Hypericin (4,5,7,4',5',7'-hexahydroxy-2,2'-dimethylnaphtodiantrone) is a naturally occurring chromophore found in plants 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.

Photodynamic therapy (PDT) is a flexible multi-target therapeutic approach. One of the main requirements of successful PDT is sufficient intracellular concentration of an applicable photosensitizer. Mechanisms of anticancer drug elimination by tumour cells are mostly linked to the elevated expression and activity of P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and P450 monooxygenases. The interaction of hypericin with this cell drug-defence system is still unclear. We report here for the first time increased activity of MRP1 and BCRP in HT-29 colon cancer cells treated with hypericin per se. On the contrary, pre-treatment with proadifen (SKF525A) affected the function of MRP1 and BCRP leading to increased hypericin content, which might indicate a possible link between proadifen and these ABC transporter proteins. Subsequent enhanced intracellular oxidative stress was accompanied by loss of mitochondrial membrane potential, activation of caspase-9 and -3, PARP cleavage and onset of apoptosis. In conclusion, our study suggests that drug efflux transporters MRP1 and BCRP affect the pharmacokinetics of hypericin in HT-29 colon adenocarcinoma cells, and the action of hypericin-mediated PDT (HY-PDT) should be modulated by pre-treatment with their specific inhibitors.

Cancer cell resistance, particularly multidrug resistance (MDR), is the leading cause of chemotherapy failure. A number of mechanisms involved in the development of MDR have been described, including the overexpression of ATP-dependent membrane-bound transport proteins. The enhanced expression of these proteins, referred to as ATP‑binding cassette (ABC) transporters, results in an increased cellular efflux of the cytotoxic drug, thereby reducing its intracellular concentration to an ineffective level. Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently consumed drugs worldwide. NSAIDs are mainly used to treat pain, fever and inflammation. Numerous studies suggest that NSAIDs also show promise as anticancer drugs. NSAIDs have been shown to reduce cancer cell proliferation, motility, angiogenesis and invasiveness. In addition to these effects, NSAIDs have been shown to induce apoptosis in a wide variety of cancer types. Moreover, several studies have indicated that NSAIDs may sensitise cancer cells to the antiproliferative effects of cytotoxic drugs by modulating ABC transporter activity. Therefore, combining specific NSAIDs with chemotherapeutic drugs may have clinical applications. Such treatments may allow for the use of a lower dose of cytotoxic drugs and may also enhance the effectiveness of therapy. The objective of this review was to discuss the possible role of NSAIDs in the modulation of antitumour drug cytotoxicity. We particularly emphasised on the use of COX-2 inhibitors in combination with chemotherapy and the molecular and cellular mechanisms underlying the alterations in outcome that occur in response to this combination therapy.