T. Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed S. Alnaim, Aedan Bird, P. Opanasopit, A. Mitra, Robert Arnold
{"title":"摘要:一种新型穿心莲内酯类似物(3A.1)通过上调热休克蛋白和下调mat2a介导的细胞迁移和侵袭,与紫杉烷衍生物协同作用于侵袭性转移性前列腺癌","authors":"T. Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed S. Alnaim, Aedan Bird, P. Opanasopit, A. Mitra, Robert Arnold","doi":"10.1158/1538-7445.AM2021-1355","DOIUrl":null,"url":null,"abstract":"BACKGROUND: Prostate cancer (PCa) is the 2nd leading cause of non-cutaneous cancer deaths among men in the USA with many progressing to aggressive metastatic castration resistant PCa (mCRPC; PCa unresponsive to androgen deprivation). Conventional treatment with taxanes (TX; docetaxel (DTX) or cabazitaxel (CBZ)) increases survival rates only slightly. The andrographolide analog, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1) has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX and CBZ against models of aggressive PCa. METHODS: Androgen receptor negative (AR-ve) mCRPC cell lines were treated with CBZ, DTX and 3A.1 as single-agent or combination over a broad concentration range, and in vitro cytotoxicity was determined. Chou-Talalay9s combination index (CI) theorem was used to determine synergism and predicted dose reduction of taxanes. Post-treatment effect of single-agent and combination regimens on gene expression profile (GEP) was assessed using mRNA sequencing. Differentially expressed genes (DEGs) and molecular pathways involved in 3A.1 mechanism of action and drug synergy were identified using DESeq2, edgeR and Ingenuity pathway analysis (IPA). Protein expression of top DE genes was confirmed by immunoblotting. Cell cycle analysis, scratch/wound healing, and COMET assays were used to functionally validate the top treatment-associated genes. RESULTS: Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. CI values of all 3A.1+ TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX by 9.5 to 18-folds (p 0.7) genes, TRA2B and SF1, were associated with worser Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). CONCLUSION: These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive prostate cancer. Citation Format: Taraswi Mitra Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed Alnaim, Aedan Bird, P Opanasopit, Amit K. Mitra, Robert Arnold. A novel andrographolide analogue (3A.1) synergizes with Taxane derivatives in aggressive metastatic prostate cancers through upregulation of heatshock proteins and downregulation of MAT2A-mediated cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. 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Mitra, Robert Arnold\",\"doi\":\"10.1158/1538-7445.AM2021-1355\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND: Prostate cancer (PCa) is the 2nd leading cause of non-cutaneous cancer deaths among men in the USA with many progressing to aggressive metastatic castration resistant PCa (mCRPC; PCa unresponsive to androgen deprivation). Conventional treatment with taxanes (TX; docetaxel (DTX) or cabazitaxel (CBZ)) increases survival rates only slightly. The andrographolide analog, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1) has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX and CBZ against models of aggressive PCa. METHODS: Androgen receptor negative (AR-ve) mCRPC cell lines were treated with CBZ, DTX and 3A.1 as single-agent or combination over a broad concentration range, and in vitro cytotoxicity was determined. Chou-Talalay9s combination index (CI) theorem was used to determine synergism and predicted dose reduction of taxanes. Post-treatment effect of single-agent and combination regimens on gene expression profile (GEP) was assessed using mRNA sequencing. Differentially expressed genes (DEGs) and molecular pathways involved in 3A.1 mechanism of action and drug synergy were identified using DESeq2, edgeR and Ingenuity pathway analysis (IPA). Protein expression of top DE genes was confirmed by immunoblotting. Cell cycle analysis, scratch/wound healing, and COMET assays were used to functionally validate the top treatment-associated genes. RESULTS: Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. CI values of all 3A.1+ TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX by 9.5 to 18-folds (p 0.7) genes, TRA2B and SF1, were associated with worser Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). CONCLUSION: These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive prostate cancer. Citation Format: Taraswi Mitra Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed Alnaim, Aedan Bird, P Opanasopit, Amit K. Mitra, Robert Arnold. A novel andrographolide analogue (3A.1) synergizes with Taxane derivatives in aggressive metastatic prostate cancers through upregulation of heatshock proteins and downregulation of MAT2A-mediated cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. 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引用次数: 0
摘要
背景:前列腺癌(PCa)是美国男性非皮肤癌死亡的第二大原因,其中许多进展为侵袭性转移性去势抵抗性PCa (mCRPC;前列腺癌对雄激素剥夺无反应)。紫杉烷(TX)常规处理;多西他赛(DTX)或卡巴他赛(CBZ)仅能略微提高生存率。穿心莲内酯类似物19-叔丁基二苯基硅基-8,7-环氧穿心莲内酯(3A.1)已显示出对多种癌症的抗癌活性。在本研究中,我们研究了3A的作用。1单独或联合DTX和CBZ治疗侵袭性前列腺癌模型。方法:用CBZ、DTX和3A处理雄激素受体阴性(AR-ve) mCRPC细胞株。1在较宽的浓度范围内单药或联合用药,并测定体外细胞毒性。采用Chou-Talalay9s联合指数(CI)定理确定了紫杉烷的协同作用,并预测了紫杉烷的剂量减少。通过mRNA测序评估单药和联合用药对基因表达谱(GEP)的治疗后影响。差异表达基因(DEGs)和3A的分子通路。采用DESeq2、edgeR和Ingenuity pathway analysis (IPA)鉴定其作用机制和药物协同作用。免疫印迹法证实顶端DE基因的蛋白表达。细胞周期分析、划痕/伤口愈合和COMET检测用于功能验证顶级治疗相关基因。结果:暴露于3A;1在mCRPC中表现出剂量和时间依赖性的抗肿瘤活性。所有3A的CI值。1+ TX组合小于0.5,说明有协同作用。共处理3A。在前列腺腺癌患者(PRAD-TCGA)中,TRA2B和SF1基因与较差的Gleason评分和淋巴结转移状态相关。结论:上述结果提示3A;1可能有助于提高紫杉烷类药物治疗侵袭性前列腺癌的抗癌效果。引文格式:Taraswi Mitra Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed Alnaim, Aedan Bird, P Opanasopit, Amit K. Mitra, Robert Arnold。一种新型穿心莲内酯类似物(3A.1)通过上调热休克蛋白和下调mat2a介导的细胞迁移和侵袭,与紫杉烷衍生物协同作用于侵袭性转移性前列腺癌[摘要]。见:美国癌症研究协会2021年年会论文集;2021年4月10日至15日和5月17日至21日。费城(PA): AACR;癌症杂志,2021;81(13 -增刊):1355。
Abstract 1355: A novel andrographolide analogue (3A.1) synergizes with Taxane derivatives in aggressive metastatic prostate cancers through upregulation of heatshock proteins and downregulation of MAT2A-mediated cell migration and invasion
BACKGROUND: Prostate cancer (PCa) is the 2nd leading cause of non-cutaneous cancer deaths among men in the USA with many progressing to aggressive metastatic castration resistant PCa (mCRPC; PCa unresponsive to androgen deprivation). Conventional treatment with taxanes (TX; docetaxel (DTX) or cabazitaxel (CBZ)) increases survival rates only slightly. The andrographolide analog, 19-tert-butyldiphenylsilyl-8,7-epoxy andrographolide (3A.1) has shown anticancer activity against various cancers. In this study, we investigated the effect of 3A.1 alone and in combination with DTX and CBZ against models of aggressive PCa. METHODS: Androgen receptor negative (AR-ve) mCRPC cell lines were treated with CBZ, DTX and 3A.1 as single-agent or combination over a broad concentration range, and in vitro cytotoxicity was determined. Chou-Talalay9s combination index (CI) theorem was used to determine synergism and predicted dose reduction of taxanes. Post-treatment effect of single-agent and combination regimens on gene expression profile (GEP) was assessed using mRNA sequencing. Differentially expressed genes (DEGs) and molecular pathways involved in 3A.1 mechanism of action and drug synergy were identified using DESeq2, edgeR and Ingenuity pathway analysis (IPA). Protein expression of top DE genes was confirmed by immunoblotting. Cell cycle analysis, scratch/wound healing, and COMET assays were used to functionally validate the top treatment-associated genes. RESULTS: Exposure to 3A.1 alone exhibited a dose- and time-dependent antitumor activity in mCRPC. CI values of all 3A.1+ TX combinations were less than 0.5, indicating synergism. Co-treatment of 3A.1 with TX reduced the required dose of DTX by 9.5 to 18-folds (p 0.7) genes, TRA2B and SF1, were associated with worser Gleason score and nodal metastasis status in prostate adenocarcinoma patients (PRAD-TCGA). CONCLUSION: These results suggest that 3A.1 may be useful in increasing the anticancer efficacy of taxanes to treat aggressive prostate cancer. Citation Format: Taraswi Mitra Ghosh, Teeratas Kansom, Suman Mazumder, Joshua Davis, Ahmed Alnaim, Aedan Bird, P Opanasopit, Amit K. Mitra, Robert Arnold. A novel andrographolide analogue (3A.1) synergizes with Taxane derivatives in aggressive metastatic prostate cancers through upregulation of heatshock proteins and downregulation of MAT2A-mediated cell migration and invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1355.