ferrand, FranceUMR 1240 INSERM IMoST, Université Clermont Auvergne, 58 Rue Montalembert, 63000 Clermont-Ferrand, FranceACCePPT—AutomédiCation aCcompagnement Pluriprofessionnel PatienT, Université Clermont Auvergne, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceUMR 1107 Inserm/UCA, CHU Clermont-Ferrand, Université Clermont Auvergne, Neuro-Dol, 63000 Clermont-Ferrand, FranceOxaliplatin, the first-line chemotherapeutic agent against colorectal cancer (CRC), induces peripheral neuropathies, which can lead to dose limitation and treatment discontinuation. Downregulation of potassium channels, which involves histone deacetylase (HDAC) activity, has been identified as an important tuner of acute oxaliplatin-induced hypersensitivity. MS-275, a class I histone deacetylase inhibitor (HDACi), prevents acute oxaliplatin-induced peripheral neuropathy (OIPN). Moreover, MS-275 exerts anti-tumor activity in several types of cancers, including CRC. We thus hypothesized that MS-275 could exert both a preventive effect against OIPN and potentially a synergistic effect combined with oxaliplatin against CRC development. We first used RNAseq to assess transcriptional changes occurring in DRG neurons from mice treated by repeated injection of oxaliplatin. Moreover, we assessed the effects of MS-275 on chronic oxaliplatin-induced peripheral neuropathy development in vivo on <i>APC<sup>Min/+</sup></i> mice and on cancer progression when combined with oxaliplatin, both in vivo on <i>APC<sup>Min/+</sup></i> mice and in a mouse model of an orthotopic allograft of the CT26 cell line as well as in vitro in T84 and HT29 human CRC cell lines. We found 741 differentially expressed genes (DEGs) between oxaliplatin- and vehicle-treated animals. While acute OIPN is known as a channelopathy involving HDAC activity, chronic OIPN exerts weak ion channel transcriptional changes and no HDAC expression changes in peripheral neurons from OIPN mice. However, MS-275 prevents the development of sensory neuropathic symptoms induced by repeated oxaliplatin administration in <i>APC<sup>Min/+</sup></i> mice. Moreover, combined with oxaliplatin, MS-275 also exerts synergistic antiproliferative and increased survival effects in CT26-bearing mice. Consistently, combined drug associations exert synergic apoptotic and cell death effects in both T84 and HT29 human CRC cell lines. Our results strongly suggest combining oxaliplatin and MS-275 administration in CRC patients in order to potentiate the antiproliferative action of chemotherapy, while preventing its neurotoxic effect.https://www.mdpi.com/1422-0067/23/1/98colorectal canceroxaliplatinperipheral neuropathyhistone deacetylase inhibitorMS-275<i>APC<sup>Min/+</sup></i> mice |
| spellingShingle | Sylvain Lamoine Mélissa Cumenal David A. Barriere Vanessa Pereira Mathilde Fereyrolles Laëtitia Prival Julie Barbier Ludivine Boudieu Emilie Brasset Benjamin Bertin Yoan Renaud Elisabeth Miot-Noirault Marie-Ange Civiale David Balayssac Youssef Aissouni Alain Eschalier Jérôme Busserolles The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice International Journal of Molecular Sciences colorectal cancer oxaliplatin peripheral neuropathy histone deacetylase inhibitor MS-275 <i>APC<sup>Min/+</sup></i> mice |
| title | The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice |
| title_full | The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice |
| title_fullStr | The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice |
| title_full_unstemmed | The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice |
| title_short | The Class I HDAC Inhibitor, MS-275, Prevents Oxaliplatin-Induced Chronic Neuropathy and Potentiates Its Antiproliferative Activity in Mice |
| title_sort | class i hdac inhibitor ms 275 prevents oxaliplatin induced chronic neuropathy and potentiates its antiproliferative activity in mice |
| topic | colorectal cancer oxaliplatin peripheral neuropathy histone deacetylase inhibitor MS-275 <i>APC<sup>Min/+</sup></i> mice |
| url | https://www.mdpi.com/1422-0067/23/1/98 |
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