267 - Biological Characterization of the Anti-Tumor Properties of Novel Dual-Target Inhibitors of Dihydrofolate Reductase and Thioredoxin Reductase

• Published in: Free radical biology & medicine Vol. 100; pp. S119 - S120
• Main Authors: Chew, Eng-Hui, Ng, Hui-Li, Kjellander, Matilda, Karuppasamy, Muthukumar, Swee-Yue Chong, Adrina, Chui, Wai-Keung, Ungerstedt, Johanna
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.11.2016
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2016.10.308

Drug resistance to chemotherapy is one reason why many cancer treatments have failed. To combat this problem, a strategy of simultaneously targeting several vital systems of the cancer cell could be effective. Dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR) are enzymes belonging to two unrelated cellular pathways that are vital for cancer cell growth. Novel dual target inhibitors of DHFR and TrxR had been synthesized and lead compounds displaying strong anti-proliferative activities against HCT116 colorectal and MCF-7 breast carcinoma cells that were correlated to their in vitro DHFR and TrxR inhibitory potencies were identified. Further biological characterization work demonstrated that in HCT116 cells, the lead compounds exhibited inhibitory effects against DHFR and TrxR activities and brought about induction of apoptosis in a dose-dependent manner. Cell viability assays carried out on wild-type and methotrexate-resistant HCT116 cells had revealed that the lead DHFR-TrxR dual targeting compounds were effective in inhibiting growth in the resistant cell line, suggesting that the novel compounds could potentially serve as clinical candidates in anticancer therapies.