Hypericin Targets Multiple Signaling Mediators in Cancer Cells Generating Unique, Anti-tumoral, Anti-metastatic, and Anti-angiogenic Activities With Evidence for Clinical Applicability

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 redoxreactive 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
polyubiquitinylation, functional inactivation and rapid degradation in a proteasome independent
manner. Hsp90 physiological association with the myriad of client proteins is disrupted and
several signaling mediators, cell cycling and proliferation regulators are destabilized and
degraded. Cell cycle checkpoints affected secondarily cause uneven, premature mitosis,
(karyokinesis with no cytokinesis), forming polykaryonic giant cells, hallmark of mitotic
catastrophe also known as mitotic cell death. HIF-1, the master regulator of VEGF synthesis
and angiogenesis inducer is also an Hsp90 client protein. HIF-1 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 differentiationpromoting genes. In GBM cells, neuroglial differentiation antigens become 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.