Towards Developing Novel Prostate Cancer Recurrence Suppressors: Acute Toxicity of Pseurotin A, an Orally Active PCSK9 Axis-Targeting Small-Molecule in Swiss Albino Mice.
Towards Developing Novel Prostate Cancer Recurrence Suppressors: Acute Toxicity of Pseurotin A, an Orally Active PCSK9 Axis-Targeting Small-Molecule in Swiss Albino Mice.
复制标题
DOI：
10.3390/molecules28031460
复制
发表时间：
2023-02-02
期刊：
影响因子：
4.6
通讯作者：
El Sayed, Khalid A.
中科院分区：
文献类型：
--
作者：
McGehee, Oliver C.;Ebrahim, Hassan Y.;Rad, Ashkan H.;Abdelwahed, Khaldoun S.;Mudhish, Ethar A.;King, Judy A.;Helal, Iman E.;Meyer, Sharon A.;El Sayed, Khalid A.
前蛋白转化酶枯草杆菌蛋白酶kexin 9型（PCSK 9）由于其通过结合和靶向LDLR以在细胞中进行溶酶体降解而降低低密度脂蛋白（LDL）胆固醇的能力而成为用于心血管疾病管理的非常感兴趣的分子靶标。初步研究表明，假丝酵母素A（PsA）是一种螺杂环γ-内酰胺生物碱，可通过LDLR双重抑制PCSK 9的表达和蛋白质-蛋白质相互作用（PPI），从而发挥抗高胆固醇血症的作用，并调节PCSK 9轴在乳腺癌和前列腺癌进展和复发中的致癌作用。因此，PsA急性毒性的初步评估代表了开发PsA作为新型口服活性PCSK 9轴调节癌症复发抑制剂的踏脚石。PsA分别对RWPE-1和CCD 841 CoN人非致瘤性前列腺和结肠细胞进行的体外毒性研究表明，细胞死亡水平是其报告抗癌活性的10倍。此外，蛋白质印迹分析揭示了促存活标记物Bcl-2的显著下调，沿着促凋亡Bax和半胱天冬酶3/7的上调，表明在非常高的浓度下PSA介导的细胞凋亡诱导。上下法测定雄性和雌性瑞士白化病小鼠中的PsA半数致死剂量值>550毫克/千克。通过经口管饲法对动物单次经口给予10、250和500 mg/kg的PsA，与溶剂对照相比。在给药后的前24小时内每天观察小鼠，持续14天，特别注意监测其行为、神经肌肉和自主反应的任何异常。14天后，将小鼠安乐死，记录并收集其体重和器官重量。对小鼠血浆样品进行全面的血液学和生化分析。对采集的小鼠器官进行组织病理学检查。PsA口服给药后未检测到发病率。500 mg/kg雌性给药组在14天后体重下降45%，但未显示其他毒性体征。与溶剂对照组相比，250 mg/kg雌性给药组的血清肝转氨酶AST和ALT水平显著升高。此外，在500 mg/kg剂量水平下，在两种性别动物的肝组织中均观察到凋亡标志物适度上调。然而，组织病理学检查显示肝、肾、心脏、脑或肺没有损伤。虽然这些发现表明在较高剂量下可能存在性别相关毒性，但缺乏组织病理学损伤意味着单次口服高达治疗剂量50倍的PsA不会引起小鼠急性器官毒性，尽管需要进一步研究。
The proprotein convertase subtilisin kexin type 9 (PCSK9) emerged as a molecular target of great interest for the management of cardiovascular disorders due to its ability to reduce low density lipoprotein (LDL) cholesterol by binding and targeting at LDLR for lysosomal degradation in cells. Preliminary studies revealed that pseurotin A (PsA), a spiro-heterocyclic γ-lactam alkaloid from several marine and terrestrial Aspergillus and Penicillium species, has the ability to dually suppress the PCSK9 expression and protein–protein interaction (PPI) with LDLR, resulting in an anti-hypercholesterolemic effect and modulating the oncogenic role of PCSK9 axis in breast and prostate cancers progression and recurrence. Thus, a preliminary assessment of the PsA acute toxicity represents the steppingstone to develop PsA as a novel orally active PCSK9 axis modulating cancer recurrence inhibitor. PsA studies for in vitro toxicity on RWPE-1 and CCD 841 CoN human non-tumorigenic prostate and colon cells, respectively, indicated a cellular death shown at a 10-fold level of its reported anticancer activity. Moreover, a Western blot analysis revealed a significant downregulation of the pro-survival marker Bcl-2, along with the upregulation of the proapoptotic Bax and caspases 3/7, suggesting PsA-mediated induction of cell apoptosis at very high concentrations. The Up-and-Down methodology determined the PsA LD50 value of >550 mg/kg in male and female Swiss albino mice. Animals were orally administered single doses of PsA at 10, 250, and 500 mg/kg by oral gavage versus vehicle control. Mice were observed daily for 14 days with special care over the first 24 h after dosing to monitor any abnormalities in their behavioral, neuromuscular, and autonomic responses. After 14 days, the mice were euthanized, and their body and organ weights were recorded and collected. Mice plasma samples were subjected to comprehensive hematological and biochemical analyses. Collected mouse organs were histopathologically examined. No morbidity was detected following the PsA oral dosing. The 500 mg/kg female dosing group showed a 45% decrease in the body weight after 14 days but displayed no other signs of toxicity. The 250 mg/kg female dosing group had significantly increased serum levels of liver transaminases AST and ALT versus vehicle control. Moreover, a modest upregulation of apoptotic markers was observed in liver tissues of both animal sexes at 500 mg/kg dose level. However, a histopathological examination revealed no damage to the liver, kidneys, heart, brain, or lungs. While these findings suggest a possible sex-related toxicity at higher doses, the lack of histopathological injury implies that single oral doses of PsA, up to 50-fold the therapeutic dose, do not cause acute organ toxicity in mice though further studies are warranted.
登录
查看更多内容
影响因子：
2.8
作者：
LaRosa, John C.;Pedersen, Terje R.;Wasserman, Scott M.
通讯作者：
Wasserman, Scott M.
影响因子：
9.8
作者：
Mora C;Tittensor DP;Adl S;Simpson AG;Worm B
通讯作者：
Worm B
影响因子：
3.7
作者：
Cholesterol Treatment Trialists' (CTT) Collaboration;Emberson JR;Kearney PM;Blackwell L;Newman C;Reith C;Bhala N;Holland L;Peto R;Keech A;Collins R;Simes J;Baigent C
通讯作者：
Baigent C
影响因子：
39.3
作者：
Da Dalt L;Castiglioni L;Baragetti A;Audano M;Svecla M;Bonacina F;Pedretti S;Uboldi P;Benzoni P;Giannetti F;Barbuti A;Pellegatta F;Indino S;Donetti E;Sironi L;Mitro N;Catapano AL;Norata GD
通讯作者：
Norata GD
影响因子：
5.2
作者：
Hayashi, Y;Shoji, M;Osada, H
通讯作者：
Osada, H