Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824
As a novel histone deacetylase inhibitor (HDACi), LAQ824 (LAQ) effectively inhibits the proliferation of hematological malignancies and solid tumors. However, phase II trials of LAQ in solid tumors were terminated due to dose-dependent toxicity. Furthermore, LAQ has been shown to induce the activati...
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MDPI AG
2023-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/17/13660 |
| _version_ | 1797582335536791552 |
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| author | Qinglang Mei Xiaohan Xu Danling Gao Yuting Xu Jinbo Yang |
| author_facet | Qinglang Mei Xiaohan Xu Danling Gao Yuting Xu Jinbo Yang |
| author_sort | Qinglang Mei |
| collection | DOAJ |
| description | As a novel histone deacetylase inhibitor (HDACi), LAQ824 (LAQ) effectively inhibits the proliferation of hematological malignancies and solid tumors. However, phase II trials of LAQ in solid tumors were terminated due to dose-dependent toxicity. Furthermore, LAQ has been shown to induce the activation of the Notch signaling pathway in hematopoietic stem cells, which is associated with tumor progression and drug resistance in colon and breast cancers. Therefore, in this study, we investigated the strategy of LAQ combined with a Notch signaling pathway inhibitor to treat solid tumors. We used RT-PCR and Western blot methods to demonstrate that LAQ upregulated the Notch signaling pathway in solid tumor cell lines at the molecular level. The combination of LAQ and a Notch signaling pathway inhibitor was shown by a Chou–Talalay assay to have a synergistic effect in inhibiting solid tumor cell line proliferation in vitro. We also demonstrated that the combination of LAQ and a Notch signaling pathway inhibitor significantly inhibited the growth of tumor cells in vivo using an allograft tumor model. This study indicates that inhibition of the Notch signaling pathway provides a valuable strategy for enhancing solid tumor sensitivity to LAQ. |
| first_indexed | 2024-03-10T23:20:39Z |
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| id | doaj.art-914bcc004a0e49c8b5515448942fbba0 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T23:20:39Z |
| publishDate | 2023-09-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-914bcc004a0e49c8b5515448942fbba02023-11-19T08:20:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124171366010.3390/ijms241713660Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824Qinglang Mei0Xiaohan Xu1Danling Gao2Yuting Xu3Jinbo Yang4Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaKey Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, ChinaAs a novel histone deacetylase inhibitor (HDACi), LAQ824 (LAQ) effectively inhibits the proliferation of hematological malignancies and solid tumors. However, phase II trials of LAQ in solid tumors were terminated due to dose-dependent toxicity. Furthermore, LAQ has been shown to induce the activation of the Notch signaling pathway in hematopoietic stem cells, which is associated with tumor progression and drug resistance in colon and breast cancers. Therefore, in this study, we investigated the strategy of LAQ combined with a Notch signaling pathway inhibitor to treat solid tumors. We used RT-PCR and Western blot methods to demonstrate that LAQ upregulated the Notch signaling pathway in solid tumor cell lines at the molecular level. The combination of LAQ and a Notch signaling pathway inhibitor was shown by a Chou–Talalay assay to have a synergistic effect in inhibiting solid tumor cell line proliferation in vitro. We also demonstrated that the combination of LAQ and a Notch signaling pathway inhibitor significantly inhibited the growth of tumor cells in vivo using an allograft tumor model. This study indicates that inhibition of the Notch signaling pathway provides a valuable strategy for enhancing solid tumor sensitivity to LAQ.https://www.mdpi.com/1422-0067/24/17/13660histone deacetylase inhibitorLAQ824Notch signaling pathwayPF03084014combination treatment |
| spellingShingle | Qinglang Mei Xiaohan Xu Danling Gao Yuting Xu Jinbo Yang Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824 International Journal of Molecular Sciences histone deacetylase inhibitor LAQ824 Notch signaling pathway PF03084014 combination treatment |
| title | Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824 |
| title_full | Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824 |
| title_fullStr | Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824 |
| title_full_unstemmed | Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824 |
| title_short | Inhibition of Notch Signaling Enhances Antitumor Activity of Histone Deacetylase Inhibitor LAQ824 |
| title_sort | inhibition of notch signaling enhances antitumor activity of histone deacetylase inhibitor laq824 |
| topic | histone deacetylase inhibitor LAQ824 Notch signaling pathway PF03084014 combination treatment |
| url | https://www.mdpi.com/1422-0067/24/17/13660 |
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