Hypericin in the Light and in the Dark: Two Sides of the Same Coin

Abstract

Hypericin (4,5,7,4′,5′,7′-hexahydroxy-2,2′-dimethylnaphtodianthrone) is a naturally occurring chromophore found in some species of the genus Hypericum, especially Hypericum perforatum L. (St. John's wort), and in some basidiomycetes (Dermocybe spp.) or endophytic fungi (Thielavia subthermophila). In recent decades, hypericin has been intensively studied for its broad pharmacological spectrum. Among its antidepressant and light-dependent antiviral actions, hypericin is a powerful natural photosensitizer that is applicable in the photodynamic therapy (PDT) of various oncological diseases. As the accumulation of hypericin is significantly higher in neoplastic tissue than in normal tissue, it can be used in photodynamic diagnosis (PDD) as an effective fluorescence marker for tumor detection and visualization. In addition, light-activated hypericin acts as a strong pro-oxidant agent with antineoplastic and antiangiogenic properties, since it effectively induces the apoptosis, necrosis or autophagy of cancer cells. Moreover, a strong affinity of hypericin for necrotic tissue was discovered. Thus, hypericin and its radiolabeled derivatives have been recently investigated as potential biomarkers for the non-invasive targeting of tissue necrosis in numerous disorders, including solid tumors. On the other hand, several light-independent actions of hypericin have also been described, even though its effects in the dark have not been studied as intensively as those of photoactivated hypericin. Various experimental studies have revealed no cytotoxicity of hypericin in the dark; however, it can serve as a potential antimetastatic and antiangiogenic agent. On the contrary, hypericin can induce the expression of some ABC transporters, which are often associated with the multidrug resistance (MDR) of cancer cells. Moreover, the hypericin-mediated attenuation of the cytotoxicity of some chemotherapeutics was revealed. Therefore, hypericin might represent another St. John's wort metabolite that is potentially responsible for negative herb–drug interactions. The main aim of this review is to summarize the benefits of photoactivated and non-activated hypericin, mainly in preclinical and clinical applications, and to uncover the “dark side” of this secondary metabolite, focusing on MDR mechanisms.

Occurrence and Distribution of Phytochemicals in the Leaves of 17 In vitro Cultured Hypericum spp. Adapted to Outdoor Conditions

“…A broad spectra of secondary metabolites with diverse biological activities have been found in this species, for example, the naphthodianthrone derivatives hypericin and pseudohypericin, their supposed precursor emodin, and/or emodin anthrone (Bais et al, 2003; Kirakosyan et al, 2004; Zobayed et al, 2006), phloroglucinols hyperforin, adhyperforin and flavonoids quercetin, quercitrin, rutin and hyperoside and/or isoquercitrin, to name a few (Nahrstedt and Butterweck, 1997; Saddiqe et al, 2010; Zorzetto et al, 2015; Hou et al, 2016; Oliveira et al, 2016). Among these compounds, the effectiveness of hypericin as a natural photosensitizer with implications in photodynamic therapy has been rigorously explored (Zhang et al, 2014; Jendželovská et al, 2016), in addition to studies on its antiviral and antimicrobial properties (Kubin et al, 2005; Karioti and Bilia, 2010; Dementavicius et al, 2016). Furthermore, both hyperforin and adhyperforin have been shown to play a role in inhibition of various neurotransmitter receptors, thereby exhibiting antidepressant efficacy (Laakmann et al, 1998; Jat, 2013).…”

Trends and targets in antiviral phototherapy

“…8a,10,204 Different antiviral mechanisms can be relevant for one compound class, e.g., fullerenes which act via Type I and Type II photosensitization but also show light-independent antiviral activity, or curcumin and hypericin which act as PSs but also show significant dark toxicity effects. 122b, 142,143 On the other hand, the psoralen derivative amotosalen, commercially applied in blood product decontamination, and 5-iodonaphthylazide are examples for compounds which are photochemically active against viruses but do not rely on ROS for their antiviral effect. In general, the 'unspecificity' of the action of 1 O 2 and other ROS generated by PSs (or positively phrased, their 'multitarget' mode of action) is seen as an advantage with respect to possible resistance formation given the genetic flexibility of viruses and bacteria.…”

“…137 There are numerous studies, including clinical trials, on the photodynamic action of hypericin and its derivatives against tumors; and also to a lesser extent against bacteria. 136,141,142 Recent research has additionally focused on the light-independent pharmacodynamic effects of hypericin derivatives. 142,143,144 Pronounced toxicity of hypericin against tumor cells in the absence of light has been reported and possible mechanisms are discussed in the literature.…”

“…136,141,142 Recent research has additionally focused on the light-independent pharmacodynamic effects of hypericin derivatives. 142,143,144 Pronounced toxicity of hypericin against tumor cells in the absence of light has been reported and possible mechanisms are discussed in the literature. 143,144 Hypericin has also been investigated for its antiviral properties.…”

Thermosensitive, fast gelling, photoluminescent, highly flexible, and degradable hydrogels for stem cell delivery

“…[58, 64] After conjugating with HYP, the hydrogels became fluorescent with a major emission peak at 607 nm (Figure 2B). Besides its photoluminescent property, HYP has antidepressant, antiviral, and antineoplastic properties [65, 66]. …”