Selective photocytotoxicity of anthrols on cancer stem-like cells: The effect of quinone methides or reactive oxygen species

Abstract

Cancer stem cells (CSCs) are a subpopulation of cancer cells that share properties of embryonic stem cells like pluripotency and self-renewal and show increased resistance to chemo- and radiotherapy. Targeting CSC, rather than cancer cells in general, is a novel and promising strategy for cancer treatment. Novel therapeutic approaches, such as photodynamic therapy (PDT) have been investigated. A promising group of phototherapeutic agents are reactive intermediates - quinone methides (QMs). This study describes preparation of QM precursor, 2-hydroxy-3-hydroxymethylanthracene (2) and a detailed photochemical and photobiological investigation on similar anthracene derivatives 3 and 4. Upon photoexcitation with near visible light at λ > 400 nm 1 and 2 give QMs, that were detected by laser flash photolysis and their reactivity with nucleophiles has been demonstrated in the preparative irradiation experiments where the corresponding adducts were isolated and characterized. 3 and 4 cannot undergo photodehydration and deliver QM, but lead to the formation of phenoxyl radical and singlet oxygen, respectively. The activity of 1-4 was tested on a panel of human tumor cell lines, while special attention was devoted to demonstrate their potential selectivity towards the cells with CSC-like properties (HMLEshEcad). Upon the irradiation of cell lines treated with 1-4, an enhancement of antiproliferative activity was demonstrated, but the DNA was not the target molecule. Confocal microscopy revealed that these compounds entered the cell and, upon irradiation, reacted with cellular membranes. Our experiments demonstrated moderate selectivity of 2 and 4 towards CSC-like cells, while necrosis was shown to be a dominant cell death mechanism. Especially interesting was the selectivity of 4 that produced higher levels of ROS in CSC-like cells, which forms the basis for further research on cancer phototherapy, as well as for the elucidation of the underlying mechanism of the observed CSC selectivity based on oxidative stress activation.

Bifunctional Phenol Quinone Methide Precursors: Synthesis and Biological Activity

“…[22] In particular, we have recently demonstrated that photogenerated QM Q formed from anthrol 1 (Scheme 1) exhibit higher cytotoxicity on cancer stem cell lines then on normal cancer cells. [23] Interestingly, our results indicate that enhanced antiproliferative effects probably does not originate from the reaction of QMs with DNA, but rather with proteins, since we have shown that compounds do not enter cell nucleus. [22d,23] However, all molecules that we studied to date were monofunctional, so in principle, they could only alkylate DNA.…”

Application of 4-amino-N-adamantylphthalimide solvatochromic dye for fluorescence microscopy in selective visualization of lipid droplets and mitochondria

“…A better correlation was obtained between the emission maxima with the Reichardt ET(30) parameter (Fig. S5 in the SI), [36] and particularly well correlated were the Stokes shifts with ET (30) (Fig. S6 in the SI).…”

“…Cell viability assay was performed as described previously. [30] Cells were seeded at 2×10 3 cells/well in a standard 96-well microtiter plates and left to attach for 24 h. Next day, test compound was added in five serial 10-fold dilutions. The cell growth rate was evaluated after 72 h of incubation, using MTT assay.…”

“…dielectric constant and refractive index of solvents. The changes in Stokes shifts are well-correlated to the empirical ET(30) solvent polarity parameter, allowing for the estimation of fluorescence maxima in different media. Fluorescence quantum yields and lifetimes do not follow any trend with solvent polarity, but the S1 state of 1 is quenched by addition of protic solvents.…”

Diet induces hepatocyte protection in fatty liver disease via modulation of PTEN signaling (Review)

“…Mitochondrial dysfunction is a contributor to ALD and this disease is linked to mitochondrial DNA fragmentation associated with active alcohol consumption (20). ROS are a group of oxygen-radical-containing molecules resulting from the metabolism of oxygen in the cells (21). Excessive concentrations of ROS result in macromolecular and genomic DNA damage, as well as cell death (22).…”