The effect of various polycyclic and macrocyclic compounds on human cancer and cancer stem cells

Ciljano uništavanje tumorskih matičnih stanica (TMS), za razliku od neselektivnog uništavanja tumorskih stanica, nova je strategija u liječenju raka. TMS su malobrojne populacije stanica unutar tumora koje imaju svojstvo samoobnavljanja i propagiranja u različite linije tumorskih stanica, jako su invazivne i izrazito neosjetljive na terapiju. U ovom smo radu ispitivali potencijalno protutumorsko djelovanje nekoliko skupina spojeva (makrocikličih krunastih etera i policikličkih derivata fenola), sintetiziranih na Institutu Ruđer Bošković, na tumorske stanične linije in vitro (HCT116, MCF-7, H460 i SUM 159) i/ili njihovo selektivno djelovanje na modelu HMLEshEcad, koja pokazuje karakteristike TMS i kontrolnoj liniji HMLEshGFP. Ispitali smo mogućnost fotoaktivacije policikličkih derivata fenola u reaktivne kinon-metide ili kisikove radikale koji alkiliraju makromolekule, odnosno izazivaju oksidativni stres. Najznačajniji učinak fotoaktivacije pokazuje nekoliko derivata antracena. Također isti spojevi pokazali su i selektivno djelovanje na modelu TMS. Ovo je istraživanje podloga za razvoj fototerapije, dok se mehanizam selektivnosti na TMS, temeljenoj na aktivaciji oksidativnog stresa, treba dodatno istražiti.Targeting cancer stem cells (CSC), rather than cancer cells in general, is a novel and highly promising strategy for cancer treatment. CSC are cells within a tumor that possess the capacity to self-renew, propagate into the heterogeneous lineages of cancerous cells and that show an increased resistance to therapy. The objective of the proposed research is to test anticancer potential of macrocyclic compounds and polycyclic derivatives of phenols. Their activity was tested on a panel of human tumor cell lines (HCT116, MCF-7, H460 i SUM 159), as well as on a unique transgenic CSC model (HMLEshEcad/HMLEshGFP). We also investigated phenol derivatives to form quinone methides upon photochemical excitation and test their ability to alkylate macromolecules, or induce oxidative stress. The most intriguing activity and selectivity towards CSC cell model was demonstrated by several anthracenes. This study forms basis for further research on cancer phototherapy, as well as for elucidation of CSC selectivity based on oxidative stress activation