Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity.
Zinc protoporphyrin binding to telomerase complexes and inhibition of telomerase activity.
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DOI：
10.1002/prp2.882
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发表时间：
2021-12
影响因子：
2.6
通讯作者：
Schmidt WN
中科院分区：
文献类型：
--
作者：
Zhu Z;Tran H;Mathahs MM;Fink BD;Albert JA;Moninger TO;Meier JL;Li M;Schmidt WN
锌原卟啉（ZnPP）是一种天然存在的金属原卟啉（MPP），目前正在开发作为化疗药物，但其机制尚不清楚。当与其他 MPP 进行测试时，ZnPP 是最有效的 DNA 合成和细胞增殖抑制剂，同时促进端粒酶阳性细胞凋亡，但不促进端粒酶阴性细胞凋亡。同时，ZnPP 下调端粒酶表达，是完整细胞和细胞提取物中端粒酶活性的最佳整体抑制剂，IC50 和 EC50 值分别约为 2.5 和 6 µM。 ZnPP 的天然荧光特性使得能够使用非变性琼脂糖凝胶电泳、蛋白质印迹和共聚焦荧光显微镜对细胞组分进行直接成像。通过免疫复合物迁移率变化、免疫沉淀和免疫印迹分析证实，ZnPP 定位于含有端粒酶和 Dyskerin 的大型细胞复合物 (>600 kD)。共聚焦荧光研究表明，ZnPP 与端粒酶逆转录酶 (TERT) 和端粒共定位于同步 S 期细胞的细胞核中。 ZnPP 还与 TERT 共定位于对数期细胞的核周区域，但不与中期染色体末端的端粒共定位，该位点已知缺乏端粒酶复合物。总体而言，这些结果表明 ZnPP 本身并不与端粒序列结合，而是与端粒酶复合物的其他结构成分相互作用以抑制端粒酶活性。总之，ZnPP 主动干扰肿瘤细胞中的端粒酶活性，从而促进促凋亡和抗增殖特性。这些数据支持进一步开发天然或合成的原卟啉作为化疗剂，以增强当前肿瘤疾病的治疗方案。 ZnPP 是一种金属原卟啉，已被研究作为潜在的化疗剂。研究发现 ZnPP 可以抑制端粒酶活性，与端粒酶复合物结合，并在原位共同标记端粒酶和端粒。这些数据支持进一步开发天然或合成原卟啉，以增强当前肿瘤疾病的治疗方案。
Zinc protoporphyrin (ZnPP), a naturally occurring metalloprotoporphyrin (MPP), is currently under development as a chemotherapeutic agent although its mechanism is unclear. When tested against other MPPs, ZnPP was the most effective DNA synthesis and cellular proliferation inhibitor while promoting apoptosis in telomerase positive but not telomerase negative cells. Concurrently, ZnPP down‐regulated telomerase expression and was the best overall inhibitor of telomerase activity in intact cells and cellular extracts with IC50 and EC50 values of ca 2.5 and 6 µM, respectively. The natural fluorescence properties of ZnPP enabled direct imaging in cellular fractions using non‐denaturing agarose gel electrophoresis, western blots, and confocal fluorescence microscopy. ZnPP localized to large cellular complexes (>600 kD) that contained telomerase and dysskerin as confirmed with immunocomplex mobility shift, immunoprecipitation, and immunoblot analyses. Confocal fluorescence studies showed that ZnPP co‐localized with telomerase reverse transcriptase (TERT) and telomeres in the nucleus of synchronized S‐phase cells. ZnPP also co‐localized with TERT in the perinuclear regions of log phase cells but did not co‐localize with telomeres on the ends of metaphase chromosomes, a site known to be devoid of telomerase complexes. Overall, these results suggest that ZnPP does not bind to telomeric sequences per se, but alternatively, interacts with other structural components of the telomerase complex to inhibit telomerase activity. In conclusion, ZnPP actively interferes with telomerase activity in neoplastic cells, thus promoting pro‐apoptotic and anti‐proliferative properties. These data support further development of natural or synthetic protoporphyrins for use as chemotherapeutic agents to augment current treatment protocols for neoplastic disease. ZnPP is a metalloprotoporphyrin that has been investigated as a potential chemotherapeutic agent. ZnPP was found to inhibit telomerase activity, bind to telomerase complexes, and co‐label telomerase and telomeres in situ. These data support further development of natural or synthetic protoporphyrins to augment current treatment protocols for neoplastic disease.
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影响因子：
5.7
作者：
Iyer, JK;Shi, LR;Sullivan, DJ
通讯作者：
Sullivan, DJ
DOI：
10.3390/antiox6010015
发表时间：
2017-02-19
期刊：
Antioxidants (Basel, Switzerland)
影响因子：
--
作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Dennery, Phyllis A.
影响因子：
4.6
作者：
Alawi, Faizan;Lin, Ping
通讯作者：
Lin, Ping
影响因子：
16
作者：
Fu, D;Collins, K
通讯作者：
Collins, K