Abstract
Sesquiterpene lactones (SLs) are plant-derived compounds that display anti-cancer effects. Some SLs derivatives have a marked killing effect on cancer cells and have therefore reached clinical trials. Little is known regarding the mechanism of action of SLs. We studied the responses of human cancer cells exposed to various concentrations of dehydroleucodine (DhL), a SL of the guaianolide group isolated and purified from Artemisia douglasiana (Besser), a medicinal herb that is commonly used in Argentina. We demonstrate for the first time that treatment of cancer cells with DhL, promotes the accumulation of DNA damage markers such as phosphorylation of ATM and focal organization of γH2AX and 53BP1. This accumulation triggers cell senescence or apoptosis depending on the concentration of the DhL delivered to cells. Transient DhL treatment also induces marked accumulation of senescent cells. Our findings help elucidate the mechanism whereby DhL triggers cell cycle arrest and cell death and provide a basis for further exploration of the effects of DhL in in vivo cancer treatment models.
Highlights
Sesquiterpene lactones (SLs) are a large and structurally diverse group of plant metabolites [1] many members of which display anti-tumor effects [2,3]
The results of this study show that the reduced proliferation of cancer cells treated with DhL is accompanied by increased focal organization of DNA-damage sensors (c-H2AX and 53BP1) and increased levels and activity of p53
We infer that DhL triggers at least certain aspects of the DNA damage response (DDR) response [41], which in turn activates apoptotic and senescence programs that are closely associated with the levels of DNA damage [30]
Summary
Sesquiterpene lactones (SLs) are a large and structurally diverse group of plant metabolites [1] many members of which display anti-tumor effects [2,3]. There is recent evidence of an intracellular cell killing effect triggered by SLs. The disruption of a calcium pump in the endoplasmic reticulum [12,13], increased generation in iron-dependent free radicals [14,15], control of nuclear factor kB (NFkB), activation of the tumor suppressor p53 [8,16,17], alteration of the epigenetic code [18,19], and DNA alkylation [20], have all been reported as target intracellular events altered by SL treatment that could account for the antitumorigenic effect of SLs [2]. The above findings indicate a potential multifactorial effect of SLs in cancer cells
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