New high-throughput screening detects compounds that suppress pancreatic stellate cell activation and attenuate pancreatic cancer growth
New high-throughput screening detects compounds that suppress pancreatic stellate cell activation and attenuate pancreatic cancer growth
复制标题
DOI：
10.1016/j.pan.2021.04.002
复制
发表时间：
2021-09-10
期刊：
影响因子：
3.6
通讯作者：
Nakamura, Masafumi
中科院分区：
文献类型：
--
作者：
Sagara, Akiko;Nakata, Kohei;Nakamura, Masafumi
背景/目标：胰腺星状细胞（PSC）参与丰富的结缔组织增生，这促进了癌细胞的侵袭性和对抗癌药物的耐药性。因此，PSC被认为是一个有前途的治疗靶点，通过减弱PSC活化来抑制肿瘤基质与胰腺癌细胞的相互作用。在这里，我们开发了一个屏幕，以确定化合物，减少PSC的活动和调查的候选人对胰腺cancer.Methods的效果：脂质小滴在PSC中的积累被用来观察PSC的活动和一个新的高通量筛选平台，定量的脂质小滴在PSC的差异建立。该平台筛选了3398种食品和药物管理局批准的药物库。结果：通过筛选，最终确定了32个化合物为候选化合物。这些化合物降低了α-平滑肌肌动蛋白的表达，并在体外抑制PSC中的自噬通量。在候选药物中，选择用于验证试验的三种药物通过破坏肿瘤-基质相互作用来抑制PSC的增殖和迁移以及癌细胞的侵袭。细胞外基质分子的产生也通过这种处理显著降低。在异种移植模型中的体内测试表明，多巴胺拮抗剂zuclopenthixol抑制肿瘤的生长，这种抑制显着增加时，结合gemcitabine.Conclusions：一个新的筛选平台，专注于PSC的形态特征的开发。来自该筛选的候选药物抑制PSC活化和肿瘤生长。该筛选系统可用于发现减弱PSC活化的新化合物。(C)2021由Elsevier B. V.代表IAP和EPC发布。
Background/objectives: Pancreatic stellate cells (PSCs) are involved in abundant desmoplasia, which promotes cancer cell aggressiveness and resistance to anti-cancer drugs. Therefore, PSCs are suggested to be a promising therapeutic target by attenuating PSC activation to inhibit tumor-stromal interactions with pancreatic cancer cells. Here, we developed a screen to identify compounds that reduce the activity of PSCs and investigated the effect of candidates on pancreatic cancer.Methods: Lipid droplet accumulation in PSCs was used to observe differences in PSC activity and a new high-throughput screening platform that quantified lipid droplets in PSCs was established. A library of 3398 Food and Drug Administration-approved drugs was screened by this platform. Validation assays were performed in vitro and in vivo.Results: Thirty-two compounds were finally selected as candidate compounds by screening. These compounds decreased alpha-smooth muscle actin expression and inhibited autophagic flux in PSCs in vitro. Among the candidates, three drugs selected for validation assays inhibited the proliferation and migration of PSCs and invasion of cancer cells by disrupting tumor-stromal interactions. Production of extracellular matrix molecules was also decreased significantly by this treatment. In vivo testing in xenograft models showed that dopamine antagonist zuclopenthixol suppressed tumor growth; this suppression was significantly increased when combined with gemcitabine.Conclusions: A new screening platform that focused on the morphological features of PSCs was developed. Candidate drugs from this screening suppressed PSC activation and tumor growth. This screening system may be useful to discover new compounds that attenuate PSC activation. (C) 2021 Published by Elsevier B.V. on behalf of IAP and EPC.