Anticancer and Antioxidant Potential of the Fruits of Vaccinium Vitis-Idaea L. and Prospects for Their Use in the Prevention of Breast Cancer Текст научной статьи по специальности «Фундаментальная медицина»

ANTICANCER AND ANTIOXIDANT POTENTIAL OF THE FRUITS

OF VACCINIUM VITIS-IDAEA L. AND PROSPECTS

FOR THEIR USE IN THE PREVENTION OF BREAST CANCER

D.G. Tikhonov1, K.M. Stepanov2*, R.N. Zakharova1

1 North Eastern Federal University, Medical Institute, 58 Belinskogo St., Yakutsk, 677000, Russia;

2 Federal Research Centre FSBEI HE Arctic SATU, "The Yakut Scientific Centre of the Siberian Branch of the Russian Academy of Sciences", Sergelyakhskoe sh. 3 km, Yakutsk, 677000, Russia.

* Corresponding author: stenko07@mail.ru

Abstract. A review using the information on the problem in domestic and foreign sources of literature was carried out. Selected wild berries of Yakutia in their composition contain anthocyanins, flavanols and other biologically active compounds with experimentally proven anticancer effect in vitro against breast cancer cells. It has been noted that there is an insufficient study of wild berries as preventive agents against breast cancer. Experimental studies have proven the role of lingonberry in inhibiting the development of carcinogen-induced epithelial cancer, and cell culture of lingonberry and cloudberry can reduce the viability and proliferative activity of breast cancer cells. It is recommended to conduct researches on the effect of extracts, juice of northern berries on the development of breast cancer cell culture and find out their possible preventive and therapeutic effect.

Keywords: wild berries, lingonberries, chemical composition, antioxidant potential, anticancer potential, breast cancer, preventive means.

List of Abbreviations

BC - breast cancer

Introduction

Currently, a large number of biologically active compounds of plant origin with antitumor activity is identified, but a significant class of these compounds: essential oils, acids, alkaloids, flavonoids, styrene's, etc. until now are not widely used in the treatment and prevention of malignant tumors. Wild berries, which are massively harvested by the population for preservation, are of particular interest: lingonberry (Vaccinium vitis-idaea L.), blueberry (Vaccinium uliginosum L.), red currant (Ribes rubrum L.), black currant (Ribes nigrum L.), cloudberry (Rubus chamaemorus). All of them contain anthocyanins, flavanols and other biologically active compounds with experimentally proven anticancer effects in vitro against breast cancer (BC) cells. The most massively consumed berry in Yakutia is lingonberry. We paid attention to this berry when studying the incidence of BC in Yakutia. Consumption of fruits and vegetables is a generally recognized protective factor, and red meat is a risk factor (Poorolajal et al., 2021). The population of Yakutia (especially the indigenous population) traditionally consumes little fruit and vegetables, but cannot do without red meat, but nevertheless age-

standardized studies of BC incidence showed a very low level, not only at the level of Russia, but also relative to world indicators. It is known that lingonberry is a berry traditionally consumed in large quantities by the population of Yakutia. In this work we tried to draw public attention to lingonberry as a protective factor for BC. Unfortunately, up to the present time not only anticancer effects of fractions of this wild local berry have been insufficiently studied but also the role of lingonberry on BC risk in the northern conditions has been extremely insufficiently studied.

The purpose of the study is to review the studies conducted around the world and to draw attention to the gap in research on the role of lingonberry in the prevention of breast cancer.

Material and Methods

The search was performed in the Pubmed and eLibrary databases with the search queries «lingonberry and breast cancer», «lingonberry and breast cancer», «Vaccinium vitis-idaea L. and breast cancer», «брусника and «рак молочной железы» with no search term limit. An additional search was conducted with the query ««Wild Berries» and Breast Cancer Prevention». Articles were also searched by reference to literary sources.

Results

Lingonberry is the most common wild berry in the Russian Far East. Thus, its average annual biological reserves in this territory are 610 thousand tons (crude weight) (Korovkova, 2017), and according to the estimated data of the Institute of Cryo-lithozone Biology of the Siberian Branch of the Russian Academy of Sciences only in Yakutia the total resource reserve of lingonberry is 2.1 million tons (Nechaev, 2018). According to the calculations of A.P. Isayev, the total biological stock of lin-gonberry on the territory of Yakutia is estimated to be 23.6 thousand tons, and the total exploitable stock is 12.6 thousand tons (Isaev, 2021). It should be noted that lingonberries harvested by different farms for production needs from 37.5 to 59.3 tons per year are purchased on the territory of the region (Malysheva & Samsonova, 2022). Our calculations based on the data of V. Seroshevsky, the Yakuts at the end of the 19th century consumed on average 9.0 g of lingonberries per person per day (Tikhonov et al., 2019). Yakut ethnographer of the early 20th century A.A. Savvin wrote: «In Central Yakutia, in places where the dominant branch of economy was cattle breeding, berries, along with wild plants, in the diet of the population played a significant role as dressing to various types of dairy products. They were stocked for the winter in almost all households. In the uluses (districts) of the Yakut region most households stocked 30-80 kg of lingonberries" (Savvin, 2005). Unfortunately, there is no exact data on how much lingonberry is currently harvested by the population of Yakutia for personal consumption, but it should be noted that until now the rural population uses lingonberry daily as part of the traditional breakfast Kyurchekh (whipped cream). According to the survey of respondents from 6 districts of Yakutia, 56.3% of the respondents prefer to consume products derived from wild berries in winter time daily (Petrova, 2018).

Chemical composition of Vaccinium vitis-idaea L. Lingonberries contain a wide range of biologically active compounds useful for health (Rasouli et al., 2017), which allowed a number of researchers to classify it as a «super berry». (Kowalska, 2021; Mane etal., 2011). It is particularly rich in polyphe-nolic compounds. They are usually called a diverse group of compounds found in food products of plant origin. Polyphenols are compounds that have more than one phenolic hydroxyl group attached to one or more benzene rings (Vermerris & Nicholson, 2009). Classification of polyphenolic compounds is a difficult task due to the fact that these compounds include a wide variety of phytochemical compounds

(Prabhu et al., 2021; Quideau et al., 2011; Rasouli et al., 2017) and, therefore, a number of researchers distinguish them into only two groups: flavonoids and non-flavonoids (Corcoran et al., 2012). Jin Biao, Department of Chemistry, Jiangxi University of Science and Technology, Ganzhou, China categorizes food polyphenols into four main groups: phenolic acids, flavonoids, stilbenes and lignans (Jin, 2022). These compounds are secondary metabolites of higher plants and are usually involved in pollinator recruitment, protection against ultraviolet (UV) radiation, microbes and viruses, and herbivory (Cutrim & Cortez, 2018). Phenolic acids are subdivided into derivatives of benzoic (hydroxybenzoic, vanillic, protocatech, gallic and ellagic) and cin-namic (hydroxycinnamic, caffeic, alpha-cyano-4-hydroxycinnamic, ferulic, coumaric, synapic) acids (Prabhu et al., 2021). High levels of benzoic acid are noted in Vaccinium berries (cranberries, lin-gonberries, blueberries) from 300-1300 mg per kg of fruit (Wibbertmann et al., 2005). Numerous representatives of phenolic acids have a wide biological effect on the human body in its use (Kumar & Goel, 2019). Flavonoids are the most numerous groups of polyphenolic compounds. Most flavonoids are present in the form of 3-O-glycosides, except flavonols. Currently, the number of unique flavonoids identified exceeds 5000 compounds (Corcoran et al., 2012). Flavonoids are divided into 6 main subclasses: Flavan-3-ols, Flavanones, Fla-vones, Isoflavones, Flavonols, Anthocyanins (Ca-zarolli et al., 2008; Corcoran et al., 2012; Shen et al., 2022). Stilbenes are a class of phenolic secondary metabolites of plant origin, characterized by the presence of 1,2-diphenylethylene core and are of significant interest due to their medicinal properties. The best-known stilbene is resveratrol (Ren et al., 2021). Lignin is one of the main components of the plant cell wall and is a natural phenolic polymer with a high molecular weight, complex composition and structure. In the biosphere, this polymer occupies 30% of the organic carbon (Liu et al., 2018). The total content of phenolic compounds in the cranberry water-alcohol extracts ranged from 468.0 ± 10.1 to 661.1 ± 22.4 mg GAE / 100 g FW (fresh weight, GAE - gallic acid equivalent) (Drozdz et al., 2017; Lyutikova & Botirov, 2015).

Lingonberry samples from Alaska had phenolic compounds of 624.4 mg/100 g FW (Grace et al., 2014). Lingonberry contains three major anthocya-nins: cyanidin-3-galactoside (79%), cyanidin-3-glu-coside (10%), and cyanidin-3-arabinoside (11%); its total content in cultivated lingonberry cultivars from Oregon was 27.4 to 51.6 mg/100 g FW (Lee &

Finn, 2012). Relatively high levels of anthocyanins mg/100g FW (Määttä-Riihinen et al., 2004). The are found in wild lingonberries from Scandinavian most biologically active components of the chemical countries: 174 mg/100g FW (Andersen, 1985), 130.3 composition of lingonberry are shown in Table 1.

Table 1

The most biologically active components of the chemical composition

of Vaccinium vitis-idaea L.

Lingonberry components Content mg/ 100 g FW

Polyphenolic compounds

Polyphenols 480.0 mg (Volkova et al., 2018)

Total phenolicc 378.6 mg (Wang et al., 2005)

Acid composition

Ursolic acid 750 mg (Lyutikova & Botirov, 2015)

Benzoic acid 100.9-141.3 mg ( Lyutikova, 2013)

Chlorogenic acid 2,3 mg (Bystrova & Alekseenko, 2017)

Chlorogenic acid * 3.5 mg ( Bystrova & Alekseenko, 2017)

Cinnamic acid 1.39 - 3.65 mg (Lyutikova, 2013)

Coumaric acid 1.08 - 4.38 mg (Lyutikova, 2013)

Ferulic acid 0.16 - 0.98 mg (Lyutikova, 2013)

Terpene compounds

D-limonen 0.51 - 1.77 mg (Lyutikova, 2013)

Oleanolic acid 209.3 - 214.8 mg (Szakiel et al., 2012)

Ursolic acid 604.0 - 676.4 mg (Szakiel et al., 2012)

sum of triterpene acids 813.3 - 891.2 mg (Szakiel et al., 2012)

Flavonoids

Flavonoids total 11.46 mg (Bystrova & Alekseenko, 2017)

Flavan-3-ols

(+)-Catechin 152.7 - 243.6 mg (Liu et al., 2020)

(-)-Epicatechin 34.1 - 38.6 mg (Liu et al., 2020)

Flavonols

Quercetin-3 -O-galactoside 35.5 - 58.8 mg (Liu et al., 2020)

Quercetin-3 -O-rhamnoside 36.5 - 46.1 mg (Liu et al., 2020)

Anthocyanidins

Anthocyanin* 45.4 mg (Wang et al., 2005)

Cyanidin-3-O-galactoside 238.9 - 308.4 mg (Liu et al., 2020)

Cyanidin-3 -O-glucoside 17.1 - 21.1 mg (Liu et al., 2020)

Cyanidin-3-O-arabinoside 49.8 - 75.3 mg (Liu et al., 2020)

Delphinidin-3-O-galactoside** 3.41 mg (Vilkickyte & Raudone, 2021)

Petunidin-3-O-glucoside** 1.61 mg (Vilkickyte & Raudone, 2021)

Peonidin-3-O-glucoside** 3.12 mg (Vilkickyte & Raudone, 2021)

Plant steroids

Campesterol 10.1 - 15.2 mg (Szakiel et al., 2012)

Sitosterol 132.8 - 135.7 mg (Szakiel et al., 2012)

Stigmastadienone 9.7 - 24.5 mg (Szakiel et al., 2012)

Stigmasterol 5.9 - 6.5 mg (Szakiel et al., 2012)

sum of steroids 159.1 - 181.4 (Szakiel et al., 2012)

Procyanidins

sum of A-type Procyanidin dimers (m/z 575) 8.05 - 9.75 mg (Jungfer et al., 2012)

sum of A-type Procyanidin trimers (m/z 863) 7.69 - 10.01 mg (Jungfer et al., 2012)

Stilbens

End of table 1

Lingonberry components Content mg/ 100 g FW

Trans-resveratrol 3.0 mg (Ehala et al., 2005)

Pectins etc

Pectin substances 0.70 mg (Volkova et al., 2018)

Vitamin C 24.2 - 31.9 mg (Lyutikova, 2013)

Note: * Lingonberry juice; ** October, these anthocyanidins appear in berries in late autumn

Discussion

Does nutrition have an effect on the risk of BC? A systematic review of 47 second level studies, meta-analyses, and literature reviews concluded that consumption of vegetables, fruits, and mushrooms are inversely related to BC. The same association has been noted with the intake of certain nutrients: calcium, folic acid, vitamin D, lignans, and carotenoids (Buja et al., 2020). It is thought that a number of dietary characteristics can be risk factors for BC: heme iron intake and high serum iron levels (Chang et al., 2019), frequent consumption of processed meat (Farvid et al., 2018), Western diet (Xiao et al., 2019), decreased serum zinc concentrations (Jouybari et al., 2019), alcohol intake, red meat (Chen et al., 2014) and vitamin D deficiency (Hossain et al., 2019). At the same time, folic acid (Chen et al., 2014), supplemental intake of vitamin D (Hossain et al., 2019), a diet that includes vegetables and limits saturated fat, red meat and processed meat, can reduce the risk of developing BC (Dan-damudi et al., 2018). It should be noted that Giuseppe Grosso et al. from leading cancer research centers in Italy, the UK and the USA state that the evidence for the effect of diet on breast cancer is not conclusive and may be due to or mediated by lifestyle factors (Grosso et al., 2017).

It is thought that a diet rich in fruits and vegetables may reduce the risk of BC due to polyphenols. It should be noted that lingonberry with its high level of polyphenols has multiple positive effects on human health (Kowalska, 2021). Lingonberry differs from other berries in its high level of antioxidant activity (Bujor et al., 2018; Drozdz et al., 2017; Heinonen, 2007; Kostka et al., 2022; Vilkickyte et al., 2022; Vilkickyte et al., 2020; Wang et al.,

2005). The main sources of reactive oxygen species in the organism are: mitochondrial respiratory chain, UV radiation, chemical oxidants, lipid/purine metabolism, physiological production of reactive oxygen species (ROS) and oxidative protein folding (Karbyshev & Abdullaev, 2018; Chesnokova et al.,

2006). Free radicals are ROS that are produced in the body during respiration. Free radicals (FR)

cause chain reactions in cell membranes, disrupting their structures. Three basic forms of FR are known: hydroxyl radical, the most reactive and unstable chemical compound, which attacks any cell structure without selectivity, it can cause oxidative modification of nucleic acids; hydrogen peroxide can penetrate into the cell nucleus and transform into hydroxyl radical in the presence of iron; superoxide radical is formed mainly in mitochondria as a result of electron leakage during electron transport along the electron transfer chain (Lysenko, 2021; Martusevich & Karuzin, 2015; Tikhonov et al., 2022). Antioxidants prevent free radical oxidation by reducing and binding free radicals. Studies have shown that lingonberry leaves and fruits possess not only antioxidant properties, but also antimicrobial (Viljanen et al., 2014), antiviral (Mattio et al., 2020; Nikolaeva-Glomb et al., 2014), antifungal activity (Ermis et al., 2015), protect against heart disease (Isaak et al., 2015) obesity (Ryyti et al., 2020), have hypolipidemic (Olennikov et al., 2022), anti-inflammatory (Kivimâki et al., 2014; Kowalska et al., 2019), neuroprotective effect (Kelly et al., 2018) and antimutagenic, anticancer activity (Lang et al., 2011; Martinez-Perez et al., 2014).

Various components of the chemical composition of lingonberry are known to have antitumor activity against BC in isolation. One of the most promising in this respect is ursolic acid, which is contained in cranberries up to 750 mg per 100 g of fresh berries (see Table 2).

Thus, ursolic acid inhibits the growth of breast cancer cells in vitro by inhibiting proliferation, inducing autophagy, apoptosis and suppressing inflammatory reactions (Kim, 2021; Luo et al., 2017), and also suppresses metastasis of BC (Wang et al., 2021). According to a number of researchers, ben-zoic acid derivatives are potential antitumor agents with clinical prospects for breast cancer therapy (Lee et al., 2014). A potential candidate for breast cancer therapy is chlorogenic acid (Changizi et al., 2021; Zeng et al., 2021), which is found in small amounts in cranberries. Clinical trials have shown that a representative of monoterpenes D-limonene

Table 2

Summary of various biologically active compounds of lingonberries, their chemical structures, and

breast anticancer effects

Biologically active compounds

Applications in Breast Cancer Therapy and mechanism of action

Experimental studies in vitro, in vivo. References

Ursolic acid

Ursolic acid inhibits breast cancer growth by inhibiting proliferation, inducing autophagy and apoptosis, and suppressing inflammatory responses via the PI3K/AKT and NF-kB signaling pathways in vitro. Inhibits the metastasis of breast cancer by suppressing glycolytic metabolism through the activation of SP1/caveolin-1 signaling.

(Kim, 2G21; Luo et al., 2G17; Wang et al., 2G21)

Benzoic acid но,. ,o

Benzoic acid significantly suppresses the viability of breast cancer cells MCF-7, MDA-MB-468. It exhibits antitumor activity by stopping the cell cycle during the G2/M phase and causing apoptosis in breast cancer cells. Increases the activity of caspase-3.

(Lee et al., 2G14)

Chlorogenic acid

Chlorogenic acid (CA) in the model of invasive breast cancer in BALB/c mice statistically significantly reduced metastatic nodes compared to the control and eliminated the tumor at the end of the experiment. CA induces apoptosis of cancer cells and affects apoptotic agents: it significantly increases the Bax/Bcl-2 ratio and increases p53 gene expression compared to the control group. By disrupting the NF-kb/EMT signaling pathways, it improves anti-tumor immunity by providing anti-tumor and anti-metastatic effects.

(Changizi et al.. 2G21; Zeng et al., 2G21)

Cinnamic acid

Cinnamic acid is an effective anticancer agent that can induce apoptosis in breast cancer cells via TNFA-TNFR1 mediated extrinsic apoptotic pathway.

(Pal et al., 2G21)

o-Coumaric acid

o-Coumaric acid exhibits anticarcinogenic effects by stimulating various pathways, including apoptosis, cell cycle regulation, and tumor suppression. It can stimulate the metabolic breakdown of toxic chemicals metabolized by CYP2E1 and CYP1A2 through increased expression of these isoenzymes, while coumaric acid inhibits the CIP3A4

(Sen et al. 2G13)

Continuation of the table 2

Biologically active compounds Applications in Breast Cancer Therapy and mechanism of action Experimental studies in vitro, in vivo. References

isoenzyme, which may reduce the level of in-activation of drugs metabolized by this isoenzyme.

I CH3 HO "erulic acid 0 Qj^^OH Treatment with ferulic acid (FA) results in decreased viability, increased apoptosis, and suppressed metastatic potential in the MDA-MB-231 breast cancer cell line. The antitumor activity of FA and its role in the suppression of metastasis are regulated by the reverse epithelial-mesenchymal transition (EMT). Because FA is a natural antioxidant that is poorly soluble in water, it is most promising to include it in a cyclodextrin nan-osponges to increase cytotoxicity and deliver it to the lesions. (Rezaei et al., 2019; Zhang et al., 2016)

D-limonen Research on d-limonene (DL) has moved from preclinical to Phase I and II clinical trials. DL is well tolerated by patients, and it accumulates in breast tissue at an average rate of 41.3 pg/g of tissue. A decrease in the expression of tumor cyclin D1 was established, which is associated with a stop in tumor proliferation. There is a dose-dependent increase in caspase-3 and annexin V only for ER-positive breast cancer cell lines (MCF-7). (Chebet et al., 2021; Lang et al., 2011)

Oleanolic acid The mechanism of action of oleanolic acid (OA) and its derivatives is mainly directed against cancer cell proliferation, induction of apoptosis and autophagy, regulation of cell cycle regulatory proteins, inhibition of vascular endothelial growth, antiangiogenesis, and inhibition of tumor cell migration and invasion. (Tang et al., 2022) '

Resveratrol Resveratrol (RV) protects DNA from reactive oxygen species (ROS), which trap hy-droxyl and superoxide groups, as well as free radicals generated in cells. RV inhibits mitochondrial respiration in breast cancer cells. The cytotoxic effect of RV is modulated by SIRT1 and inhibition of mitochondrial complex I. (Deus et al., 2017; Leonard et al., 2003)

The end of the table 2

Biologically active compounds

Applications in Breast Cancer Therapy and mechanism of action

Experimental studies in vitro, in vivo. References

Quercetin

Quercetin (Qu) leads to apoptosis by mitochondrial cytochrome c. Suppresses the formation of cancer stem cells (RCCs), which are responsible for the recurrence of cancer. Qu inhibits metastasis by reversing EMT through MMP, TGFB1, and mTOR/c-Myc inhibition. Stabilization of the telomeric DNA structure and reduction of the P38MAPK and PI3K signaling pathways lead to the antiproliferative property of Qu.

(Ezzati et al. 2020)

(-)-Epicatechin

Treatment with (-)-epicatechin causes a decrease in MDA-MB-231 cell proliferation through an increase in reactive oxygen species (ROS), activation of the death receptors (DR4 and DR5), and an increase in pro-apop-totic proteins. In MCF-7 cell culture, a decrease in the viability of cancer cells occurs due to an increase in ROS and upregulation of proapoptotic proteins (Bad and Bax).

(Pereyra-Vergara et al.. 2020)

Cyanidin-3 -O-glucoside

Cyanidin-3-O-glucoside (C3G) inhibits EMT and the migration and invasion of breast cancer cells by upregulating Kruppel-like factor 4 (KLF4).

KLF4 is involved in the regulation of proliferation, differentiation, apoptosis, and reprogramming of somatic cells.

C3G attenuates breast cancer-induced angio-genesis by inhibiting VEGF.

(Chen et al., 2020; Ma & Ning, 2019)

Delphinidin

Delphinidin markedly inhibits the viability of HER-2 positive breast cancer cell lines by modulating cell cycle arrest and inducing apoptosis.

(Wu et al.. 2021)

Abbreviations: AKT - The collective name of a set of three serine/threonine-specific protein kinases; BAD - The BCL2 associated agonist of cell death protein; BAX - The Bcl-2-associated X protein; C-Myc -protein is a member of a family of proteins that regulate cell proliferation and apoptosis; DR4 and DR5 -Dead receptor 4 and Dead receptor 5; EMT - Epithelial-mesenchymal transition; MMP - Matrix metallopro-tease; mTOR - Mammalian target of rapamycin signaling pathway; NF-kB - Nuclear factor kappa-light-chain-enhancer of activated B cells; P38MAPK - p38 mitogen-activated protein kinases; PI3K - Phospho-inositide 3-kinase; SIRT1 - Sirtuin 1; Sp1 - Specificity protein 1; TGFB - The transforming growth factor beta signaling pathway.

predominantly accumulates in breast tissue and induces apoptosis of ER-positive breast cancer cell lines (Lang et al., 2011), but a systematic review of articles about the effect of D-limonene on breast cancer showed a lack of evidence base and requires additional placebo-controlled studies (Chebet et al., 2021). Of the triterpenoids, oleanolic acid (Liang et al., 2021), which is found in cranberries about 200 mg/100 g of fresh berries, has anti-tumor activity against BC. In his review article M. Ezzati et al. showed that quercetin can be used as natural compounds in the therapy of BC (Ezzati et al., 2020). Flavonoids (Martinez-Perez et al., 2014), anthocya-nidins (Li et al., 2022), phytosterols (Hutchinson et al., 2019), procyanidins (Gao & Tollefsbol, 2018) have shown anti-cancer and chemo preventive effects against BC. There is a large number of researches on the effects of resveratrol against BC (Deus et al., 2017; Gao & Tollefsbol, 2018). All these compounds are present to a greater or lesser extent in cranberry berries.

We found articles in the PubMed databases with the results of a study of the effects of lingonberry on cell proliferation in models of BC cell lines and epithelial cells of ectodermal origin (Olsson et al., 2004; Rischer et al., 2022; Wang et al., 2005). Thus, lingonberry juice from Oregon (USA) in experiments with mouse skin epithelial cells significantly suppressed cancer transformation induced by 12-O-tetradecanoylphorbol-13-acetate (cancer promoter) and ultraviolet irradiation. This effect is attributed to the antioxidant properties of lingonberry juice and the anthocyanins and flavonoids it contains. Thus, lingonberry juice actively reduced peroxyl (ROO*), hydroperoxyl (*ON) radicals by 83.0% and reactive oxygen species by 99.0% from the cultured medium. It inhibits: AP-1 (activating protein-1) transcriptional activity via MARK (mitogen activating protein kinase) and NF-kB (universal transcription factor controlling expression of immune response, apoptosis and cell cycle genes). It should be noted that the average levels of phenolic compounds and anthocyanins in the juice of ripened lin-gonberry used in the experiment were 378.6 and 45.4 mg/100g, respectively. Based on the results of their studies, the authors conclude that lingonberry juice can be a very effective chemo preventive agent (Wang et al., 2005). M.E. Olsson et al. found no effect of lingonberry extract from Sweden on the proliferative activity of estrogen receptor positive MCF-7 breast cancer cells (Olsson et al., 2004). Finnish researcher H. Rischer et al. studied the chemical composition and effect of cell cultures of five northern berries: cloudberry, lingonberry, bear-

berry, arctic blackberry, strawberry on antioxidant activity and antiproliferative effects on MCF-7 breast cancer cells. Of the 5 cell cultures of these berries, lingonberries were significantly superior in anthocyanins, flavones and other flavonoids, phenolic acids, lignans, and total carotenoids. Lingonberry showed the highest antiproliferative activity against BC cells at concentrations of 200.0 and 300.0 ^g/ml, reducing cancer cell growth by about 20.0%, and lingonberry at 600.0 ^g/ml reduced cell growth by about 70.0%. Lingonberry has the highest antioxidant activity compared to the above 4 berries (Rischer et al., 2022). Thus, lingonberry has an antiproliferative effect on BC cell cultures that is inferior in expression at lower concentrations to cloudberry, but significantly superior at higher concentrations. It should be noted that it is unlikely that the concentration of biologically active compounds of berries in human blood could reach the level that was used in the experiment to inhibit the development of cancer cells. Much more significant for practical health care is the effect of neutralization of carcinogens by lingonberry juice, due to the antioxidant activity of its nutrients. Benzoic acid isolated from Rubus fairholmianus berries was found to decrease viability and proliferative activity of MCF-7 breast cancer cells in vitro. Under the influence of this acid there was a release of cytochrome C, a change in mitochondrial membrane potential with subsequent induction of BC cell apoptosis (George, Abrahamse, 2019). In lingonberry, benzoic acid is found 73-158 mg/100g (Lyutikova & Botirov, 2015), which is a rather high level and is probably one of its chemical compounds with anticancer effects.

Conclusion

It should be noted that up to now, insufficient attention has been paid to the study of wild berries as prophylactic agents against BC. A methodologically flawless experimental study proved the role of lingonberries in inhibiting the development of carcinogen-induced epithelial cancer, and cell culture of lingonberry and cloudberry can reduce the viability and proliferative activity of BC cells. Lingonberry (Vaccinium vitis-idaea L.) and cloudberry (Rubus chamaemorus) are the most promising wild berries with protective potential to prevent this serious pathology. It cannot be ruled out that the traditionally constant level of their consumption by the native population of the region may be one of the reasons for the low incidence of BC. It is recommended to study the effect of extracts and juice of northern varieties of lingonberry and cloudberry on

the development of BC cells as well as to identify Funding source: this work was supported

chemical compounds with prophylactic and thera- by the Russian Science Foundation (grant peutic effect. No. 22-25-20032).

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