Satoru Sasagawa, Jun Kumai, Toru Wakamatsu, Yoshihiro Yui
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To provide further molecular evidence for the advantages of HDACi treatment and its limitations due to drug resistance induced by the microenvironment in SS cells, we examined cellular responses to HDACi treatment in combination with two-dimensional (2D) and 3D culture conditions.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Using several SS cell lines, biochemical and cell biological assays were performed with romidepsin, an HDAC1/2 selective inhibitor. SN38 was concomitantly used as an ameliorant drug with romidepsin treatment. Cytostasis, apoptosis induction, and MHC class I polypeptide-related sequence A/B (MICA/B) induction were monitored to evaluate the drug efficacy. In addition to the conventional 2D culture condition, spheroid culture was adopted to evaluate the influence of cell-mass microenvironment on chemoresistance.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>By monitoring the cellular behavior with romidepsin and/or SN38 in SS cells, we observed that responsiveness is diverse in each cell line. In the apoptotic inducible cells, co-treatment with SN38 enhanced cell death. In nonapoptotic inducible cells, cytostasis and MICA/B induction were observed, and SN38 improved MICA/B induction further. As a novel efficacy of SN38, we revealed TWIST1 suppression in SS cells. In the spheroid (3D) condition, romidepsin efficacy was severely restricted in TWIST1-positive cells. We demonstrated that TWIST1 downregulation restored romidepsin efficacy even in spheroid form, and concomitant SN38 treatment along with romidepsin reproduced the reaction.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>The current study demonstrated the benefits and concerns of using HDACi for SS treatment in 2D and 3D culture conditions and provided molecular evidence that concomitant treatment with SN38 can overcome drug resistance to HDACi by suppressing TWIST1 expression.</p>\n </section>\n </div>","PeriodicalId":100212,"journal":{"name":"Cancer Innovation","volume":"3 2","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cai2.113","citationCount":"0","resultStr":"{\"title\":\"Improvement of histone deacetylase inhibitor efficacy by SN38 through TWIST1 suppression in synovial sarcoma\",\"authors\":\"Satoru Sasagawa, Jun Kumai, Toru Wakamatsu, Yoshihiro Yui\",\"doi\":\"10.1002/cai2.113\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>Synovial sarcoma (SS) is an <i>SS18-SSX</i> fusion gene-driven soft tissue sarcoma with mesenchymal characteristics, associated with a poor prognosis due to frequent metastasis to a distant organ, such as the lung. Histone deacetylase (HDAC) inhibitors (HDACis) are arising as potent molecular targeted drugs, as HDACi treatment disrupts the SS oncoprotein complex, which includes HDACs, in addition to general HDACi effects. To provide further molecular evidence for the advantages of HDACi treatment and its limitations due to drug resistance induced by the microenvironment in SS cells, we examined cellular responses to HDACi treatment in combination with two-dimensional (2D) and 3D culture conditions.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Using several SS cell lines, biochemical and cell biological assays were performed with romidepsin, an HDAC1/2 selective inhibitor. SN38 was concomitantly used as an ameliorant drug with romidepsin treatment. Cytostasis, apoptosis induction, and MHC class I polypeptide-related sequence A/B (MICA/B) induction were monitored to evaluate the drug efficacy. 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引用次数: 0
摘要
背景滑膜肉瘤（SS）是一种由SS18-SSX融合基因驱动的软组织肉瘤，具有间质特性，由于经常转移至肺部等远处器官，预后较差。组蛋白去乙酰化酶（HDAC）抑制剂（HDACis）作为强效分子靶向药物应运而生，因为HDACi治疗除了一般的HDACi作用外，还能破坏包括HDACs在内的SS癌蛋白复合物。为了进一步从分子角度证明 HDACi 治疗的优势及其因 SS 细胞微环境诱导的耐药性而产生的局限性，我们结合二维（2D）和三维培养条件研究了细胞对 HDACi 治疗的反应。 方法 利用几种 SS 细胞系，使用 HDAC1/2 选择性抑制剂罗米地辛进行生化和细胞生物学检测。在使用罗米地辛治疗的同时，还使用 SN38 作为改善药物。通过监测细胞凋亡、细胞凋亡诱导和 MHC I 类多肽相关序列 A/B（MICA/B）诱导来评估药物疗效。除了传统的二维培养条件外，还采用了球形培养来评估细胞质微环境对化疗耐药性的影响。 结果 通过监测romidepsin和/或SN38在SS细胞中的细胞行为，我们观察到各细胞系的反应性各不相同。在凋亡诱导型细胞中，与 SN38 联合处理可增强细胞死亡。在非凋亡诱导型细胞中，观察到细胞停滞和 MICA/B 诱导，SN38 进一步改善了 MICA/B 诱导。作为 SN38 的一项新功效，我们发现了 SS 细胞中 TWIST1 的抑制作用。在球形（3D）条件下，罗米地辛在 TWIST1 阳性细胞中的疗效受到严重限制。我们证明，即使在球形细胞中，TWIST1 的下调也能恢复罗米地辛的疗效，而且在罗米地辛治疗的同时，SN38 治疗也能再现这种反应。 结论 目前的研究证明了在二维和三维培养条件下使用 HDACi 治疗 SS 的益处和顾虑，并提供了分子证据，证明同时使用 SN38 治疗可通过抑制 TWIST1 的表达克服对 HDACi 的耐药性。
Improvement of histone deacetylase inhibitor efficacy by SN38 through TWIST1 suppression in synovial sarcoma
Background
Synovial sarcoma (SS) is an SS18-SSX fusion gene-driven soft tissue sarcoma with mesenchymal characteristics, associated with a poor prognosis due to frequent metastasis to a distant organ, such as the lung. Histone deacetylase (HDAC) inhibitors (HDACis) are arising as potent molecular targeted drugs, as HDACi treatment disrupts the SS oncoprotein complex, which includes HDACs, in addition to general HDACi effects. To provide further molecular evidence for the advantages of HDACi treatment and its limitations due to drug resistance induced by the microenvironment in SS cells, we examined cellular responses to HDACi treatment in combination with two-dimensional (2D) and 3D culture conditions.
Methods
Using several SS cell lines, biochemical and cell biological assays were performed with romidepsin, an HDAC1/2 selective inhibitor. SN38 was concomitantly used as an ameliorant drug with romidepsin treatment. Cytostasis, apoptosis induction, and MHC class I polypeptide-related sequence A/B (MICA/B) induction were monitored to evaluate the drug efficacy. In addition to the conventional 2D culture condition, spheroid culture was adopted to evaluate the influence of cell-mass microenvironment on chemoresistance.
Results
By monitoring the cellular behavior with romidepsin and/or SN38 in SS cells, we observed that responsiveness is diverse in each cell line. In the apoptotic inducible cells, co-treatment with SN38 enhanced cell death. In nonapoptotic inducible cells, cytostasis and MICA/B induction were observed, and SN38 improved MICA/B induction further. As a novel efficacy of SN38, we revealed TWIST1 suppression in SS cells. In the spheroid (3D) condition, romidepsin efficacy was severely restricted in TWIST1-positive cells. We demonstrated that TWIST1 downregulation restored romidepsin efficacy even in spheroid form, and concomitant SN38 treatment along with romidepsin reproduced the reaction.
Conclusions
The current study demonstrated the benefits and concerns of using HDACi for SS treatment in 2D and 3D culture conditions and provided molecular evidence that concomitant treatment with SN38 can overcome drug resistance to HDACi by suppressing TWIST1 expression.
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