Furanocoumarins in anticancer therapy – For and against

Fitoterapia 142 (2020) 104492

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Review

Furanocoumarins in anticancer therapy – For and against Joanna Sumorek-Wiadro, Adrian Zając, Aleksandra Maciejczyk, Joanna Jakubowicz-Gil

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Department of Functional Anatomy and Cytobiology, Maria Curie-Sklodowska University, Akademicka 19, 20-033 Lublin, Poland

A R T I C LE I N FO

A B S T R A C T

Keywords: Furanocoumarins Psoralen Angelicin Cancer Programmed cell death

Furanocoumarins are a class of natural compounds produced by several plants, including those consumed by humans. They have been used medicinally in eastern countries for ages. Given the growing body of evidence about their anticancer potential and observations that naturally occurring compounds potentiate the antitumor activity of chemotherapeutics, more attention is paid to elucidation of the nature of furanocoumarins and the possibility of using thereof in practice. The general mechanism by which furanocoumarins eliminate cancer cells is based on cell cycle blockage and initiation of programmed death like apoptosis or autophagy. The precise molecular mechanism of such an action depends on the chemical structure of furanocoumarins, which is based on the furan ring attached to the coumarin backbone in a linear or angular form as well as the type, location, and number of the substituents attached. The review summarizes the current evidence of the antitumor properties of linear and angular furanocoumarins with special emphasis on the molecular mechanism of elimination of cancer cells via apoptosis and autophagy. Negative aspects of the use of coumarins in anticancer therapy will be also discussed especially in the context of their phototoxicity and potential cancerogenic effect.

1. Introduction Furanocoumarins are natural compounds occurring in the world of plants and belonging to the coumarin derivatives, produced in plants in response to stress and as protection against fungal, bacterial and insect attack (also named as natural pesticides) [13]. In medicine, they are used in combination with ultraviolet radiation in the treatment of autoimmune skin diseases (psoriasis, vitiligo, eczema, alopecia, and lichen planus) and primary T-cell lymphomas (fungal mycosis). Beneficial effects of furanocoumarins on the central nervous system (analgesic, anticonvulsive, and sedative effects) and the circulatory system (anticoagulant and hypotensive effects) were also observed. They have been applied as anti-depressants and anti-oxidants. Their anti-bacterial, anti-fungal, anti-inflammatory, anti-allergic, and anti-viral properties have been proved. In addition to these medical activities, furanocoumarins display anticancer properties. The interest in this field began from reports by Thornes, who observed the immunomodulatory activity of coumarin and its usefulness in malignant melanoma [67]. Since then, many molecular mechanisms involved in the elimination of cancer cells by furanocoumarin have been observed. An important step in the study of the anticancer properties of furanocoumarins was the discovery of anti-proliferative activity correlated with cell-cycle arrest and cell death initiation, which gave hope for using these compounds as

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anticancer drugs [2,26,33,64,72,86]. Furanocoumarins have also been shown to affect the adhesion and motility of neoplastic cells by affecting the assembly of actin filaments, which may be useful in metastasis prevention [71]. What is also noteworthy and may have practical value is the fast absorption of furanocoumarins from food into the human bloodstream and detection in plasma even within 2–15 min after administration [41]. Unfortunately, enthusiasm on such beneficial properties decreased after discovering the photoactivity of furanocoumarins what in contact with UV may lead to the development of phytophotodermatitis and was associated with greater risk of skin cancers [56,83,84]. It follows that the effect of furanocoumarins on human health is complex and the decision to use them in cancer therapy should be taken carefully. Therefore, the present article will summarize the knowledge on the possible use of furanocoumarins as anticancer agents with special emphasis on the relation between their chemical structure and therapeutic effectiveness, not forgetting the negative side effects of such treatment. 2. Furanocoumarin metabolism in the human body 2.1. Chemical structure of furanocoumarins The structure of furanocoumarins is based on the furan ring

Corresponding author. E-mail address: [email protected] (J. Jakubowicz-Gil).

https://doi.org/10.1016/j.fitote.2020.104492 Received 27 November 2019; Received in revised form 3 February 2020; Accepted 3 February 2020 Available online 04 February 2020 0367-326X/ © 2020 Elsevier B.V. All rights reserved.

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place of metabolism is the liver via cytochrome P450-dependent monooxygenases. Then, furanocoumarins are excreted into urine as hydroxylated or glucuronated products within 1 h after ingestion. They remain in urine as long as 24 h. It was also observed that furanocoumarins are converted to bergaptol before excretion, as this compound exhibited the highest concentration. Consumption of 900 mL grapefruit juice containing 12.5 mg of bergaptol and 6.9 mg of bergamottin resulted in average urinary excretion of 0.36 mg and 13.23 mg of free and conjugated bergaptol, respectively, within 6 h. No other furanocoumarins were found. Psoralen, present in plasma, has not been detected in urine frequently. This suggests extensive metabolism of furanocoumarins in the organism, which requires more comprehensive studies [18,39,40,42,43].

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Fig. 1. General structures of linear (A) and angular (B) furanocoumarins.

attached to the coumarin backbone. Depending on the location of the substituent, the psoralen (linear) and angelic (angular) types are distinguished. In the former, the furan ring is connected with 6 and 7 carbon atoms in the backbone, while the substituent in the latter one takes positions C7 and C8 (Fig. 1) [45,59,65]. In the plant kingdom, the linear type is the most common, especially in plants from the Apiaceae and Rutaceae families. The occurrence of angular furanocoumarins is limited to plants from the Apiaceae and Leguminosae (Fabaceae) families [22,28]. Both linear and angular types can give many derivatives. They are formed by replacing the hydrogen atom in the coumarin ring with a hydroxyl or alkoxy group [44]. The type, location, and number of substituents attached determine the physicochemical and biological properties of the compound what will be analyzed in the next chapters.

3. Anticancer potential of furanocoumarins 3.1. Psoralen and its derivatives In terms of the structure, psoralen is the simplest linear furanocoumarin with anticancer properties. As shown in in vitro studies, it can arrest the cell cycle and inhibits proliferation, directing cells to the path of programmed death, e.g. apoptosis or autophagy. Studies carried out on breast cancer cells also showed anti-migratory properties of psoralen (> 21,5 μM). The mechanism of this action was based on the inhibition of the activation of transcription factor NFκB (Nuclear Factor kappa B), which is responsible in cancer cells for the initiation and maintenance of the so-called epithelial mesenchymal transition (EMT). This process leads to the transformation of polarized epithelial cells into mesenchymal ones, characterized by aggressive migration and an invasive phenotype [79,80]. In cancer cells, NFκB also plays an important role in the inhibition of apoptosis and is responsible for the consequent ineffectiveness of treatment. The blocking of its activity by psoralen leads to inhibition of expression of antiapoptotic proteins, e.g. c-FLIP (FADD-like IL-1β-converting enzyme)-inhibitory protein (c-FLIP)) and IAP (Inhibitor of Apoptosis Proteins) as well as activation of proapoptotic polypeptides (Bax, c-Jun N-terminal kinases (JNKs)). The initiation of apoptosis under the influence of psoralen (80 μg/mL) may also be a result of blocking the cell cycle in the G1/S phase, as observed in many oral (KB, KBv200) and leukemia (K562 and K562 / ADM) cancer cell lines [11,81]. An interesting mechanism of the antineoplastic activity of psoralen was described by Wang and colleagues [79,80]. In their research conducted on MCF-7 and MCF-7/ADR breast cancer cell lines, the authors focused their attention on the multidrug resistance (MDR) phenomenon responsible for cancer treatment failure. The molecular mechanism of this process was based on the decline in the intracellular level of an anticancer drug by its accumulation in cytoplasmic exosomes, which were then secreted outside the cell. Psoralen significantly reduced the number of exosomes, which was correlated with increased sensitivity of the breast cancer cells to the induction of programmed death under the influence of chemotherapy. Similar observations were carried out on lung cancer cell lines [20,79,80]. Not only psoralen but also its derivatives possess documented anticancer properties, for instance the most frequently occurring linear furanocoumarins with an attached to the C5 or C8 position methoxy (bergapten (5-methoxypsoralen, 5-MOP) or xanthotoxin (8-methoxypsoralen, 8-MOP) or isoprenyl (isopentenyloxy) (isoimperatorin or imperatorin) group. According to Widelski and colleagues [82], the presence of the methoxy group enhanced the anti-tumor properties of psoralen, regardless of the substituent location, which indicated that the activity of 5-MOP and 8-MOP were similar. In human HL 60 leukemia cells, both compounds (100 μM) exhibited pro-apoptotic, anti-proliferative properties and inhibited the cell cycle in the G1 phase with the same intensity. The same studies showed that substitution of the methoxy group with an isopentenyloxy moiety in the C5 position led to a

2.2. Absorption and metabolism of furanocoumarins Furanocoumarin metabolism in the human body is a very complex issue studied intensively in many laboratories around the world. Because detailed scientific studies have appeared in the literature [41,42], only general aspects of the mechanism of absorption will be presented in this article. The bioavailability of furanocoumarins should be considered at several levels e.g. their concentration in consumed food, absorption, distribution, metabolism, and excretion. Daily consumed fruits and vegetables, e.g. grapefruit, lime, lemon, oranges, carrots celery, parsnip, and parsley, are the richest sources. Precise estimation of the content of furanocoumarin is difficult. It varies depending on cultivars and is correlated with different genetic backgrounds as well as environmental factors such as the geographic location, weather, and agricultural conditions. The post-harvest storage and transport as well as processing techniques affect the composition of furanocoumarins in food. Their biosynthesis in plants is also increased in response to the attack of pathogens such as bacteria, viruses, fungi, or insects [5]. Another important aspect is associated with the techniques of measurement of the concentration of compounds, which should be used uniformly to obtain comparable results. Despite these differences, a few publications on the general daily intake of furanocoumarins have appeared. The reports have shown that it varies between 1.2 and 1.5 mg per day in the western countries, but the amount can change depending on the diet. Besides consumption, furanocoumarins can be absorbed into bloodstream after dermal contact, which additionally increases the concentration and bioavailability of these compounds. The most beneficial source of information about the distribution of furanocoumarins in the human body are experiments with encapsulated labeled and orally administered compounds. For example, encapsulation of 8-MOP (8-methoxypsoralen) revealed that it is rapidly absorbed in the gastrointestinal tract and distributed to the skin, blood, liver, brain, spleen, kidney, and testis. It was also observed that furanocoumarins isolated from grapefruits were detected in the plasma of healthy adults 15 min after ingestion with the concentration peak at 30–60 min. In plasma, furanocoumarins bind to albumins and other plasma proteins. As observed in animal models, the metabolism of furanocoumarins begins through the activity of intestinal bacteria in the digestive tract, where furanocoumarins are metabolized to psoralen and isopsoralen. Another 2

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Fig. 2. Molecular mechanism of anti-tumor activity of bergapten.

Fig. 3. Apoptosis induction in tumor cells upon xanthotoxin treatment.

decrease in the pro-apoptotic properties of the compound [82]. Studies conducted on the human cervical cancer (HeLa S3) and gastric adenocarcinoma (MK-1) cell lines showed that the presence of the methoxy group at the C5 position increased the anti-proliferative properties, compared to the substituent at the C8 position. In addition, this activity was reduced due to the replacement of the methoxy group with the isopentenyloxy one [16,17]. As demonstrated in in vitro studies using liver (Hep-G2) and gastric (SGC-7901) cancer cell lines as an experimental model, bergapten (100 μg/mL) appeared to act as an effective anticancer compound directing tumor cells to programmed death (Fig. 2) [12]. In studies with estrogen-dependent breast cancer cells (MCF-7 and SKBR-3), 5-MOP reduced tumor invasiveness by degradation of estrogen receptors responsible for overexpression of genes related with survival, proliferation, and tumor growth [22,51]. An interesting example of the anti-tumor activity of bergapten was noticed in human liver cancer cells (Hep-G2). This furanocoumarin blocked the cell cycle in the G2/M phase, which in consequence led to induction of apoptosis. The modulation of this control point by 5-MOP was associated with the inhibition of the activity of cyclin 1, i.e. a regulatory subunit of cyclin-dependent kinase 1 (Cdk1) [33]. What was more interesting, not only apoptosis but also autophagy was observed in the cancer cell lines upon the bergapten treatment. It seems that PTEN (phosphatase and tensin homolog deleted on chromosome ten), well known antagonist of the PI3K-Akt/PKB-mTOR survival pathway, play a crucial role in this process. 5-MOP increased PTEN expression, which resulted in the limitation of proliferation, metabolism, and coincidence of both apoptosis and autophagy in consequence. At the molecular level it was accompanied by the expression of typical for both types of death markers like pro-apoptotic caspases 8 and 9 as well as pro-autophagic UVRAG (UV resistance-associated gene) and Beclin-1 [1,22,51]. Since autophagy may be a survival mechanism, this problem requires further detailed investigations. Like bergapten, xanthotoxin shows antitumor activity (Fig. 3). Studies conducted on human liver cancer cells (HepG2) proved that this compound (dose dependently 25-100 μM) had pro-apoptotic properties. The mechanism of this type of programmed cell death induction by xanthotoxin was based on reducing the expression of the anti-apoptotic Bcl-2 protein and increasing the synthesis of the Bax protein. This was accompanied by an increase in the amount of cytoplasmic cytochrome c released from the mitochondria. The decrease in the mitochondrial membrane potential, the translocation of pro-apoptotic mitochondrial proteins to the cytoplasm, and the activation of caspase 3 suggest that the apoptosis of HepG2 cells proceeded via the mitochondrial pathway. Another mechanism of the anti-tumor activity of 8-MOP was based on

the ability to form reactive oxygen species, which led to induction of oxidative stress and apoptosis. The elimination of cancer cells by programmed death upon xanthotoxin is also associated with the suppression of survival signals through the intracellular Ras-Raf-MEK-ERK pathway. Moreover, 8-MOP could bind directly to DNA, thereby inhibiting the cell cycle. This was accompanied by an increase in the amount of the active p53 protein that induced p21 transcription. The p21 protein bound directly to the Cdk-cyclin complexes and inhibited the cell cycle in the G2/M phase [87]. Linear furanocoumarins like psoralen and its methoxy derivatives, 5-MOP and 8-MOP, are potent photo-reactive compounds, acquiring cytotoxicity after activation by ultraviolet (UVA) light in the wavelength range 320–400 nm. Hence, the name PUVA has been coined (acronym for psoralen and UVA light). The compounds are successfully used to treat cutaneous T-cell lymphoma [4,9,38,52,53]. When photoactivated, psoralens form mono-adducts and di-adducts with DNA leading to marked tumor cytotoxicity and apoptosis [10,19]. Cell signaling events in response to DNA damage include up-regulation of p21waf/Cip and p53 activation, with induced mitochondrial cytochrome c release and consequent cell death. Photo-activated psoralen can also induce apoptosis by blocking oncogenic receptor tyrosine kinase signaling and the PI3K pathway by interfering with efficient recruitment of effector Akt kinase to the activated plasma membrane [57,70,85]. Despite positive clinical results, the use of psoralen has todate been restricted to superficial or extra-corporeal applications because of the inability of UVA light to penetrate into tissue (maximum penetration depth < 1 mm). Therefore, a new approach, X-PACT (Xray Psoralen Activated Cancer Therapy) has been introduced, which has potential to extend psoralen therapy to a wide range of solid tumors at deep-seated sites in the body. The key innovation in X-PACT is to combine psoralen with novel phosphor particles that absorb and downconvert x-ray energy to re-radiate as UVA light. Low x-ray doses (~1Gy) are sufficient to achieve photo-activation, greatly reducing the risks of normal tissue damage from radiation [48] Isopentenyloxy derivatives of psoralen like isoimperatorin and imperatorin induced significant inhibition of cancer cell proliferation but unfortunately, were less effective in the elimination of tumor cells in comparison to psoralen and its methoxy derivatives, suggesting that the isoprenyl substituent decreased the antiproliferative properties [16,17,25,82]. Anticancer properties of imperatorin were observed in many types of cancer, including leukemias, cervical carcinoma, gliomas, and liver cancer [3,29,36,86]. This activity had a complex mechanism (Fig. 4). Generally, it was based on inhibition of the cell cycle in the G1/S phase, 3

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Fig. 4. Molecular mechanism of apoptosis and autophagy initiation by imperatorin.

Fig. 5. Anti-tumor activity of isoimperatorin.

DU145, furanocoumarin (dose-dependently 25-100 μM) increased the expression of inhibitors of cyclin-dependent kinases (Cdk2 and Cdk4) like Cip1/p21 and Kip1/p27 and disrupted the synthesis of Cdk4 kinase, which resulted in blocking the cell cycle in the G1 phase [24]. Another mechanism of the anticancer action of isoimperatorin was observed in SGC-7901 gastric cancer cells, where mitochondrial apoptosis was observed after furanocoumarin treatment (dose dependent manner 5-20 μg/mL). At the molecular level, it was correlated with increased expression of the pro-apoptotic Bax protein involved in the formation of PTP (Permeability Transition Pore), through which cytochrome c was released from the mitochondria to the cytoplasm. At the same time, the furanocoumarin blocked the synthesis of the antiapoptotic Bcl-2 protein and survivin, i.e. a protein from the IAP family (Inhibitors of Apoptosis) and a well-known caspase inhibitor. Thus, the decrease in the survivin expression induced by imperatorin was beneficial for activation of caspases 9 and 3 [68].

thereby directing the cells to the path of apoptosis or autophagy. Imperatorin initiated apoptosis through an extrinsic/receptor pathway (involving death receptors on the membrane) or an intrinsic/mitochondrial pathway (with mitochondrial involvement). Current studies showed that stimulation of the receptor pathway was accompanied by an increase in the expression of TNF (Tumor Necrosis Factor) and FADD (Fas-Associated Death Domain) proteins as well as activation of caspases 3 and 8. The participation of the mitochondrial pathway was facilitated by the release of cytochrome c into the cytosol and increased caspase 3 and 9 activity [29,36]. An interesting example of the antitumor activity of imperatorin (dose-dependently 30-90 μM) was its ability to modulate the expression of proteins from the Bcl-2 family. In this group, proteins with pro-apoptotic (Bax, Bag, Bcl-xS, Bock) and anti-apoptotic (Bcl-2, Bcl-xL, A1, Mcl-1) properties were distinguished. The ratio between the expression rates of proteins from those two groups determined the initiation or inhibition of programmed death. The furanocoumarin contributed to an increase in the synthesis of proapoptotic proteins: Bax in lung (H23 line) and large intestine (HCT-15 line) tumors and Bad in liver cancer (Hep2 line). A decrease in the expression of the anti-apoptotic proteins Bcl-2 in colon cancer (HCT-15 line) and leukemia (HL-60) cells and the Mcl-1 protein in liver (HCC line) and lung (H23 line) cancers was observed as well. The dominance of pro-apoptotic proteins in the tumor cells was correlated with a decrease in the mitochondrial transmembrane potential, which was accompanied by the release of cytochrome c into the cytosol and overexpression of the p21 and p53 proteins [7,21,36,54]. The pro-apoptotic properties of imperatorin (50 μM) were also connected with the inhibition of expression of Heat Shock Proteins (Hsp27 and Hsp72). The high level of these chaperones was characteristic for tumors, which consequently increased the resistance to programmed death induction in transformed cells. The mechanism of this phenomenon was related to the ability of Hsps to block the association of cytochrome c with the Apaf-1 factor (Apoptotic Protease Activating Factor-1), which led to inhibition of activation of caspases 3 and 9 [3]. Therefore, by blocking the expression of Hsps, the furanocoumarin contributed to an increase in the susceptibility of the tumor cells to induction of programmed death. Studies conducted on the HeLa line showed that not only apoptosis but also autophagy was initiated after inhibition of Hsp27 expression caused by imperatorin treatment (100 μM). It was correlated with the activation of an autophagy marker - LC3II (Microtubule-associated protein 1A/1B-light chain 3-II). This form of protein, in combination with phosphatidylethanolamine (PE), formed the LC3II-PE complex necessary for the formation of autophagosomes and the further process of autophagy [23]. Isoimperatorin is another linear furanocoumarin with defined antitumor activity (Fig. 5). The mechanism of its anti-cancer activity was well established in prostate and gastric cancer cells [24,68]. In line

3.2. Angelicin and its derivatives Similar to linear furocoumarins, angular analogues can be substituted with a methoxy or isopentenyloxy group. Methoxy derivatives of angelicin include isobergapten and sphondin. Isobergapten, i.e. 5methoxyangelicine, is a linear isomer of bergapten with a methoxy group attached to the fifth (C5) carbon atom. In turn, sphondin (6methoxyangelicin) can be considered as an angular analogue of xanthotoxin. The difference is, however, that the methoxy group is attached to the C6 position in 6-methoxyangelicin and to the C8 atom in the 8-MOP. Lanatin and herotomin are angular analogues of isopentenyloxy derivatives of psoralen, namely imperatorin and isoimperatorin, respectively. Like imperatorin, lanatin (5-isopentenyloxyangelicin) has an isoprenyl group attached to the C5 position. Herotomin (6-isopentenyloxyangelicin) and isoimperatorin differ in the localization of the isopentenyloxy group, due to the different position of the furanic ring. The group is attached to the C6 position in herotomin and to C8 in imperatorin [75]. Unfortunately, very little is known about the anti-cancer potential of angular furanocoumarins substituted with the isopentenyloxy group, therefore we will concentrate on the methoxy derivatives of angelicin in this article. Angelicin is the simplest representative of angular furanocoumarins. Like its linear analogue – psoralen, it exhibits many anticancer properties (Fig. 6). It has both anti-proliferative and pro-apoptotic activity. It blocked the cell cycle in the G1 phase in human prostate cancer (PC-3 line) and leukemia cells (Jurkat and K562 lines), (dose dependent manner 5-100 μM). In lung cancer (line A549), in turn, angelicin (1050 μM) disturbed the cell transition to the M phase. The molecular mechanism of such activity was correlated with inhibition of the 4

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(Cyclooxygenase-2), whose overexpression was observed in epithelialderived tumors and was associated with increased angiogenesis and invasiveness of transformed cells. COX-2 was also responsible for resistance to apoptosis by activation of anti-apoptotic proteins from the Bcl-2 family [88]. Therefore, it seems that sphondin may exert a beneficial effect in the anticancer treatment of tumors characterized by overexpression of the COX-2 protein.

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3.3. Synthetic furanocoumarin derivatives Pharmacologically active furanocoumarins are characterized by a large variety in terms of structure. The medical properties, potency, and potential side effects of compounds can be modulated with appropriate substituents. This property forms the basis for the attempt to obtain synthetic coumarin-like structures with selective action to prevent the formation and development of cancer [69]. It has been proven that available benzopsoralen-coumarin derivatives with a methoxy, hydroxyl, or dimethylaminopropoxy moiety in the 5 or 8 position of the furanocoumarin backbone exhibit antiproliferative activity. Substitution with pyrrole and imidazole groups increases their photoinduction activity and anticancer potential in chronic myeloid leukemia (line K562). In these studies, the phototoxicity was found to be 300-fold higher than the phototoxicity of 8methoxypsoralen, 250-fold higher than that of the corresponding coumarin conjugates, and 15-fold more potent than that of its imidazole analogue [32]. Furthermore, the benzene derivative of 8-MOP containing the dimethylaminopropoxy chain exhibited approximately 100fold stronger antiproliferative activity in comparison to the HeLA line treated with 8-MOP [73]. In addition, a xanthotoxin with an attached pyridazine ring limited proliferation of HeLa cells more effectively than the precursor [74]. Synthetic benzopsoralen analogues also inhibited the proliferation of human tumor cell lines MDA MB 231 (breast adenocarcinoma), HeLa, and TCC-SUP (bladder transitional cell carcinoma). The psoralen derivatives used in the study had the same ring and differed only in the group attached in the C2 position. As it turned out, substitution of a carboxylic or ester moiety gave the best results, while the presence of large carboxamide groups led to a decrease in the anti-tumor activity of benzofuranocoumarin [14]. These compounds had the ability to inhibit the activity of the CYP2A6 enzyme by interacting with its heme group, thereby limiting the proliferation of tumor cells. Furthermore, synthetic linear benzofuranocoumarins (benzopsoralens) had stronger anticancer properties compared to the same angelicin analogues [15]. The presence of the phenyl group, likewise the benzene ring, increased the antiproliferative activity of psoralen and angelicin in relation to several cell lines - human breast carcinoma (MCF-7), human gastric carcinoma (BGC-823), and human lung cancer (A549). What is more, the presence of an additional furan ring in the angelicin analog significantly stimulated these properties [58]. As reported by the Oliveira team, the antitumor activity of psoralen analogs depend on the distribution of electron density and their molecular conformation, which indicates that compounds with similar characteristics possess similar antitumor properties [49]. In addition, compounds with angular structure exhibit the highest antitumor activity [50]. Mattarei and colleagues have shown that a synthetic derivative of psoralen connected by a labile carbonate bond to a triphenylphosphate cation leads to the induction of programmed death in leukemia (Jurkat, K562) and melanoma (B16F10) cancer cells. At the molecular level, this is accompanied by the inhibition of Kv1.3 channels located in the inner mitochondrial membrane, which is a signal initiating the activation of apoptotic intracellular pathways [37].

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Fig. 6. Molecular mechanism of anti-tumor activity of angelicin.

expression of Cdk2 partner proteins, like cyclinB1 and cyclinE1, which blocked the formation of a complex between those proteins and, in consequence, the transition to the next phase of the cell cycle. Besides the anti-proliferative properties, angelicin inhibited the migration of tumor cells. As observed in lung cancer cells (A549 line), this furanocoumarin increased the expression of adhesion protein E-cadherin, which was associated with smaller tumor metastasis. This was accompanied by a decrease in the level of matrix metalloproteinases (MMP): MMP2 and MMP9, i.e. enzymes responsible for E-cadherin hydrolysis [31,35,76,77]. Angelicin had also pro-apoptotic properties associated with the ability to modulate the expression of the Bcl-2 family of proteins. In lung cancer cells, the furanocoumarin (dose-dependently 10-50 μM) inhibited the activity of the anti-apoptotic Bcl-2 protein as well as BclxL and Mcl-1 in human neuroblastoma cells (SH-SY5Y line). This was accompanied by an increase in Bax protein expression, activation of caspases 9 and 3, and initiation of apoptosis via the mitochondrial pathway [35,55]. The literature describing the methoxy derivatives of angelicin, e.g. sphondin and isobergapten, is not rich; yet available results prove that those furanocoumarins inhibited the growth of stomach, lung, and melanoma cancer cells (Fig. 7). The molecular mechanism was based on cell cycle blocking in the G2/M phase, which was accompanied by increased phosphorylation of Chk1 kinase (Checkpoint Kinase 1) responsible for preventing the cell from entering the mitotic phase [64,88]. Another mechanism of anti-cancer activity was noticed in lung cancer cells (A549) incubated with sphondin. This furanocoumarin (50 μM) inhibited the expression of the COX-2 protein

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4. Furanocoumarins and health risks

Fig. 7. Cell cycle arrest and angiogenesis blocking by sphondin and isobergapten.

In addition to the apparent beneficial effects of furanocoumarins on human health, numerous studies provide evidence of health risk that 5

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the most common death causes. It is known that tumors have developed many mechanisms at the molecular level enabling cell survival during chemotherapy. Therefore, inhibition of cell proliferation and elimination of tumor cells via programmed death may be a valuable target in developing new treatments. Due to widespread availability, fast absorption from food sources, and rapid distribution into human tissues, plant-derived compounds, including furanocoumarins, have received great attention. Their chemical structure is well understood, which facilitates the construction of a new therapeutic layout and highly precise prediction of the effects of application thereof. Despite the intensive research, the number of reports on the anticancer properties of furanocoumarins in literature is still limited, and further elucidation of the mechanisms of action of these compounds will be beneficial and may have significant practical application. Studies regarding anticancer properties should be continued but with respect to all disadvantages and potential risk of side effects. Much attention should be paid to synthetic derivatives [30], which application seems to be more safe what may be regulated by chemical structure and selection of appropriate substituents.

cannot be ignored. This is especially evident in the case of psoralen and 8- methoxypsoralen, which possess phototoxic properties and form a basis for PUVA therapy based on psoralen and UVA. It has been shown to be beneficial for patients with vitiligo, psoriasis, and skin diseases. Unfortunately, a PUVA follow-up study showed that such therapy was strongly associated with a risk of basal cell carcinoma and moderately related to a risk of squamous cell carcinoma [61,63]. It also demonstrated that, after 25 years, more than half of patients who had received at least 400 PUVA treatments developed at least one squamous carcinoma and almost one third of patients exposed to 200 treatments developed at least one basal carcinoma [47]. Nearly all PUVA patients are predicted to develop some form of non-melanoma skin cancer [8]. The data from the PUVA follow-up study also indicated that the risk of malignant melanoma ca. 15 years after the first PUVA treatment increased more than fivefold, with the greatest risk observed in patients who had received 250 treatments or more [62]. Prolonged therapy has reported to affect liver, eyes, immune system, may cause renal complications, blistering, malaise, sleeplessness or mental depression [28]. Because of the potential cancer risks, doctors recommend that patients who receive long-term PUVA treatment should be carefully monitored throughout their lives. These patients should also report any peculiar skin abnormalities, including abnormally pigmented areas and skin that is changing color or size, itching, or painful, to their health care professionals. Another example of a controversial use of furanocoumarins is their presence in some sunscreen lotions as a UVA-stimulated factor responsible for increased melanogenesis and reduction of the UVB radiation danger. In practice, increased erythema and tumorigenesis has been observed [61]. Epidemiological studies have also suggested that the toxic effects of furanocoumarins may not be limited to the UVA exposure but are also related to increased consumption of citrus products (1.4 times per day in comparison to less than two citrus products per week), especially grapefruits. This was associated with a higher risk of basal and squamous cell carcinoma [83,84]. Prolonged administration (60–90 days) of a mixture of psoralen and imperatorin in rats and mice caused hypertrophy of the liver, kidney, and spleen and decreased the whole body and gonad weight [28]. Cases of liver injury have been reported in Chinese population associated with consumption of Psoralea corylifolia dried seeds or leaves in which psoralen and isopsoralen were the two main culprits [6,34,46,66]. Both psoralen and isopsoralen elevated the levels of aspartate aminotransferase (AST), alkaline phosphatase (ALP), and albumin. Furthermore, the hepatoxicity was correlated with cytochrome P450 metabolism. The endoplasmic reticulum was the main target subcellular structure in the hepatotoxicity induced by psoralen and isopsoralen. Disturbance in amino acid metabolism, especially valine, leucine, and isoleucine biosynthesis, was reported as well [60,78,89]. The aspect of consumption and metabolism of furanocoumarins is also important during pharmacotherapy, especially with statins, antihistamines, chemotherapeutics, and several other orally administered drugs. Bergamottin and 6′,7′-dihydroxybergamottin, i.e. the bioactive furanocoumarins in grapefruits, are responsible for the “grapefruit effect”. They acts as inhibitors of some isoforms of the cytochrome P450 (CYP) enzyme, particularly CYP3A4, which can lead to increased concentrations of drugs in the bloodstream and a potential risk of serious side effects from the drugs. On the other hand, many studies have demonstrated that grapefruit juice can augment the bioavailability of drugs that are CYP3A4 substrates. However, among various studies considering correlations between grapefruits and drugs, only a few are clinically relevant and it seems that a balanced diet may compensate the negative effects [22,27].

References [1] F. Amicis, S. Aquila, C. Morelli, et al., Bergapten drives autophagy through the upregulation of PTEN expression in breast cancer cells, Mol. Cancer 14 (2015) 130. [2] M. Asif, Pharmacologically potentials of different substituted coumarin derivatives, Chem. Int. 1 (2015) 1–11. [3] D. Bądziul, J. Jakubowicz-Gil, R. Paduch, et al., Combined treatment with quercetin and imperatorin as a potent strategy for killing HeLa and Hep-2 cells, Mol. Cell. Biochem. 392 (2014) 213–227. [4] D. Bethea, B. Fullmer, S. Syed, et al., Psoralen photobiology and photochemotherapy: 50 years of science and medicine, J. Dermatol. Sci. 19 (2) (1999) 78–88. [5] R. Bruni, D. Barreca, M. Protti, et al., Botanical sources, chemistry, analysis, and biological activity of furanocoumarins of pharmaceutical interest, Molecules 24 (11) (2019) E2163. [6] W.I. Cheung, M.L. Tse, T. Ngan, et al., Liver injury associated with the use of Fructus Psoraleae (Bol-gol-zhee or Bu-gu-zhi) and its related propriety medicine, Clin. Toxicol. 47 (2009) 683–685. [7] K. Choochuay, P. Chunhacha, V. Pongrakhananon, et al., Imperatorin sensitizes anoikis and inhibits anchorage-independent growth of lung cancer cells, J. Nat. Med. 67 (3) (2013) 599–606. [8] J.C. Dowdy, R.M. Sayre, Melanoma risk from dietary furocoumarins: how much more evidence is required? J. Clin. Oncol. 34 (2016) 636–637. [9] R. Edelson, C. Berger, F. Gasparro, et al., Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results, The New Eng J Med 316 (6) (1987) 297–303. [10] M. El-Domyati, N.H. Moftah, G.A. Nasif, et al., Evaluation of apoptosis regulatory proteins in response to PUVA therapy for psoriasis, Photoderm Photoimmun Photomed 29 (1) (2013) 18–26. [11] R.O. Escarega, S. Fuentes-Alexandro, M. Garcia-Carrasco, et al., The transcription nuclear factor-kappa B and cancer, Clinic Oncol (R Coll Radiol) 19 (2) (2007) 154–161. [12] D. Fang, L. Zhu, S. Yang, et al., Isolation and identification of bergapten in dry root of Glehnia littoralis and preliminary determination of its antitumor activity in vitro, J Plant Res Envir 19 (1) (2010) 95–96. [13] L. Fracarolli, G.B. Rodrigues, A.C. Pereira, et al., Inactivation of plant-pathogenic fungus Colletotrichum acutatum with natural plant-produced photosensitizers under solar radiation, J. Photochem. Photobiol. B 162 (2016) 402–411. [14] C. Francisco, L. Rodrigues, N. Cerqueira, et al., Synthesis of novel benzofurocoumarin analogues and their antiproliferative effect on human cancer cell lines, Eur. J. Med. Chem. 47 (2012) 370–376. [15] C. Francisco, L. Rodrigues, N. Cerqueira, et al., Synthesis of novel psoralen analogues and their in vitro antitumor activity, Bioorg. Med. Chem. 21 (2013) 5047–5053. [16] T. Fujioka, K. Furumi, H. Fujii, et al., Antiproliferative constituents from Umbelliferae plants. V. a new furanocoumarin and falcarindiol furanocoumarin ethers from the root of Angelica japonica, Chem Pharm Bull 47 (1) (1999) 96–100. [17] A. Gawron, K. Głowniak, Cytostatic activity of coumarins in vitro, Planta Med. 53 (6) (1987) 526–529. [18] E. Gorgus, C. Lohr, N. Raquet, et al., Limettin and furanocoumarins in beverages conteining citrus juices or extracts, Food Chem. Toxicol. 48 (2010) 93–98. [19] U. Holtick, X.N. Wang, S.R. Marshall, et al., In vitro PUVA treatment preferentially induces apoptosis in alloactivated T cells, Transplantation. 94 (5) (2012) e31–e34. [20] M.J. Hsieh, M.K. Chen, Y.Y. Yu, et al., Psoralen reverses docetaxel-induced multidrug resistance in A549/D16 human lung cancer cells lines, Phytomedicine 21 (7) (2014) 970–977. [21] J. Hu, C. Xu, B. Cheng, et al., Imperatorin acts as a cisplatin sensitizer via downregulating Mcl-1 expression in HCC chemotherapy, Tumor Biol. 37 (1) (2016) 331–339.

5. Conclusions Cancer diseases are a widespread health issue in the present-day world. Despite the continuous development of medicine, they are one of 6

Fitoterapia 142 (2020) 104492

J. Sumorek-Wiadro, et al.

335–368. [54] A. Rahman, S.A. Siddiqui, R. Jakhar, et al., Growth inhibition of various human cancer cell lines by imperatorin and limonin from Poncirus trifoliata rafin, Seeds. Anticancer Agents Med Chem 5 (2) (2015) 236–241. [55] A. Rahman, N.H. Kim, H. Yang, et al., Angelicin induces apoptosis through intrinsic caspase-dependent pathway in human SH-SY5Y neuroblastoma cells, Mol. Cell. Biochem. 369 (1–2) (2012) 95–104. [56] R.M. Sayre, J.C. Dowdy, The increase in melanoma: are dietary furocoumarin responsible? Med. Hypotheses 70 (2008) 855–859. [57] I.M. Schmitt, S. Chimenti, F.P. Gasparro, Psoralen-protein photochemistry - a forgotten field, J. Photochem. Photobiol. B 27 (2) (1995) 101–107. [58] Y. Selim, M. El-Ahwany, Synthesis and antiproliferative activity of new furocoumarin derivatives, Chem. Heterocycl. Compd. 53 (8) (2017) 867–870. [59] P.P. Song, J. Zhao, Z.L. Liu, et al., Evaluation of antifungal activities and structureactivity relationships of coumarin derivatives, Pest Manag. Sci. 73 (1) (2017) 94–101. [60] L. Song, B. Yu, L. Yang, et al., The mechanism of psoralen and isopsoralen hepatotoxicity as revealed by hepatic gene expression profiling in SD rats, Basic Clin Pharmacol Toxicol 125 (2019) 527–535. [61] R.S. Stern, The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet a therapy: a 30-year prospective study. PUVA Follow-Up Study, J Am Acad Dermatol 66 (4) (2012) 553–562. [62] R.S. Stern, K.T. Nichols, L.H. Väkevä, Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet a radiation (PUVA), New England J Med 336 (1997) 1041–1045. [63] R.S. Stern, The risk of melanoma in association with long-term exposure to PUVA, J. Am. Acad. Dermatol. 44 (2001) 755–761. [64] M. Sumiyoshi, M. Sakanaka, M. Taniguchi, et al., Anti-tumor effects of various furocoumarins isolated from the roots, seeds and fruits of Angelica and Cnidium species under ultraviolet a irradiation, I Nat Med 68 (1) (2014) 83–94. [65] K. Szewczyk, A. Bogucka-Kocka, Analytical methods for isolation, separation and Identification of selected furanocoumarins in plant material, in: V. Rao (Ed.), Phytochemicals - A Global Perspective of Their Role in Nutrition and Health, InTech, Rijeka, 2012, pp. 57–92. [66] R. Teschke, A. Eickhoff, Herbal hepatotoxicity in traditional and modern medicine: actual key issues and new encouraging steps, Front Pharmacol (2015), https://doi. org/10.3389/fphar.2015.00072. [67] R.D. Thornes, G. Lynch, M.V. Sheehan, Cimetidine and coumarin therapy of melanoma, Lancet 2 (8293) (1982) 328. [68] K. Tong, C. Xin, W. Chen, Isoimperatorin induces apoptosis of the SGC-7901 human gastric cancer cell line via the mitochondria-mediated pathway, Oncol. Lett. 13 (1) (2017) 518–524. [69] V.F. Traven, New synthetic routes to furanocoumarins and their analogs: a review, Molecules 9 (2004) 50–66. [70] B. Van Aelst, R. Devloo, P. Zachée, et al., Psoralen and ultraviolet a light treatment directly affects phosphatidylinositol 3-kinase signal transduction by altering plasma membrane packing, J. Biol. Chem. 291 (47) (2016) 24364–24376. [71] M.A. Velasco-Velázquez, J. Agramonte-Hevia, D. Barrera, et al., 4Hydroxycoumarin disorganizes the actin cytoskeleton in B16-F10 melanoma cells but not in B82 fibroblasts, decreasing their adhesion to extracellular matrix proteins and motility, Cancer Lett. 198 (2) (2003) 179–186. [72] K.N. Venugopala, V. Rashmi, B. Odhav, Review on natural coumarin lead compounds for their pharmacological activity, BioMed Res Int (2013) 963248. [73] L. Via, O. Gia, S. Magno, et al., New tetracyclic analogues of photochemotherapeutic drugs 5-MOP and 8-MOP: synthesis, DNA interaction, and antiproliferative activity, J. Med. Chem. 42 (1999) 4405–4413. [74] L. Via, J. Gonzáles-Gómez, L. Pérez-Montoto, et al., A new psoralen derivative with enlarged antiproliferative properties, Med Chem Lett 19 (2009) 2874–2876. [75] G. Viola, A. Salvador, D. Vedaldi, et al., Differentiation and apoptosis in UVA-irradiated cells treated with furocoumarin derivatives, Ann. N. Y. Acad. Sci. 1171 (2009) 334–344. [76] G. Viola, E. Fortunato, L. Cecconet, et al., Induction of apoptosis in Jurkat cells by photoexcited psoralen derivatives: implication of mitochondrial dysfunctions and caspases activation, Toxicol. in Vitro 21 (2) (2007) 211–216. [77] Q. Wang, Y. Wang, H. Lin, et al., Antiproliferative and apoptotic effects of angelicin in highly invasive prostate cancer cells, Trop. J. Pharm. Res. 14 (8) (2015) 1405. [78] X. Wang, Y.-J. Lou, M.-X. Wang, et al., Furanocoumarins affect hepatic cytochrome P450 and renal organic ion transporters in mice, Toxicol. Lett. 209 (1) (2012) 67–77. [79] X. Wang, K. Cheng, Y. Han, et al., Effects of psoralen as an anti-tumor agent in human breast cancer MCF-7/ADR cells, Biol. Pharm. Bull. 39 (5) (2016) 815–822. [80] X. Wang, C. Xu, Y. Hua, et al., Exosomes play an important role in the process of psoralen reverse multidrug resistance of breast cancer, J. Exp. Clin. Cancer Res. 35 (2016) 186. [81] Y. Wang, H. Ch, Z. Ch, et al., Screening antitumor compounds psoralen and isopsoralen from Psoralea corylifolia L. seeds, Evid. Based Complement. Alternat. Med. (2011) 363052, , https://doi.org/10.1093/ecam/nen087 7 pages. [82] J. Widelski, W. Kukula-Koch, T. Baj, et al., Rare coumarins induce apoptosis, G1 cell block and reduce RNA content in HL60 cells, Open Chem 15 (1) (2017) 1–6. [83] S. Wu, E. Cho, D. Feskanich, et al., Citrus consumption and risk of basal cell carcinoma and squamous cell carcinoma of the skin, Carcinogenesis 36 (2015) 1162–1168. [84] S. Wu, J. Han, D. Feskanich, et al., Citrus consumption and risk of cutaneous malignant melanoma, J. Clin. Oncol. 33 (2015) 2500–2508. [85] W. Xia, D. Gooden, L. Liu, et al., Photo-activated psoralen binds the ErbB2 catalytic kinase domain, blocking ErbB2 signaling and triggering tumor cell apoptosis, PLoS

[22] W. Hung, J. Suh, Y. Wang, Chemistry and health effects of furanocoumarins in grapefruit, J. Food Drug Anal. 25 (1) (2017) 71–83. [23] J. Jakubowicz-Gil, R. Paduch, Z. Ulz, et al., Cell death in HeLa cells upon imperatorin and cisplatin treatment, Folia Histochem. Cytobiol. 50 (3) (2012) 381–391. [24] J.H. Kang, S.K. Lee, D.S. Yim, Effect of isoimperatorin on the proliferation of prostate cancer cell line du145 cells, Biomol. Ther. 13 (3) (2005) 185–189. [25] Y. Kim, Y. Kim, S. Ryu, Antiproliferative effect of furanocoumarins from the root of Angelica dahurica on cultured human tumor cell lines, Phytother. Res. 21 (3) (2007) 288–290. [26] G. Kirsch, A.B. Abdelwahab, P. Chaimbault, Natural and synthetic coumarins with effects on inflammation, Molecules 21 (10) (2016) 1322. [27] J.H. Ko, F. Arfuso, G. Sethi, K.S. Ahn, Pharmacological utilization of bergamottin, derived from grapefruits, in cancer prevention and therapy, Int. J. Mol. Sci. 19 (12) (2018) E4048. [28] B. Koul, P. Taak, A. Kumar, et al., Genus Psoralea: a review of the traditional and modern uses, phytochemistry and pharmacology, J. Ethnopharmacol. 32 (2019) 201–226. [29] E. Kozioł, K. Skalicka-Woźniak, Imperatorin–pharmacological meaning and analytical clues:profound investigation, Phytochem. Rev. 15 (2016) 627–649. [30] T. Kubrak, R. Podgórski, M. Stompor, Natural and synthetic coumarins and their pharmacological activity, Eur J Clin Exp Med 15 (2) (2017) 169–175. [31] I. Lampronti, N. Bianchi, C. Zuccato, et al., Increase in gamma-globin mRNA content in human erythroid cells treated with angelicin analogs, Int. J. Hematol. 90 (3) (2009) 318–327. [32] M. Lee, M. Roldan, M. Haskell, et al., In vitro photoinduced cytotoxicity and DNA binding properties of psoralen and coumarin, J. Med. Chem. 37 (8) (1994) 1208–1213. [33] Y.M. Lee, T.H. Wu, S.F. Chen, et al., Effect of 5-methoxypsoralen (5-MOP) on cell apoptosis and cell cycle in human hepatocellular carcinoma cell line, Toxicol. in Vitro 17 (3) (2003) 279–287. [34] A. Li, M. Gao, N. Zhao, et al., Acute liver failure associated with Fructus Psoraleae: a case report and literature review, BMC Complement. Altern. Med. 19 (1) (2019) 84. [35] G. Li, Y. He, J. Yao, et al., Angelicin inhibits human lung carcinoma A549 cell growth and migration through regulating JNK and ERK pathways, Oncol. Rep. 36 (6) (2016) 3504–3512. [36] K. Luo, J. Sun, J.Y.-W. Chan, et al., Anticancer effects of imperatorin isolated from Angelica dahurica: induction of apoptosis in HepG2 cells through both death-receptor- and mitochondria-mediated pathways, Chemotherapy 57 (6) (2011) 449–459. [37] A. Mattarei, M. Romio, A. Managò, et al., Novel mitochondria-targeted furocoumarin derivatives as possible anti-cancer agents, Front. Oncol. 8 (2018) 122. [38] K.E. McKenna, PUVA, Psoralens and skin Cancer, in: P. Altmeyer, K. Hoffmann, M. Stücker (Eds.), Skin Cancer and UV Radiation, Springer, Berlin, Heidelberg, 1997, pp. 416–424. [39] M.M. Melough, S.G. Lee, E. Cho, et al., Identification and uantitation of furocoumarins in popularly consumed foods in the u.s. using QuEChERS extraction coupled with UPLC-MS/MS analysis, J. Agric. Food Chem. 65 (24) (2017) 5049–5055. [40] M.M. Melough, T.M. Vance, S.G. Lee, et al., Furocoumarin kinetics in plasma and urine of healthy adults following consumption of grapefruit (Citrus paradisi Macf.) and grapefruit juice, J. Agric. Food Chem. 65 (14) (2017) 3006–3012. [41] M.M. Melough, O.K. Chun, Dietary furanocoumarins and skin cancer: a review of current biological evidence, Food Chem. Toxicol. 122 (2018) 163–171. [42] M.M. Melough, E. Cho, O.K. Chun, Furocoumarins: a review of biochemical activities, dietary sources and intake, and potential health risks, Food Chem. Toxicol. 113 (2018) 99–107. [43] A. Messer, A. Nieborowski, C. Strasser, C. Lohr, D. Schrenk, Major furanocoumarins in grapefruit juice I: levels and urinary metabolite(s), Food Chem. Toxicol. 49 (2011) 3224–3231. [44] R. Munakata, A. Olry, F. Karamat, et al., Molecular evolution of parsnip (Pastinaca sativa) membrane-bound prenyltransferases for linear and/or angular furanocoumarin biosynthesis, New Phytol. 211 (1) (2016) 332–344. [45] R.H. Murray, J. Mendez, S.A. Brown, The Natural Coumarins: Occurrence, Chemistry and Biochemistry, Johns Wiley&Sons, Chichester, UK, 1982. [46] S.W. Nam, J.T. Baek, D.S. Lee, et al., A case of acute cholestatic hepatitis associated with the seeds of Psoralea corylifolia (Boh-Gol-Zhee), Clin. Toxicol. 43 (2005) 5890–5891. [47] T.E. Nijsten, R.S. Stern, The increased risk of skin cancer is persistent after discontinuation of psoralen+ultraviolet a: a cohort study, J Invest Dermatol 121 (2) (2003) 252–258. [48] M. Oldham, P. Yoon, Z. Fathi, et al., X-ray psoralen activated cancer therapy (XPACT), PLoS One 11 (9) (2016) e0162078. [49] A. Oliveira, M. Raposo, A. Oliveira-Camposa, et al., Psoralen analogues: synthesis, inhibitory activity of growth of human tumor cell lines and computational studies, Eur. J. Med. Chem. 41 (3) (2006) 367–372. [50] A. Oliveira, A. Oliveira-Camposa, L. Rodrigues, et al., Synthesis and antitumour evaluation of benzopsoralen analogues, Chem. Biodivers. 4 (5) (2007) 980–990. [51] M. Panno, F. Giordano, Effects of psoralens as anti-tumoral agents in breast cancer cells, World J Clin Oncol 5 (3) (2014) 348–358. [52] J.A. Parrish, T.B. Fitzpatrick, L. Tanebaum, et al., Photochemotherapy of psoriasis with oral methoxsalen and long-wave ultraviolet light, N. Engl. J. Med. 1291 (1974) 1207–1211. [53] M.A. Pathak, D.M. Kramer, T.B. Fitzpatrick, Photobiology and photochemistry of furocoumarins (psoralens), in: T.B. Fitzpatrick, M.A. Pathak, L.C. Harber, M. Seiji, A. Kukita (Eds.), Sunlight and Man, University of Tokyo Press, Tokyo, 1974, pp.

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Fitoterapia 142 (2020) 104492

J. Sumorek-Wiadro, et al.

[88] L. Yang, Y. Liang, C. Chang, et al., Effects of sphondin, isolated from Heracleum laciniatum, on IL-1beta-induced cyclooxygenase-2 expression in human pulmonary epithelial cells, (2002). [89] Y. Zhang, Q. Wang, Z.-X. Wang, et al., A study of NMR-based hepatic and serum metabolomics in a liver injury Spraque-Dawley rat model induced by psoralen, Chem. Res. Toxicol. 31 (2018) 852–860.

One 9 (2) (2014) e88983. [86] L. Xu, Y.L. Wu, X.Y. Zhao, et al., The study on biological and pharmacological activity of coumarins, AP3ER 2015 (2015) 135–138. [87] H. Yang, J. Xiong, W. Luo, et al., 8-Methoxypsoralen induces intrinsic apoptosis in HepG2 cells: involvement of reactive oxygen species generation and ERK1/2 pathway inhibition, Cell. Physiol. Biochem. 37 (1) (2015) 361–374.

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