Department of Physics and Astronomy, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada ; Departments of Biology and Chemistry, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada.
Department of Physics and Astronomy, University of Waterloo, 200 University Avenue West, Waterloo, Ontario, Canada.
EBioMedicine. 2015 Apr 20;2(6):544-53. doi: 10.1016/j.ebiom.2015.04.011. eCollection 2015 Jun.
Based on a molecular-mechanism-based anticancer drug discovery program enabled by an innovative femtomedicine approach, we have found a previously unknown class of non-platinum-based halogenated molecules (called FMD compounds) as potent antitumor agents for effective treatment of cancers. Here, we present in vitro and in vivo studies of the compounds for targeted chemotherapy of cervical, breast, ovarian, and lung cancers. Our results show that these FMD agents led to DNA damage, cell cycle arrest in the S phase, and apoptosis in cancer cells. We also observed that such a FMD compound caused an increase of reduced glutathione (GSH, an endogenous antioxidant) levels in human normal cells, while it largely depleted GSH in cancer cells. We correspondingly found that these FMD agents exhibited no or little toxicity toward normal cells/tissues, while causing significant cytotoxicity against cancer cells, as well as suppression and delay in tumor growth in mouse xenograft models of cervical, ovarian, breast and lung cancers. These compounds are therefore a previously undiscovered class of potent antitumor agents that can be translated into clinical trials for natural targeted chemotherapy of multiple cancers.
基于一种创新的飞秒医学方法支持的基于分子机制的抗癌药物发现计划，我们发现了一类以前未知的非铂类卤代分子（称为 FMD 化合物），它们是有效的癌症治疗的有效抗肿瘤药物。在这里，我们介绍了这些化合物针对宫颈癌、乳腺癌、卵巢癌和肺癌的靶向化疗的体外和体内研究。我们的研究结果表明，这些 FMD 药物可导致 DNA 损伤、癌细胞的 S 期细胞周期停滞和细胞凋亡。我们还观察到，这种 FMD 化合物会导致人正常细胞中还原型谷胱甘肽（GSH，一种内源性抗氧化剂）水平升高，而在癌细胞中则大量耗尽 GSH。我们相应地发现，这些 FMD 药物对正常细胞/组织没有或几乎没有毒性，而对癌细胞具有显著的细胞毒性，并抑制和延迟宫颈癌、卵巢癌、乳腺癌和肺癌的小鼠异种移植模型中的肿瘤生长。因此，这些化合物是一类以前未被发现的有效抗肿瘤药物，可以转化为多种癌症的天然靶向化疗的临床试验。
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