Catecholamines play
a crucial role in signal transduction and are
also expected to act as endogeneous antioxidants, but the mechanism
of their antioxidant action is not fully understood. Here, we describe
the impact of pH on the kinetics of reaction of four catecholamines
(L-DOPA, dopamine, adrenaline, and noradrenaline) with model 2,2-diphenyl-1-picrylhydrazyl
radical (dpph
•
) in methanol/water. The increase
in pH from 5.5 to 7.4 is followed by a 2 order of magnitude increase
in the rate constant, e.g., for dopamine (DA)
k
pH5.5
= 1,200 M
–1
s
–1
versus
k
pH7.4
= 170,000 M
–1
s
–1
, and such rate acceleration is attributed to a fast
electron transfer from the DA anion to dpph
•
. We
also proved that at pH 7.0 DA breaks the peroxidation chain of methyl
linoleate in liposomes assembled from neutral and negatively charged
phospholipids. In contrast to no inhibitory effect during peroxidation
in non-ionic emulsions, in bilayers one molecule of DA traps approximately
four peroxyl radicals, with a rate constant
k
inh
>10
3
M
–1
s
–1
. Our results from a homogeneous system and bilayers prove that catecholamines
act as effective, radical trapping antioxidants with activity depending
on the ionization status of the catechol moiety, as well as microenvironment:
organization of the lipid system (emulsions vs bilayers) and interactions
of catecholamines with the biomembrane.
Concentration dependent contribution of hydrogen atom transfer and electron transfer to the overall kinetics of reaction of phenols with a 2,2-diphenyl-1-picrylhydrazyl radical in methanol.
Drug-induced senescence program may be activated both in normal and cancer cells as a consequence of chemotherapeutic treatment, leading to some adverse side effects such as senescence-associated secretory phenotype (SASP), secondary senescence, and cancer promotion. Targeted elimination of senescent cells can be achieved by drugs with senolytic activity (senolytics), for example, the plant-derived natural compound quercetin, especially when co-treated with kinase inhibitor dasatinib. In the present study, three quercetin derivatives were synthesized and tested for improved senolytic action against etoposide-induced senescent human normal mammary epithelial cells and triple-negative breast cancer cells in vitro. Transformation of catechol moiety into diphenylmethylene ketal and addition of three acetyl groups to the quercetin molecule (QD3 derivative) promoted the clearance of senescent cancer cells as judged by increased apoptosis compared to etoposide-treated cells. A QD3-mediated senolytic effect was accompanied by decreased SA-beta galactosidase activity and the levels of p27, IL-1β, IL-8, and HSP70 in cancer cells. Similar effects were not observed in senescent normal cells. In conclusion, a novel senolytic agent QD3 was described as acting against etoposide-induced senescent breast cancer cells in vitro. Thus, a new one-two punch anti-cancer strategy based on combined action of a pro-senescence anti-cancer drug and a senolytic agent is proposed.
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