University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR) area of Environment Genetics and Oncobiology (CIMAGO), Biophysics Institute of Faculty of Medicine, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, Coimbra, 3000-548, Portugal; Clinical Academic Center of Coimbra, Praceta Prof. Mota Pinto, Coimbra, 3004-561, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, Coimbra, 3000-548, Portugal.
University of Coimbra, CIEPQPF, FFUC, Laboratory of Pharmaceutical Chemistry, Azinhaga de Santa Comba, Pólo III - Pólo das Ciências da Saúde, Coimbra, 3000-548, Portugal.
J Steroid Biochem Mol Biol. 2021 Sep;212:105950. doi: 10.1016/j.jsbmb.2021.105950. Epub 2021 Jul 14.
A new promising steroid derivative of Exemestane (Exe), the drug used for the treatment of estrogen-dependent breast cancer, was synthesized and evaluated against a set of human cancer cell lines. The new compound (Oxymestane-D1, Oxy) was tested comparatively with Exe against colon (C2BBe1, WiDr), liver (HepG2, HuH-7), lung (A549, H1299) and prostate (LNCaP, PC3) human cancer cell lines. Likewise, its effect on human colon normal cells (CCD-841 CoN) and human normal fibroblast cells (HFF-1) was studied. The cytostatic activity of Oxy was also compared with that of the reference cytostatic drugs used in chemotherapy protocols, namely carboplatin, cisplatin, doxorubicin, epirubicin, etoposide, flutamide, 5-fluorouracil, irinotecan, oxaliplatin and sorafenib. In all cell lines tested, Oxy proved to be more powerful cytostatic than Exe. Additionally, the IC at 72 h showed a three-fold activity greater than 5-fluorouracil in the WiDr cell line, twice as high as cisplatin for cell line A549 and five times higher than cisplatin for cell line H1299. Also, Oxy surprisingly revealed to induce DNA damage and inhibit the DNA damage response (DDR) proteins ATM, ATR, CHK1 and CHK2. The results obtained allow concluding that Oxy can be a promising anticancer agent to be used in chemotherapy protocols. Furthermore, its ability to inhibit crucial components of DDR can also be useful for the monotherapy or for combination with chemo and/or radiotherapy of cancer.
一种新的有前途的依西美坦（Exe）甾体衍生物，该药物用于治疗雌激素依赖性乳腺癌，已被合成并针对一组人类癌细胞系进行了评估。新化合物（Oxymestane-D1，Oxy）与 Exe 进行了比较，针对结肠（C2BBe1、WiDr）、肝（HepG2、HuH-7）、肺（A549、H1299）和前列腺（LNCaP、PC3）人类癌细胞系进行了测试。同样，研究了其对人结肠正常细胞（CCD-841 CoN）和人正常成纤维细胞（HFF-1）的影响。还比较了 Oxy 的细胞抑制活性与化疗方案中使用的参考细胞抑制药物，即卡铂、顺铂、多柔比星、表柔比星、依托泊苷、氟他胺、5-氟尿嘧啶、伊立替康、奥沙利铂和索拉非尼。在所有测试的细胞系中，Oxy 被证明比 Exe 更具细胞抑制活性。此外，在 WiDr 细胞系中，IC72 显示出比 5-氟尿嘧啶高三倍的活性，在 A549 细胞系中比顺铂高两倍，在 H1299 细胞系中比顺铂高五倍。此外，Oxy 出人意料地显示出诱导 DNA 损伤并抑制 DNA 损伤反应 (DDR) 蛋白 ATM、ATR、CHK1 和 CHK2。所得结果表明，Oxy 可能是一种有前途的抗癌药物，可用于化疗方案。此外，其抑制 DDR 关键成分的能力也可用于癌症的单独治疗或与化疗和/或放疗联合使用。
