大麻二酚对胰腺癌的细胞毒性是通过上调神经酰胺合成酶1和ER应激诱导的。

IF 4.1 Q1 PHARMACOLOGY & PHARMACY
Nagina Mangal, Vikash Reebye, Nagy Habib, Mikael H Sodergren
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引用次数: 0

摘要

胰腺导管腺癌(PDAC)仍然是最具侵袭性的恶性肿瘤之一,5 年生存率中位数为 12%。研究发现,大麻二酚(CBD)具有抗肿瘤潜力,可增强吉西他滨等细胞毒性药物的抗癌效果。大麻二酚疗法与神经酰胺的从头合成有关。鞘脂神经酰胺是一种有效的肿瘤抑制脂质,在细胞凋亡和自噬中发挥作用。神经酰胺合成酶是其中的关键角色之一,该酶有六种同工酶(CerS1-CerS6),据报道具有疾病预后价值。定量实时 PCR 被用来测定神经酰胺合成酶同工酶、GRP78、ATF4 和 CHOP 的 mRNA 表达水平。通过 siRNA 敲除 CerS1 和 GRP78,并用上述两种方法进行确认。通过腹腔注射法给小鼠腹腔内注射药物,用流式细胞仪分析肿瘤,并用 H&E 和 IHC 染色法处理肿瘤。 siRNA 敲除神经酰胺合成酶 1(CerS1)并进行分析,证明 CBD 在激活内质网(ER)应激靶标 GRP78 的过程中存在一个依赖于 CerS1 的假定途径。CBD 处理后,CerS1 上调,下游导致未折叠蛋白反应(UPR)途径的 GRP78/ATF4/CHOP 部分被激活。在一个体内 PDAC 模型中,CerS1 在 IHC 上没有上调,没有观察到动物存活率的改善,但在化疗和 CBD 联合治疗组中观察到肿瘤生长的减少,这表明还需要在体内进行进一步研究。这些发现为 CBD 在胰腺导管腺癌中潜在的神经酰胺诱导细胞毒性作用机制提供了证据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Cannabidiol's cytotoxicity in pancreatic cancer is induced via an upregulation of ceramide synthase 1 and ER stress.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a median 5 year-survival rate of 12%. Cannabidiol (CBD) has been found to exhibit antineoplastic potential and may potentiate the anticancer effects of cytotoxic's such as gemcitabine. CBD therapy has been linked to de novo synthesis of ceramide. The sphingolipid ceramide is a potent tumour suppressor lipid with roles in apoptosis and autophagy. One of the key players involved is ceramide synthase, an enzyme with six isoforms (CerS1-CerS6), reported to have disease prognostic value. Quantitative real time PCR was used to determine mRNA expression levels of ceramide synthase isoforms, GRP78, ATF4 and CHOP. Western blotting was used to analyze protein expression of these markers and knockdown of CerS1 and GRP78 were applied via an siRNA and confirmed by the two mentioned methods. Mice with PDAC xenografts were injected via intraperitoneal method with drugs and tumours were analysed with flow cytometry and processed using H&E and IHC staining. siRNA knockdown of ceramide synthase 1 (CerS1) and analysis point to evidence of a putative CerS1 dependent pathway driven by CBD in activating endoplasmic reticulum (ER) stress target; GRP78. Upon CBD treatment, CerS1 was upregulated and downstream this led to the GRP78/ATF4/CHOP arm of the unfolded protein response (UPR) pathway being activated. In an in vivo model of PDAC in which CerS1 was not upregulated on IHC, there was no observed improvement in survival of animals, however a reduction in tumour growth was observed in combination chemotherapy and CBD group, indicating further investigations in vivo. These findings provide evidence of a potential ceramide induced cytotoxic mechanism of action of CBD in pancreatic ductal adenocarcinoma.

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