双对应的odomain 抑制剂 MT-1 抑制前列腺癌的生长
Sanjeev Shukla1, Carlos Riveros1, Mohammed Al-Toubat1
1Department of Urology, University of Florida Health, Jacksonville, FL 32209, USA.
Cancers
|August 12, 2023
概括
一种新型的原体抑制剂MT-1有效向前列腺癌 (PC) 细胞中的c-Myc,降低活力和瘤生长. 这项临床前研究突出了MT-1的特点.
科学领域:
- 表观遗传学和分子生物学
- 癌症治疗方法 癌症治疗方法
- 前列腺癌研究 研究前列腺癌
背景情况:
- 瘤原体 (BD) 是表观遗传阅读器,调节基因转录,包括原型瘤基因c-Myc.
- c-Myc上调与晚期前列腺癌 (PC) 有关,由于其结构和定位,这对治疗构成了挑战.
- 通过表观遗传机制向c-Myc为PC治疗提供了一个有希望的策略.
研究的目的:
- 为了评估MT-1的疗效,一种强大的双价代胺抑制剂,对前列腺癌中的c-Myc失调.
- 评估MT-1对PC细胞活力,细胞周期和下游分子点的影响.
- 在先进的,耐治疗前列腺癌的临床前模型中研究MT-1的治疗潜力.
主要方法:
- 用MT-1治疗PC细胞系和患者衍生异种移植 (PDX) 模型.
- 评估细胞活力,细胞循环进展 (G0/G1停止) 和c-Myc抑制.
- 对c-Myc下游目标的分子分析,包括蛋白激酶D1 (PrKD) 和其基质.
- 在3D培养和正位点小鼠模型中评估MT-1的疗效,包括与MAX抑制剂的联合治疗.
主要成果:
- MT-1 证明了PC细胞活力的剂量依赖性降低,并诱导了G0/G1细胞周期停止.
- MT-1治疗导致PrKD的去抑制,并改变了关键基质的酸化,证实了c-Myc抑制.
- 在PC PDX模型中观察到MT-1的最低IC50值,具有c-Myc放大和对标准疗法的耐药性.
- 单独使用MT-1,或与MAX抑制剂结合使用,可显著降低瘤生长在orthotopic PC PDX小鼠模型.
结论:
- MT-1是一种强效的代蛋白抑制剂,有效抵御前列腺癌中c-Myc失调.
- 在先进的,耐治疗的前列腺癌模型中,MT-1表现出临床前的疗效.
- 这项研究确立了MT-1作为c-Myc驱动前列腺癌的潜在治疗剂.
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