Kul Pinar, Tuncbilek Meral, Ergul Mustafa, Yenilmez Tunoglu Ezgi Nurdan, Tutar Yusuf
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ankara University, Ankara, Turkey.
Division of Pharmaceutical Chemistry, Health Sciences Institutes, Ankara University, Ankara, Turkey.
Anticancer Agents Med Chem. 2023;23(5):585-598. doi: 10.2174/1871520622666220905122346.
Cancer cells restrain apoptotic and senescence pathways through intracellular heat shock protein 70 (Hsp 70). These cells aid stimulus-independent growth, and their higher metabolism rate requires Hsps. Hsps compensate abnormally increased substrate protein folding rate of cancer cells.
Misfolding of substrate proteins especially signaling substrate proteins, may not function properly. Therefore, Hsp70 folds these substrate proteins into their native-fully functional states, and this mode of action helps cancer cell survival.
Targeting Hsps is promising cancer therapy, and in this study, 6,8,9-trisubstituted purine derivatives were designed and synthesized to inhibit Hsp70 and drive cancer cells to apoptosis. Further, oncogenic stimuli through inhibitors can induce an irreversible senescent state and senescence is a barrier to transformation.
Hsp70 helps cancer cells to bypass the cellular senescence program, however, binding of N6-(4- isopropylaniline) analogue (7) depletes Hsp70 function as evidenced by aggregation assay and Hsp70 depletion induces senescence pathway.
The purine-based inhibitor-compound 7 effectively inhibits MCF-7 cell line. Moreover, the therapeutic potential with regard to the senescence-associated secretory phenotype has complementary action. Dual action of the inhibitor not only drives the cells to apoptosis but also force the cells to be in the senescence state and provides promising results specially for luminal A type breast cancer therapy.
癌细胞通过细胞内热休克蛋白70（Hsp 70）抑制凋亡和衰老途径。这些细胞有助于非刺激依赖性生长，其较高的代谢率需要热休克蛋白。热休克蛋白可补偿癌细胞中异常增加的底物蛋白折叠率。
底物蛋白尤其是信号底物蛋白的错误折叠可能无法正常发挥功能。因此，Hsp70将这些底物蛋白折叠成其天然的全功能状态，这种作用方式有助于癌细胞存活。
靶向热休克蛋白是一种很有前景的癌症治疗方法，在本研究中，设计并合成了6,8,9-三取代嘌呤衍生物以抑制Hsp70并促使癌细胞凋亡。此外，通过抑制剂产生的致癌刺激可诱导不可逆的衰老状态，而衰老则是细胞转化的障碍。
Hsp70帮助癌细胞绕过细胞衰老程序，然而，N6-（4-异丙基苯胺）类似物（7）的结合会耗尽Hsp70的功能，这在聚集试验中得到了证实，并且Hsp70的耗尽会诱导衰老途径。
基于嘌呤的抑制剂化合物7可有效抑制MCF-7细胞系。此外，其在衰老相关分泌表型方面的治疗潜力具有互补作用。该抑制剂的双重作用不仅促使细胞凋亡，还迫使细胞处于衰老状态，尤其为腔面A型乳腺癌治疗提供了有前景的结果。
