Abstract
Gallic acid (GA) is a natural anti-cancer compound that can be found in many food sources, including edible mushrooms, fruits, and vegetables. Studies generally attribute the anti-cancer activity of GA to the induction of apoptosis. Here, we reported that GA activated iron-dependent cell death mechanisms with apoptotic, ferroptotic, and necroptotic features. Our time-lapse live-cell microscopy study demonstrated that GA could induce coexistence of multiple types of cell death pathways, including apoptosis characterized by mitochondrial cytochrome c release and caspase-3 activation, ferroptosis characterized by lipid peroxidation, and necroptosis characterized by the loss of plasma membrane integrity. This GA-induced cell death could be completely suppressed by exposure to an iron chelator deferoxamine, indicating that it is an iron-dependent cell death process. Importantly, MLKL (mixed lineage kinase domain-like protein) inhibitor necrosulfonamide exerted a synergistic effect by increasing the sensitivity of cancer cells to GA. Taken together, our results provide new mechanistic insights, and also suggest new strategies to enhance the efficacy of this natural anti-cancer compound by identifying the agents that can promote or suppress the GA-induced cell death process.
Highlights
Despite dramatic scientific gains and technological advancement, cancer remains a major and growing public health problem in the world
It is generally believed that Gallic acid (GA) triggers cancer cells to die through apoptosis, as the GA-induced cells display hallmarks of apoptosis, including mitochondrial fragmentation, the release of cytochrome c from mitochondria to cytosol, nuclear condensation, DNA damage, and caspase-3 activation [20]
We applied 50 μg/mL of GA to trigger cancer cell death, as in vivo studies demonstrated that administration of this dosage of GA is well-tolerated by animals, such as rats, without adverse physiological response detected [22,23]
Summary
Despite dramatic scientific gains and technological advancement, cancer remains a major and growing public health problem in the world. Many primary cancers, including highly fatal metastatic small cell lung carcinoma and melanoma, often response to aggressive cancer therapy [4,5], there are severe side effects, such as cardiotoxicity and blood disorders [6,7,8]. Such side effects exceed the tolerance of the patients, and most chemotherapy and radiotherapy are delivered episodically to let patients recover from the side effects between successive treatments. There is a pressing need to devise new and effective strategies for fighting cancer, with less side effect on the patients
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