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Moghadam, E.R.; Ang, H.L.; Asnaf, S.E.; Zabolian, A.; Saleki, H.; Yavari, M.; Esmaeili, H.; Zarrabi, A.; Ashrafizadeh, M.; Kumar, A.P.; et al. Chrysin. Encyclopedia. Available online: (accessed on 17 June 2024).
Moghadam ER, Ang HL, Asnaf SE, Zabolian A, Saleki H, Yavari M, et al. Chrysin. Encyclopedia. Available at: Accessed June 17, 2024.
Moghadam, Ebrahim Rahmani, Hui Li Ang, Sholeh Etehad Asnaf, Amirhossein Zabolian, Hossein Saleki, Mohammad Yavari, Hossein Esmaeili, Ali Zarrabi, Milad Ashrafizadeh, Alan Prem Kumar, et al. "Chrysin" Encyclopedia, (accessed June 17, 2024).
Moghadam, E.R., Ang, H.L., Asnaf, S.E., Zabolian, A., Saleki, H., Yavari, M., Esmaeili, H., Zarrabi, A., Ashrafizadeh, M., Kumar, A.P., & Kumar, A. (2020, October 08). Chrysin. In Encyclopedia.
Moghadam, Ebrahim Rahmani, et al. "Chrysin." Encyclopedia. Web. 08 October, 2020.

Pharmacological profile of phytochemicals has attracted much attention to their use in disease therapy. Since cancer is a major problem for public health with high mortality and morbidity worldwide, experiments have focused on revealing the anti-tumor activity of natural products. Flavonoids comprise a large family of natural products with different categories. Chrysin is a hydroxylated flavonoid belonging to the flavone category. Chrysin has demonstrated great potential in treating different disorders, due to possessing biological and therapeutic activities, such as antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, etc. Over recent years, the anti-tumor activity of chrysin has been investigated, and in the present review, we provide a mechanistic discussion of the inhibitory effect of chrysin on proliferation and invasion of different cancer cells. Molecular pathways, such as Notch1, microRNAs, signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappaB (NF-κB), PI3K/Akt, MAPK, etc., as targets of chrysin are discussed. The efficiency of chrysin in promoting anti-tumor activity of chemotherapeutic agents and suppressing drug resistance is described. Moreover, poor bioavailability, as one of the drawbacks of chrysin, is improved using various nanocarriers, such as micelles, polymeric nanoparticles, etc. This updated review will provide a direction for further studies in evaluating the anti-tumor activity of chrysin.

chrysin cancer therapy nanoparticle flavonoid chemotherapy

1. Introduction

Flavonoids are the largest group of plant secondary metabolites with favorable health-promoting effects [1][2][3][4]. The interest in flavonoids has been increased, since these valuable compounds act through various physiological mechanisms and affect a wide variety of signaling networks. Dietary intake of flavonoids is estimated to be 50 and 800 mg per day [5][6]. Chrysin is a hydroxylated flavonoid belonging to flavone class, and is extensively found in sources, such as honey, propolis, and plant species [7][8]. Noteworthy, chrysin occurs in natural sources with different concentrations. For instance, the concentration of chrysin in honeydew honey is 0.10 mg/kg, while it has a higher concentration (5.3 mg/kg) in forest honeys [9]. The content of chrysin in propolis is estimated to be 25 g/L [10]. Chrysin concentration in mushrooms is at the range of 0.17–0.34 mg/kg [11]. The IUPAC name of chrysin is 5,7-dihydroxy-2-phenyl-4H-chromen4-one and 5,7-dihydroxyflavone. Figure 1 demonstrates the chemical structure of chrysin. The chrysin structure has similarities and differences with the flavonoid family. Structurally, chrysin has two benzene rings (A and B) with one oxygen consisting of a heterocyclic ring. Chrysin lacks a 3-carbon hydroxyl group, but it has 2–3 double-bound carbon with a carbonyl group attached to 4th carbon. The chemical structure of chrysin demonstrates that it has –OH group at 5th and 7th carbon atoms. There is a difference in the structure of chrysin and other flavonoids, so that chrysin does not possess any oxygenation in ring B (Figure 1). It has been reported that changes in ring A of chrysin account for the generation of different derivatives of chrysin, such as wogonin, baicalein, and oroxylin [12].

Figure 1. Chemical structure of chrysin.

Accumulating data demonstrates that poor absorption, rapid metabolism, and systemic elimination are responsible for poor bioavailability of chrysin in humans that, subsequently, restrict its therapeutic effects [13]. It is worth mentioning that oxidation in intestinal and hepatic cells is not responsible for the metabolism of chrysin in the body. In contrast, conjugation pathways, such as glucuronidation and sulfation catalyze chrysin. Enzymes, such as P-PST, M-PST, and UGT1A6, contribute to the metabolism of chrysin, and their high affinity for chrysin can justify the poor bioavailability of this natural compound. Clinical studies have shown that the plasma concentration of chrysin following oral administration is very low [14]. Notably, serum concentrations of chrysin have not been reported yet, but it can be predicted based on other flavonoids. Since flavonoid aglycones demonstrate serum concentration as low as 1 µmol/L [15], the serum concentration of chrysin would be at the range of nanomolar. The studies related to the absorption of chrysin demonstrate that its sulfation and glucuronidation limit the absorption of this valuable compound in the intestine. MRP2 transporters are involved in the efflux of chrysin metabolites from the intestine, and in the lumen, sulfatases and glucuronidases hydrolyze metabolites into chrysin. This leads to the emergence of chrysin in stool, but high contents of chrysin in stool demonstrates that it has low absorption [16]. Some strategies have been applied in promoting bioavailability and absorption of chrysin, such as using nanoscale delivery systems [17].

2. Chrysin and Its Pharmacological Activities

In previous sections, we provided explanations about the role of natural products in cancer therapy, and then, we introduced the chemistry and pharmacokinetics of chrysin. In this section, we aim to describe the pharmacological activities of chrysin, based on the newly published article—which is summarized in Table 1.

Table 1. Various pharmacological activities of chrysin in treating diseases.

Figure 2. A schematic representation of the health-promoting effects of chrysin in pre-clinical experiments.

3. Chrysin-Loaded Nanoparticles in Cancer Therapy

Micelles have attracted much attention in cancer therapy, due to their potential to deliver anti-tumor agents [48][49]. Self-assembled micelles are amphiphilic copolymers with size at the range of 10–100 nm. Micelles have high cellular uptake and passive targeting functions to tumor known as enhanced permeability [50][51]. Recently, chrysin- and docetaxel-loaded micelles have been applied in enhancing the efficacy of chemotherapy. This co-delivery by micelles exerts a synergistic effect on chemotherapy and effectively suppresses migration and invasion of cancer stem cells. Chrysin- and docetaxel-loaded micelles enhance levels of ROS to impair cancer stem cell viability. Notably, enhanced the anti-tumor activity of chrysin and docetaxel against cancer cells is due to their enhanced accumulation in cancer cells by micelles [52]. Polymeric micelles have also been designed in co-delivery of chrysin and methotrexate in the chemotherapy of breast cancer cells. The idea of using a chemotherapeutic agent with a natural anti-tumor agent is that this combination is important in sensitizing cancer cells into chemotherapy. Using nanoparticles promotes cytotoxicity against cancer cells via enhancing cellular uptake. Based on the small size of polymeric micelles (around 55 nm), they can escape from macrophages and kidney filtration to reach into the tumor site, providing targeted delivery of anti-tumor compounds [53].

Another study has applied polyurea dendrimers for delivery of chrysin in ovarian cancer therapy. Polyurea dendrimers are three-dimensional polymers with urea moieties in the backbone and peripheral amine groups. They possess various beneficial properties, including water-solubility, biocompatibility, biodegradability, and pH-sensitivity, making them suitable options in drug delivery [54]. Furthermore, as cancer cells overexpress folate receptors on their surface [55][56], surface functionalization of nanoparticles with folate can be advantageous in enhancing cellular uptake of these nanoparticles and providing selective targeting. Chrysin- and selenium-loaded dendrimers are capable of induction of oxidative stress and reducing the viability of OC cells. Furthermore, they demonstrate no toxicity against normal cells that can be attributed to using folate for the functionalization of dendrimers [57].

Polymeric nanoparticles possess a core-shell structure that self-assemble in an aqueous medium. The hydrophilic shell is responsible for preserving the stability of nanoparticle, and the hydrophobic core encapsulates anti-tumor drug. Synthetic polymers, including poly (e-caprolactone) (PCL), polyglycolide (PGA), and polylactides (PLA), are applied in biomedical applications, due to their features, such as biocompatibility, high permeability, predictable degradation kinetics, etc., that are important in the field of biomedicine [58][59][60]. However, crystallinity and low biodegradation are drawbacks of PCL that can be solved using monomers. Poly (ethylene glycol) (PEG) is a safe, flexible, and hydrophilic agent approved by the Food and Drug Administration (FDA) that can be used internally in the human body [58][61][62][63]. Chrysin-loaded polymeric nanoparticles have been applied in breast cancer therapy. The results demonstrate that targeted delivery of chrysin at the tumor site by polymeric nanoparticles leads to enhanced anti-tumor activity, due to enhanced cellular uptake [64].

Nanoparticles can provide a platform for co-loading of chrysin with other natural anti-tumor compounds, such as curcumin. Briefly, curcumin is isolated from the rhizome of curcuma longa and has potent anti-tumor activity against different cancer cells [65]. Using nanoparticles can significantly enhance the bioavailability and therapeutic effects of curcumin [66]. Curcumin- and chrysin-loaded PLGA-PEG nanoparticles have been designed in CRC therapy. This co-loading exerts a synergistic effect and enhances the cytotoxicity of these phytochemicals against CRC cells [67]. Studies demonstrate that telomerase activity is associated with enhanced proliferation and invasion of cancer cells. Catalytic domain (hTERT) participates in telomerase gene overexpression that has been reported in CRC [68][69]. Chrysin- and curcumin-loaded nanoparticles effectively down-regulate the expression of hTERT in suppressing the progression of CRC cells [67]. In addition to the anti-proliferative activity via hTERT down-regulation, chrysin- and curcumin-loaded nanoparticles can suppress metastasis of cancer cells via reducing expressions of MMP-2 and MMP-9 [70].

Several homologous proteins known as tissue inhibitors of metalloproteinase (TIMPs) can regulate the activity of MMPs. TIMP-1 and TIMP-2 are capable of reducing the expression of MMP-2 and MMP-9 in suppressing metastasis and migration of cancer cells [71]. Chrysin- and curcumin-loaded nanoparticles significantly promote the expression of TIMP-1 and TIMP-2 to exert a reduction in melanoma invasion [70]. Taking everything into account, studies agree with the fact that nanoparticles can enhance the anti-tumor activity of chrysin against cancer cells [17][72][73][74][75][76]. Nanoparticles can provide a platform for the co-delivery of chrysin and other anti-tumor agents that is important in promoting its inhibitory effect against cancer cells (Figure 3) (Table 2). Further studies can focus on developing other types of nanocarriers, such as carbon nanotubes, liposomes, etc., for delivery of chrysin in cancer therapy.

Figure 3. Chrysin-loaded nanoparticles in cancer therapy.

Table 2. Chrysin-loaded nanoparticles in cancer therapy.

4. Conclusions and Remarks

Chrysin affects various molecular pathways and mechanisms in cancer therapy. Apoptosis is the most well-known target of chrysin in cancer therapy, and both intrinsic and extrinsic pathways of apoptosis are induced by chrysin in cancer cells. Disrupting homeostasis of mitochondria and ER are followed by chrysin in apoptosis induction in cancer cells. Autophagy is another programmed cell death that is activated by chrysin in cancer therapy. As autophagy has a dual role in cancer, meaning it may suppress cancer progression, or may function as a pro-survival factor in promoting the proliferation of cancer cells [83][84][85][86], much attention should be directed towards the regulation of autophagy by chrysin in cancer therapy. It has been reported that chrysin induces autophagy in cancer therapy, showing the anti-tumor role of autophagy. However, more studies will reveal a relationship between chrysin and autophagy in cancer therapy. In terms of molecular pathways, oncogenic ones, such as STAT3, NF-κB, and PI3K, that are involved in cancer growth and metastasis, are suppressed upon chrysin administration. MiRs are also potential targets of chrysin in cancer therapy that their expression is regulated. Noteworthy, since studies have shown that chrysin is capable of modulating the expression of miRs, further studies can focus on evaluating the effect of chrysin on other types of non-coding RNAs, such as long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs).

Another potential application of chrysin is in suppressing chemoresistance. One of the major challenges in the field of chemotherapy is the resistance of cancer cells into the inhibitory effect of currently applied chemotherapeutic agents. Chrysin induces apoptosis to sensitize cancer cells into chemotherapy. Moreover, molecular pathways, such as Nrf2, that induce chemoresistance, are suppressed via chrysin. Further studies can focus on revealing other molecular pathways, such as miRs in chemoresistance, and the role of chrysin in their regulation.

In fact, different aspects of cancer cells are affected by chrysin, including proliferation, metastasis, and chemoresistance. These inhibitory effects are mediated via affecting both molecular pathways and mechanisms that were comprehensively discussed in the main text. As poor bioavailability is one of the drawbacks of chrysin in cancer therapy, a section was allotted to examine the role of nanoparticles for promoting bioavailability and the therapeutic effects of chrysin in cancer therapy. It is worth mentioning that these results were based on in vitro and in vivo experiments. Further studies can focus on evaluating the role of chrysin in clinical studies, which is important for clinical translation of chrysin.


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