PO-411 Novel HIF1α inhibitors suppress cancer cell growth and circumvent multidrug resistance

Abstract

Introduction Hypoxia is one of the causes of the resistance of tumours to various chemotherapeutic agents. Most solid tumours contain hypoxic regions and adapt to low levels of oxygen by producing hypoxia-activated molecules, among which HIF-1α (Hypoxia-Inducible Factor 1-alpha) is key. HIF-1α is upregulated in many types of solid cancers and contributes to tumour progression by stimulation of VEGF-A expression and subsequent neoangiogenesis. The goal of the study was to synthesise a series of novel hypoxic cytotoxins and to evaluate their anticancer potencies. Material and methods A series of 3-aryl/heteroarylquinoxaline-2-carbonitrile 1,4-dioxides was synthesised by Beirut reaction. Cancer cell lines were purchased from ATCC. The cytotoxic activity of quinoxaline 1,4-dioxides was evaluated in normoxia (21%O2) and hypoxia (1%O2). The cytotoxicity was assessed by MTT test (72 hour growth with compounds). HIF-1α and p53 activation was assessed by reporter analysis. The presence of ROS in MDA-MB-231 breast cancer cells was detected using the fluorescent probe 2′,7′-dichlorofluorescin diacetate. Results and discussions Lead compounds in series new quinoxaline 1,4-dioxides demonstrated better cytotoxicity and comparable hypoxia selectivity for human breast adenocarcinoma cell lines MCF-7 and MDA-MB-231 than the reference agent tirapazamine. In contrast to reference antibiotic doxorubicin, quinoxaline 1,4-dioxides inhibited hypoxia-mediated HIF-1α activation and showed potent cytotoxicity against multidrug resistant human chronic myeloid leukaemia K562/4 cells with overexpression P-glycoprotein (Pgp). Selected compound LCTA-2809 (6,7-dichloro-3-phenylquinoxaline-2-carbonitrile 1,4-dioxide) inhibited of cancer cell growth through p53-independent mechanisms. Compound LCTA-2809 showed no effects on p53-dependant luciferase activity, when doxorubicin revealed high potency to activate p53-dependant reporter in MCF-7 cells. Our results revealed that compound LCTA-2809 sensitised MCF-7 cells to biguanide metformin in hypoxia. Short-term treatment with LCTA-2809 resulted in the fast increase of ROS accumulation in cancer cells. Conclusion HIF-1α inhibitor LCTA-2809 can be considered as the lead compound for further anticancer drug design, evaluation, and development of new potent antitumor agents. The biology experiments of the research were supported by RSF 14-15-00362.