Abstract
Sesquiterpene lactones (SLs) such as parthenolide (PTL) and dehydroleucodine (DhL) selectively kill cancer cells without exerting normal tissue toxicity, potentially due to presence of α-methylene-γ-lactone (αMγL) fragment. We hypothesize that the addition of an azido group to the αMγL fragment of PTL or DhL further augments their anticancer properties as well as radiation sensitivity of cancer cells. Azido-SLs containing the azido group at the C14 methyl position of PTL (i.e., azido-melampomagnolide B, AzMMB) while preserving the mechanistically crucial exomethylene unit of αMγL fragment were also prepared. Sham-irradiated (i.e., unirradiated control) or irradiated human breast cancer cells (MCF7) were treated with different concentrations of azido-PTL (AzPTL) or azido-DhL (AzDhL) along with parental SLs. Proliferation rate of MCF7 cells were measured by MTT-assay, and their colony forming ability was determined by colony formation assay. Both AzPTL and AzDhL significantly suppress proliferation rate and colony forming ability of MCF-7 cells. AzPTL suppressed colony forming ability, not cellular proliferation, following irradiation to a greater extent than PTL at lower concentrations (5 and 10 μM). Electron spin resonance (ESR) studies were performed employing gamma-irradiated homogeneous supercooled aqueous solutions to investigate radical formation through addition of radiation-mediated prehydrated electrons to the azide group of AzPTL and AzDhL and to follow subsequent reactions of these radicals. In AzPTL, formation of a tertiary carbon-centered radical plausibly via a metastable aminyl radical was observed, whereas AzDhL produced both π-aminyl and α-azidoalkyl radicals. These radicals may contribute to the antitumor activities of AzPTL and AzDhL.