Targeting BRCAness Cancer Cells with DNA Alkylator and Its Derivatives

• Main Authors: Min-Yu Ko, 柯旻佑
• Other Authors: Hung-Yuan Chi
• Format: Others
• Language: en_US
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/brmt65

碩士 === 國立臺灣大學 === 生化科學研究所 === 106 === DNA interstrand cross-link (ICL) is one of the most cytotoxic lesions among many kinds of DNA damages. ICLs block essential cellular processes such as DNA replication and transcription, and thus generate DNA double-strand breaks (DSBs). It has been well documented that nitrogen mustards induce ICLs by DNA alkylation on both strands. Here we introduced a new DNA alkylating agent COOH-SW, generated by Professor Chao-Tsen Chen’s lab. Interestingly, my cell-based studies showed that cancer cells defective in a homology-directed repair (HDR), such as BRCA1/2-deficient cells, are sensitive to COOH-SW. Furthermore, Professor Chen’s lab further synthesized a novel DNA alkylator that combines alkylating warhead of COOH-SW and G-quadruplex (G4) ligand 3,6-bis (1-methyl-4-vinylpyridinium iodide) carbazole (BMVC) named BMVC-SW. Cell-based fluorescent images evidenced that BMVC-SW steadily bound to nucleus DNA. Moreover, I found BMVC-SW had more cytotoxicity than COOH-SW, BMVC, and combination treatment of both together in different types of cancers. Importantly, similar to COOH-SW, my cell-based studies showed that cancer cells defective in a homology-directed repair are sensitive to BMVC-SW. Thus, our collaborative research demonstrated BMVC-SW possesses more cytotoxicity than DNA alkylator alone and reveals novel selective chemicals toward BRCA-deficient (BRCAness) cancers.