Ascorbate and endocytosed Motexafin gadolinium induce lysosomal rupture.

• Motexafin gadolinium (MGd) sensitizes malignant cells to ionizing radiation, although the underlying mechanisms for uptake and sensitization are both unclear. Here we show that MGd is endocytosed by the clathrin-dependent pathway with ensuing lysosomal membrane permeabilization, most likely via formation of reactive oxygen species involving redox-active metabolites, such as ascorbate. We propose that subsequent apoptosis is a synergistic effect of irradiation and high MGd concentrations in malignant cells due to their pronounced endocytic activity. The results provide novel insights into the mode of action of this promising anti-cancer drug, which is currently under clinical trials.

Nyckelord

Lysosomes

Endocytosis

Cancer therapy

Oxidative stress

Thioredoxin reductase

MEDICINE

MEDICIN

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