Preet Ranjan, Siddharth Sumit, Satapathy Shakti Ranjan, Das Sarita, Nayak Anmada, Das Dipon, Wyatt Michael D, Kundu Chanakya Nath
Cancer Biology Laboratory, KIIT School of Biotechnology, Campus-11, KIIT University, Patia, Bhubaneswar, Orissa 751024, India.
Department of Drug Discovery and Biomedical Sciences, South Carolina College of Pharmacy, University of South Carolina, Columbia, SC, USA.
Biochem Pharmacol. 2016 Apr 1;105:23-33. doi: 10.1016/j.bcp.2016.01.017. Epub 2016 Feb 2.
Quinacrine (QC) causes apoptosis in breast cancer cells by induction of DNA damage, arrest of cells in S-phase, and by topoisomerase inhibition. Here, we show that QC-mediated apoptosis is not only due to increased DNA damage but also by compromising cell cycle checkpoints and base excision repair (BER) capacity in breast cancer cells. QC decreased CHK1, CDKs (CDC2, MDM2, CDC6), cyclins (B1, E1) and CDC25-A in a dose dependent manner. The expression of basal ATR remains unaltered but pATR (Ser-428) increased after QC treatment. A CHK1 inhibitor, SB218078, was also tested alone and in combination with QC. Like QC, SB218078 caused apoptosis by DNA damage and S-phase arrest. The combination of QC and SB218078 increased apoptosis by blocking the cell cycle in G2/M, which caused a mitotic catastrophe, and induced DNA damage at a higher level in comparison to individual compound treatments. Both drugs individually or in combination decreased the levels of replication protein A (RPA). Measurement of the expression of BER (SP- and LP-BER) proteins and direct in vivo BER activity revealed that the QC/SB218078 combination caused apoptosis in cancer cells by disrupting the induction of BER, which represents a novel means of potentially treating breast cancer.
喹吖因（QC）通过诱导DNA损伤、使细胞停滞于S期以及抑制拓扑异构酶，从而导致乳腺癌细胞凋亡。在此，我们表明，QC介导的细胞凋亡不仅归因于DNA损伤增加，还归因于破坏乳腺癌细胞的细胞周期检查点和碱基切除修复（BER）能力。QC以剂量依赖性方式降低CHK1、周期蛋白依赖性激酶（CDK，包括CDC2、MDM2、CDC6）、细胞周期蛋白（细胞周期蛋白B1、E1）和CDC25 - A的水平。基础ATR的表达保持不变，但QC处理后pATR（Ser - 428）增加。还单独测试了CHK1抑制剂SB218078以及它与QC联合使用的情况。与QC一样，SB218078通过DNA损伤和S期停滞导致细胞凋亡。QC与SB218078联合使用通过阻断G2/M期的细胞周期增加细胞凋亡，这导致有丝分裂灾难，并与单独使用化合物处理相比，在更高水平上诱导DNA损伤。两种药物单独或联合使用均降低了复制蛋白A（RPA）的水平。对BER（短补丁和长补丁BER）蛋白表达的测量以及直接的体内BER活性显示，QC/SB218078联合使用通过破坏BER的诱导导致癌细胞凋亡，这代表了一种潜在治疗乳腺癌的新方法。
