Home > Medical Research Archives > Issue 149 > Hypericin targets multiple signaling mediators in cancer cells generating unique, diverse anti-tumoral, anti-metastatic, and anti-angiogenic activities with evidence for clinical applicability
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Published in the Medical Research Archives
Mar 2017 Issue
Hypericin targets multiple signaling mediators in cancer cells generating unique, diverse anti-tumoral, anti-metastatic, and anti-angiogenic activities with evidence for clinical applicability
Published on Mar 15, 2017
DOI
Abstract
The goals of this review are to comprehensively analyze the diverse biological activities displayed by a most potent photodynamic agent–hypericin. Hypericin is a lipophilic redox-reactive molecule possessing a redox potential low enough to act as electron acceptor, subsequently discharging these electrons to oxygen, generating ROS. This property enables intracellular hypericin to retain redox activities in the dark. In cells hypericin sequesters in endoplasmic reticulum and Golgi apparatus membranes and photo-oxidizes membranal lipoproteins. However, the most relevant cytosolic hypericin target is the Hsp90 chaperone. We have shown that hypericin selectively binds to and oxidizes Hsp90, inducing its forced polyubiquitiylation, functional inactivation and rapid degradation in a proteasome independent manner. Hsp90 physiological association with a myriad of client proteins is disrupted and several signaling mediators, cell cycling and proliferation regulators are destabilized and degraded. Secondarily affected cell cycle checkpoints cause uneven, premature mitosis, (karyokinesis with no cytokinesis), forming polykaryonic giant cells, hallmark of mitotic catastrophe also known as mitotic cell death. HIF-1a, the master regulator of VEGF synthesis and angiogenesis inducer is also an Hsp90 client protein. HIF-1a is physiologically degraded by oxygen but also by the hypericin-induced Hsp90 ablation, inducing potent tumor neoangiogenesis inhibition. Hsp90 is implicated in mediating inheritable epigenetic modifications, causing epigenetic signature changes in key developmentally regulated genes and tumor cell exit from proliferation cycles. Expression of EZH2, the Polycomb repressor complex-2 catalytic subunit, which trimethylates histone H3lys27 is suppressed, class-I HDACs expression downregulated and HDAC1-Dnmt1-EZH2 complex formations diminish. Deficiencies in HDACs cellular contents lead to histones H3 and H4 hyperacetylation, which together with diminished H3K27-trimethylation relax chromatin structure, activating transcription including of differentiation-promoting genes. In GBM cells neuroglial differentiation antigens are expressed, cytoarchitecture modulated and the cells undergo tumor cell differentiation. Indeed, clinically significant anti-GBM effects were obtained in a clinical trial in recurrent, progressive GBM patients.
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