Screening a small library of xanthones for antitumor activity and identification of a hit compound which induces apoptosis

Our previous work has described a library of thioxanthones designed to have dual activity as P-glycoprotein modulators and antitumor agents. Some of these compounds had shown a significant cell growth inhibitory activity towards leukemia cell lines, without affecting the growth of non-tumor human fibroblasts. However, their effect in cell lines derived from solid tumors has not been previously studied. The present work aimed at: (i) screening this small series of compounds from an in-house library, for their in vitro cell growth inhibitory activity in human tumor cell lines derived from solid tumors; and (ii) initiate a study of the effect of the most potent compound on apoptosis. The tumor cell growth inhibitory effect of 27 compounds was first analysed in different human tumor cell lines, allowing the identification of a hit compound, TXA1. Its hydrochloride salt TXA1 HCl was then synthesized, to improve solubility and bioavailability. Both TXA1 and TXA1 HCl inhibited the growth of MCF-7, NCI-H460, A375-C5, HeLa, 786-O, Caki-2 and AGS cell lines. The effect of TXA1 HCl in MCF-7 cells was found to be irreversible and was associated, at least in part, with an increase in cellular apoptosis. IPATIMUP integrates the i3S Research Unit, which is partially supported by FCT, the Portuguese Foundation for Science and Technology. This work is funded by FEDER funds through the Operational Programme for Competitiveness Factors-COMPETE and National Funds through the FCT-Foundation for Science and Technology, under the projects FEDER COMPETE FCOMP-01-0124-FEDER-015752, FCOMP-01-0124-FEDER-011057, NORTE-07-0162-FEDER-00018—“Contributos para o reforço da capacidade do IPATIMUP enquanto actor do sistema regional de inovação” and NORTE-07-0162-FEDER-000067—“Reforço e consolidação da capacidade infraestrutural do IPATIMUP para o sistema regional de inovação”, both supported by Programa Operacional Regional do Norte (ON.2—O Novo Norte), through FEDER funds under the Quadro de Referência Estratégico Nacional (QREN). This research was partially supported by the Strategic Funding UID/Multi/04423/2013 through national funds provided by FCT—Foundation for Science and Technology and European Regional Development Fund (ERDF), in the framework of the programme PT2020. The authors also thank FCT for the grant of R.T. Lima (SFRH/BPD/68787/2010) and QREN for the grant of D. Sousa (NORTE-07-0124-FEDER-000023).