Nichol Ryan J O, Khalaf Abedawn I, Sooda Kartheek, Hussain Omar, Griffiths Hollie B S, Phillips Roger, Javid Farideh A, Suckling Colin J, Allison Simon J, Scott Fraser J
Department of Biological and Geographical Sciences , School of Applied Sciences , University of Huddersfield , Huddersfield , UK.
Department of Pure and Applied Chemistry , WestCHEM , University of Strathclyde , Glasgow , UK . Email:
Medchemcomm. 2019 Jul 18;10(9):1620-1634. doi: 10.1039/c9md00268e. eCollection 2019 Sep 1.
Traditional cytotoxic agents which act through a DNA-alkylating mechanism are relatively non-specific, resulting in a small therapeutic window and thus limiting their effectiveness. In this study, we evaluate a panel of 24 non-alkylating Strathclyde Minor Groove Binders (S-MGBs), including 14 novel compounds, for anti-cancer activity against a human colon carcinoma cell line, a cisplatin-sensitive ovarian cancer cell line and a cisplatin-resistant ovarian cancer cell line. A human non-cancerous retinal epithelial cell line was used to measure selectivity of any response. We have identified several S-MGBs with activities comparable to cis-platin and carboplatin, but with better selectivity indices, particularly S-MGB-4, S-MGB-74 and S-MGB-317. Moreover, a comparison of the cis-platin resistant and cis-platin sensitive ovarian cancer cell lines reveals that our S-MGBs do not show cross resistance with cisplatin or carboplatin and that they likely have a different mechanism of action. Finally, we present an initial investigation into the mechanism of action of one compound from this class, S-MGB-4, demonstrating that neither DNA double strand breaks nor the DNA damage stress sensor protein p53 are induced. This indicates that our S-MGBs are unlikely to act through an alkylating or DNA damage response mechanism.
通过DNA烷基化机制发挥作用的传统细胞毒性药物相对缺乏特异性，导致治疗窗口较小，从而限制了它们的有效性。在本研究中，我们评估了一组24种非烷基化的斯特拉斯克莱德小沟结合剂（S-MGBs），包括14种新型化合物，针对人结肠癌细胞系、顺铂敏感的卵巢癌细胞系和顺铂耐药的卵巢癌细胞系的抗癌活性。使用人非癌性视网膜上皮细胞系来测量任何反应的选择性。我们已经鉴定出几种活性与顺铂和卡铂相当，但选择性指数更好的S-MGBs，特别是S-MGB-4、S-MGB-74和S-MGB-317。此外，对顺铂耐药和顺铂敏感的卵巢癌细胞系的比较表明，我们的S-MGBs与顺铂或卡铂没有交叉耐药性，并且它们可能具有不同的作用机制。最后，我们对这类化合物中的一种化合物S-MGB-4的作用机制进行了初步研究，证明既未诱导DNA双链断裂，也未诱导DNA损伤应激传感器蛋白p53。这表明我们的S-MGBs不太可能通过烷基化或DNA损伤反应机制发挥作用。
