1. Introduction

2. Phytoestrogens: Chemical Classification and General Aspects

Figure 1. Basic chemical structures of the major classes of phytoestrogens. The different types of phytoestrogens share a structural similarity with 17β-Estradiol. In green, the flavonoid skeleton showing rings A, B and C and the numbering.

Figure 1. Basic chemical structures of the major classes of phytoestrogens. The different types of phytoestrogens share a structural similarity with 17β-Estradiol. In green, the flavonoid skeleton showing rings A, B and C and the numbering.

3. Phytoestrogen Mechanisms of Action - Anticancer Related Effects

Table 1. Relative binding affinities of various dietary phytoestrogens for ERα and ERβ, with values for E2 arbitrarily set as 100. The phytoestrogens reported are those discussed in the sections 6 and 7.

Figure 2. Intracellular mediators of the effects of phytoestrogens on cancer cells. Phytoestrogen can interact with the two types of ER, the intracellular ERα and ERβ and membrane-associated mERs and GPER, activating downstream genomic and non-genomic effects which ultimately affect cell cancer phenotypes. The genomic pathway can involve ER interactions with other transcription factors (TFs) such as, CREB, AP-1, Sp1 and NF-κB. Phytoestrogens can also act through ER-independent mechanisms which induce oxidative stress-mediated signaling by generating ROS, as well as interacting with other nuclear receptors, such as PPARs and ERRα/γ.

Figure 2. Intracellular mediators of the effects of phytoestrogens on cancer cells. Phytoestrogen can interact with the two types of ER, the intracellular ERα and ERβ and membrane-associated mERs and GPER, activating downstream genomic and non-genomic effects which ultimately affect cell cancer phenotypes. The genomic pathway can involve ER interactions with other transcription factors (TFs) such as, CREB, AP-1, Sp1 and NF-κB. Phytoestrogens can also act through ER-independent mechanisms which induce oxidative stress-mediated signaling by generating ROS, as well as interacting with other nuclear receptors, such as PPARs and ERRα/γ.

4. Molecular Basis of Osteosarcoma Pathogeneses

5. Estrogen Receptors as a Potential Target for the Treatment of Osteosarcoma

6. Anti-Osteosarcoma Effects of Flavonoids

6.1. Genistein and Related Isoflavones

Genistein is a 15-carbon skeleton compound, chemically known as 5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one, which was first isolated from Genista tinctoria. It is the most prominent isoflavone from soy, and soy-based food products [138,139].

In addition to genistein, soy foods are rich in daidzein, which differs from genistein due to the lack of the hydroxyl group at position 5 [140,141]. Genistein and daidzein derive from the O-methylated precursors biochanin A and formononetin, respectively [141,142] (Figure 3), which are generally less prevalent in soy and are found mostly in clover and alfalfa sprouts [141,143]. They are present as either aglycons or as glycosides [143,144]. The presence of hydroxyl groups and sugars increases their solubility in water, whilst methyl groups confer them lipophilicity [23].

Figure 3. Chemical structure of the most common isoflavones and some of their possible targets in OS cells. Isoflavones, especially genistein, bind ERβ with a significant higher affinity than ERα. Downward arrows represent downregulation or reduction. Upward arrows represent upregulation or increase.

Figure 3. Chemical structure of the most common isoflavones and some of their possible targets in OS cells. Isoflavones, especially genistein, bind ERβ with a significant higher affinity than ERα. Downward arrows represent downregulation or reduction. Upward arrows represent upregulation or increase.

Genistein and its related compounds are well known for their weak estrogen-like activity in mammals, including the prevention of bone loss and other estrogen decrease-related conditions [145]. Indeed, data have revealed a reduced occurrence of breast and prostate tumors, as well as osteoporosis, in human populations that consume a soybean-rich diet [146]. Isoflavones interfere with ERα and ERβ isoforms with higher binding affinity for the latter, particularly genistein (20- to 30-fold higher) and daidzein (five-fold) [19] (Table 1), producing distinct clinical effects from estrogens and contributing to the treatment of various cancers, such as gastric, breast, prostate and non-small cell lung cancer prostate cancer [139,147,148,149].

Consistent with the above-reported Erβ anti-proliferative effects [10], it is believed that the chemotherapeutic potential of isoflavones is mainly due to their interactions with ERβ and vary in different cancer types, based upon their specific selectivity for target cells and their concentration, highlighting the complexity of dietary isoflavone functions [150,151,152]. ER-independent signaling mechanisms have also been described for isoflavones, including protein kinase regulation, enzymatic inhibition, growth factor modulation, antioxidant activity, or epigenetic changes [43].

Among the soybean isoflavones, genistein has shown to be one of the most potent inhibitors of cell proliferation in vitro, by affecting the protein tyrosine kinase (PTK) activity [153], suppressing the mammalian DNA topoisomerase II [139], and interacting with ERs on the nuclear envelope to promote G2/M phase arrest in various types of cancer cell lines [170,180]. The anticancer efficiency of genistein has been proven in numerous preclinical investigations [139]. Genistein from soy extracts, its free form, and its glycoside genistin are readily bioavailable and well tolerated with minimal toxicity [139,142]. Studies on OS cells suggested that genistein and its naturally occurring prenylated derivatives exert an inhibitory activity by binding ER isoforms with a statistically significant effect from 1 nmol/l [155]. The specific activation of ER signaling by genistein has been reported to be involved in the down-regulation of the expression of the EGFR gene. This influences events strictly controlled by its signaling pathway, such as the differentiation of U2OS human OS cells that stably express ERs [156]. Indeed, previous studies have demonstrated that genistein and daidzein can induce osteoblast differentiation through the enhanced expression of ALP, bone morphogenetic protein 2 (BMP-2), and OPG, [157,158], which suggests that soybeans are able to prevent osteoporosis. In addition, the treatment of osteoblasts with genistein, and other soybean isoflavones, induces calcified bone noduli [159]. The osteogenic activity of genistein was also observed in human MG-63 OS cell line [160], and murine cell line LM8 [161], using a variety of approaches. Treatment with genistein switched the osteoblasts towards a more differentiated phenotype that was able to synthesize many of the essential factors required for the production of new mineralized extracellular matrix, such as collagen type I (Col I) and ALP, even in a nonosteogenic growth medium [160].

As mentioned earlier, extensive vascularization and rapid growth are considered to be associated with the high metastatic potential and recurrence rate of OS [83,100].

The modulation of ECM components is a key element in cancer progression and invasion [101,102]. Glycosaminoglycans (GAGs)/proteoglycans (PGs) are the major macromolecules composing ECM [162]. Their localization can be both extracellular and cellular (cell membrane and intracellular granules) and they participate in the regulation of various cellular events, such as cell adhesion, migration, differentiation and proliferation, critically affecting broader aspects in cancer initiation and progression [162]. In vitro studies have shown that pathogenesis of OS implies qualitative and quantitative changes in PGs, which have important consequences on cell proliferation and/or differentiation [163]. Nikitovic and coauthors [164] investigated the activity of genistein on the synthesis and distribution of GAGs/PGs in MG-63 and SaOS-2 cell lines, which differ in the density of the ERs they express. They observed a dose-dependent inhibitory effect of genistein on OS cell growth, which was accompanied by a reduction of both secreted and cell-associated GAGs/PGs by both cell lines, so suggesting a PTK mechanism. On the other hand, MG-63 cell line showed a complex pattern of PG synthesis, indicating a dual action of genistein via the PTK mechanism and through the ER receptors, which are present in much higher density in MG-63 cells compared to SaOS-2 cells [164].

Other than ERs, genistein can also regulate other nuclear malignancy-related receptors such as peroxisome proliferator-activated receptor γ (PPARγ), an isotype of PPARs, which may further explain its activity against a range of cancers, including OS [165,166]. In OS, PPARγ plays a key role in suppressing cell proliferation and promoting osteoblastic terminal differentiation, suggesting a potential use of PPARγ agonists as chemotherapeutic and/or chemopreventive agents for human OS [113]. It has been reported that genistein treatment triggers growth inhibition and G2/M cell cycle arrest in human MG-63 cells, by acting as a non-toxic activator of PPARγ expression [166]. In addition, the genistein-induced PPARγ signaling resulted in the downstream activation of the tumor suppressor phosphatase and tensin homolog (PTEN), which in turn potently regulated the PI3K/Akt pathway, involved in cell proliferation and survival [166]. Additionally, the anti-OS activity of genistein was examined in SaOS-2 and MG-63 OS cells in combination with Calcitriol [167], the most active component of the vitamin D family [168]. The synergistic action of both these substances had already proven effective in preventing osteoporosis and reducing hip fracture risk in postmenopausal women [169]. In OS cells, combined treatment significantly increased the expression of the enzyme sphingosine-1-phosphate lyase (SGPL1) [167], which irreversibly degrades sphingosine-1-phosphate (S1P), whose production and secretion is associated with an increased capability of migration and invasion of cancer cells [170]. Besides the synergistic effects on the proliferation behavior, co-treatment increased the expression of vitamin D receptor (VDR) and ERβ and influenced the cellular metabolism by decreasing extracellular acidification (which is a measure of glycolytic flux in cancer cells) as well as cell respiration rates (a measure of mitochondrial respiration) [167].

Gemcitabine is one of the commonly used anti-metabolite drugs. It is an analog of cytosine arabinoside which shows pronounced anti-tumor activity, in vitro and in vivo, in a variety of solid tumors, including OS [171]. Data reported by Zhang et al., showed that the combination of gemcitabine and genistein enhance the antitumor efficacy of gemcitabine in MG-63 and U2OS cell lines and help to overcome resistance to gemcitabine treatment [172]. The induction of NF-kB activation and up-regulation of its target genes by many anticancer agents, including gemcitabine, may mediate the cellular resistance to anticancer drugs [173]. In contrast, the activation of the Akt and NF-kB signaling pathways can be inhibited by genistein [147]. Combined treatment of genistein with gemcitabine reversed the cancer’s resistance to gemcitabine by abrogating the Akt/NF-κB pathway, which led to a significant reduction in cell viability and induction of apoptosis in OS cell lines [172,174]. The structure of genistein and some of its potential effects on OS cells are reported in Figure 3 and Table 2.

6.1.1. Daidzein

The analog of genistein, daidzein (7,4-dihydroxyisoflavone) (Figure 3), is a well-studied isoflavone with a high nutritive value. It is predominantly found in soy and many unfermented foods not only in the form of daidzein, a glycoside conjugate, but also as acetylglycoside and aglycone [175]. The complex daidzein pharmacokinetic features, along with its insolubility in water and oil, have blocked their use as a highly common compound in medicine or as a nutraceutical [175].

Although daidzein has been proven to have in vitro antitumor effects on a variety of cancers [8,176,177,178], there are few reports concerning its inhibitory activity towards OS [156,179] (Table 2). Daidzein inhibited proliferation and cell cycle progression and promoted apoptosis in U2OS cell lines that stably express ERs [156]. In addition, similarly to genistein, daidzein is able to modulate the level of EGFR through the specific activation of both ER isoforms, thus affecting multiple intracellular events that are tightly controlled by the EGFR transduction pathway, such as the maturation of osteoblasts [156].

Recently, Zhu and coworkers investigated the underlying mechanism of daidzein against OS by means of an in-depth systematic pharmacology analysis, which identified the Src-MAPK pathway as the highest-ranked target of daidzein in 143B and U2OS cells and in in vivo OS models [179].

6.1.2. Biochanin A

Biochanin A (5,7-dihydroxy-4’-methoxy-isoflavone) (Figure 3) is a phytoestrogenic isoflavone found in legumes, particularly red clover (Trifolium pratense), but it is also present in cabbage, alfalfa, and many other herbal products [180]. The biological effects of biochanin A observed in vitro and in vivo are different from those observed for its derivative genistein. It plays complex roles in the regulation of multiple biological functions by binding DNA and some specific proteins or acting as a competitive substrate for some enzymes. Biochanin A extract from plants is already commercially available because of its potential benefits to human health despite its limited bioavailability [181,182]. It is used for the reduction of oxidative stress, treatment of osteoporosis, anti-inflammatory effects, regulation of blood glucose levels, and for treatment of allergies [183,184]. Moreover, like other isoflavones, biochanin A exhibits chemopreventive activity against various cancers [182].

Several studies have suggested that biochanin A has the potential to prevent and treat OS [185,186] (Table 2). The antiproliferative potential of biochanin A and its underlying mechanisms in human OS have been investigated by Hsu and et al. They reported that biochanin A dose-dependently inhibits cell growth and induces apoptosis in MG-63 and U2OS OS cells by triggering the activation of the intrinsic mitochondrial pathway and caspase-9 and -3 and increasing the Bax: Bcl-2/Bcl-XL ratio.

DOX is probably the most studied drug in combination with phytoestrogens. It is an antitumor antibiotic which acts by interfering with the enzymes involved in DNA replication or by causing strand breakage [187]. Hsu et al. also demonstrated that a combination of the chemotherapeutic agent DOX with biochanin A had synergistic cytotoxicity [185]. Supporting evidence for the anti-OS activity of biochanin A has been recently reported by Zhao et al. [186]. Biochanin A treatment clearly increased apoptotic rates and decreased migration and invasion ability in MG-63 and U2OS cells, in a time and dose dependent manner. Relevant genes involved in cell proliferation, apoptosis, invation and migration (i.e. proliferating cell nuclear antigen (PCNA), caspase-3, cyclinD1, Bcl-2, MMP-9, N-cadherin and E-cadherin) showed altered expressions in both OS cell lines [186].

E-cadherin is an important factor of cell-cell adhesion. It is classified as a cancer depressor because the loss of E-cadherin may lead to destruction of cytoskeleton promoting cells invasion and migration [188]. The expression of N-cadherin in epithelial tumour characterizes tumorigenesis as it may induce EMT, reinforce tumour cell activeity and promote the interaction between tumour and neighbouring cells [189]. OS cells treated with biochanin A exhibited decreased expression of MMP-9 and N-cadherin, while showing increased expression of E-cadherin. These findings strongly indicated that biochanin A may possess a suppressive function in cancer invasion and migration by mediating the process of tumor EMT [186].

6.1.3. Formononetin

Formononetin (7-hydroxy, 4′-methoxy isoflavone) (Figure 3) is the active ingredient of the traditional Chinese medicine astragalus, angelica, and Pueraria lobate. Formononetin exhibits anticancer effects against ovarian cancer, colorectal cancer, and gastric cancer, by suppressing cell viability and inducing apoptosis through the regulation of the estrogen-dependent signalling pathway [190,191].

Reports have also documented the anti-OS activity of formononetin (Table 2). It promoted the apoptosis of human bone cancer in vitro and in vivo in nude mice that had undergone orthotopic tumor implants, by modulating the expression levels of the apoptosis-related factors ERK, Akt [192], Bcl-2, Bax, caspase-3 and decreasing the level of miR-375, an ER signaling related miRNA, in ER-positive U2OS cells [193]. Further evidence showed that in MG-63 cells, the anti-proliferative function of formononetin is related to the up-regulation of the expression of the tumor suppressor PTEN gene, via miR-214-3p [194], which is one of the miRs with oncogene properties that is considerably increased in OS [195]. Recently a bioinformatic-based network pharmacology has been used to disclose other therapeutic targets and bio-mechanisms of anti-OS formononetin activity [196]. The biological processes of formononetin against OS were principally linked to the regulation of cell motility, cell proliferation as well as the regulation of gene expression. The main core targets of formononetin were determined as estrogen receptor 1 (ESR1), TP53 and receptor tyrosine-protein kinase erbB-2 (ERBB2). Interestingly, they were representatively validated following formononetin treatment in vivo, in tumor-bearing mice and clinical cases, suggesting that these predictive targets might be potential biomarkers for the screening and treatment of OS [196].

6.2. Flavonols

6.2.1. Quercetin

An intake of flavonols is found to be associated with a wide range of health benefits which includes antioxidant potential and anti-inflammatory effects. Flavonols may also play a role in reducing the risk of chronic diseases such as cardiovascular disease, cancer, and neurodegenerative disorders [197].

Quercetin (3,5,7,3′,4′-pentahydroxyflavone) (Figure 4) is the most abundant plant pigment in the extensive class of flavonols. It can be found in numerous plant species and in daily foods such as vegetables (caper contains the greatest quantity in relation to its weight), fruit, nuts and teas. The average daily dietary intake of quercetin is estimated to be 16 mg [198]. Due to its potent anti-inflammatory and antioxidant effects, quercetin is considered to be an advantageous agent for therapeutic purposes for a number of diseases including cardiovascular diseases, arthritis, allergy and diabetes [199]. Indeed, it is commercially accessible as a supplementary agent. Oral administration of 1 g quercetin per day is safe and is absorbed up to 60% [200].

Figure 4. Chemical structure of flavonoids discussed throughout the text.

Figure 4. Chemical structure of flavonoids discussed throughout the text.

Extensive studies have demonstrated the efficacy of quercetin for the prevention and treatment of several types of cancer, in in vivo and in vitro models [201]. Quercetin can significantly prevent the cell cycle, promote cell apoptosis, and suppress tumor invasive behaviour via a variety of mechanisms [202]. There is evidence that several of the effects of quercetin on the survival of cancer cells might rely on ER-dependent mechanisms.

In particular, it has been shown that quercetin can impair the ERα-mediated rapid signaling, preventing the anti-apoptotic and proliferative ERK/MAPK and PI3K/AKT pathway activation [203]. Thus, quercetin can influence cancer cell proliferation and survival by acting as partial antagonists of ERα-activated rapid signals [204,205]. On the contrary, quercetin can behave as an E2-mimetic agent in the presence of ERβ, by activating the p38/MAPK and the downstream pro-apoptotic pathway, indicating a differential agonist or partial antagonistic effect of this compound in the definition of their anti-carcinogenic potential [206].

A strong cytotoxic activity of quercetin against OS has been largely demonstrated (Table 2). Although the related studies are mainly limited to in vivo and in vitro investigations, findings are promising. Quercetin treatment results in the suppression of proliferation, cell cycle arrest, induction of apoptosis, and reduced potential for adhesion and migration in several human OS cells lines, including 143B [207,208], HOS, MG-63 [209,210], U2OS and SaOS-2 cells [211]. Regarding the effect on OS cell growth, a number of key elements of the cellular apoptotic signaling pathway seems to be involved in the quercetin-dependent regulation of apoptosis. In an early study, Liang and coworkers [209] evaluated the effects of quercetin on the viability of human OS MG-63 cells. Quercetin treatment resulted in a decreased expression of the anti-apoptotic protein Bcl-2, which was paralleled with the increase of pro-apoptotic proteins BAX and cytochrome C, activation of caspase-3 and -9, and loss of mitochondrial membrane potential, indicating that quercetin was able to promote apoptosis via activation of the mitochondrial-dependent pathway [209]. Additional evidence demonstrated that the administration of quercetin to HOS and ATCC 1543 human OS cell lines leads to the cell cycle arrest at the G(1)/S phase accompanied by downregulation of cyclin D1, one of the cyclins required for G(1) to S progression. Subsequent apoptosis was induced by gradual activation of caspase-3 and subsequent poly (ADP-ribose) polymerase (PARP) cleavage [212].

The ability of quercetin to induce apoptotic cell death has also been associated with overcoming drug-resistance in OS cells. High-dose methotrexate (HDMTX) is considered to be a key agent in determining the chemotherapeutic outcome of OS patients [213]. However, drug resistance often develops in the late stage of treatment. Data reported by Xie et al., [214] revealed an apoptosis-inducing activity of quercetinin in an MTX-resistant OS model (U2OS/MTX300 cells). Exploring the mechanism underlying these effects, the authors found that cell death was accompanied by mitochondrial dysfunction and dephosphorylation of Akt, suggesting that quercetin-induced apoptosis might be associated with the apoptosis pathway of mitochondria and Akt activity [214]. Similar evidence was provided by Yin et al. [215], further sustaining the role of quercetin as a potential chemotherapeutic agent for MTX-resistant osteosarcoma.

OS is known to be a disease with a high propensity for metastasis to the lung [5]. In comparison to other cell lines, only 143B cells are able to generate a reliable and reproducible in vivo mouse model that develops primary tumors after intratibial injection within three to five weeks [216]. This mouse model also more closely reflects human disease because it develops metastases in the lung, which is the main location of metastasis in humans [217]. An early study by Berndt et al., [207] evaluated the anticancer properties of quercetin in human a 143B OS cell line. Quercetin treatment caused an arrest of 143B cells in the G2/M transition of the cell cycle. The cell cycle arrest was followed by cell death via activation of the apoptotic signaling pathway, as shown by a dose-dependent caspase-3, caspase-7 and PARP cleavage, after 36 h of incubation with quercetin. The pan-caspase inhibitor Z-VAD prevented PARP cleavage-dependent apoptosis. Quercetin also effectively blocked some hallmarks of metastatic behavior such as adhesion and migration. Overall, these findings suggested a role of quercetin as a potential drug that can target cells of the primary tumor and metastasizing foci [207].

Quercetin’s ability to induce cell death in OS cell lines is not limited to apoptosis. A recent work by Wu et al., [218] showed for the first time a role of quercetin in promoting autophagic cell death in human OS cells. It is well accepted that autophagy plays a two-faced role in cancer as a tumor suppressor or as a pro-oncogenic mechanism. Indeed, there is a dynamic relationship between the rate of protein degradation through autophagy, i.e. autophagic flux, and the susceptibility of tumors to undergo apoptosis which is critical in the autophagy/cancer relationship [219]. Therefore, an accurate modulation of this pathway is the challenge faced when targeting autophagy in the clinical setting [220].

The quercetin dependent increase of autophagic flux was shown by a dose-dependent up-regulation of LC3B-II/LC3B-I ratio, a hallmark of autophagy, in quercetin-treated MG-63 cells. Moreover, pharmacological inhibition of autophagy or genetic blocking autophagy by autophagy-related gene 5 (ATG5) knockdown efficiently protected against quercetin-induced cell death, supporting the role of quercetin in triggering autophagic cell death in MG-63 cells [218]. The authors also investigated the effect of quercetin exposure on the transcription factor nuclear protein 1 (NUPR1) activity [218]. NUPR1 is a master regulator of autophagy flux typically expressed in response to stress signals induced by genotoxic signals and agents [221]. Under stressful conditions such as chemotherapy treatment, an interplay between the homeostatic NUPR1 and autophagy pathways may occur in cancer cells, ultimately dictating their fate between cell death or survival [221]. Data revealed that quercetin increased NUPR1 expression and activated NUPR1 reporter activity, which contributed to the expression of autophagy-related genes by disturbing ROS homeostasis, indicating an important role for NUPR1 signalling in quercetin-induced autophagy in MG-63 cells [218].

Activating local cell invasion and distant metastasis represents another important hallmark of cancer that mainly reflects the progression of carcinomas to a higher grade of malignancy. Cell migration is a critical process for cancer cell spread, invasion, and distant metastasis [222]. Hypoxia-inducible factor (HIF)-1α was shown to be correlated with tumor grade, metastasis, and poor outcomes in various cancers including OS.

Its upregulation results in increased cell proliferation and migration, as well as the development of chemotherapeutic resistance [223]. Lan et al., [210] reported a dose- and time-dependent reduction of cell migration and invasion in human HOS and MG-63 cell lines, which was paralleled with a significant quercetin-induced downregulation of the expression of HIF-1α and downstream genes such as, VEGF, MMP-2, and MMP-9, which play essential roles in promoting cancer invasion and metastasis. In addition, quercetin treatment suppressed the formation and proliferation of metastatic lung tumors in vivo, in an OS nude mouse model [210]. In U2OS and SaOS-2 cells, the quercetin-mediated inhibition of the metastatic phenotype was associated with a significant downregulation of parathyroid hormone receptor 1 (PTHR1) [211], an important G-protein coupled receptor involved in OS pathophysiology [224].

Many lines of compelling data indicated the role of quercetin in sensitizing cancer cells to the action of several anti-cancer drugs [225,226]. In this respect, synergistic anti-tumor activities of quercetin and CDDP, a widely used chemotherapeutic agent, have been reported in cancer treatment in several in vivo and in vitro models [225,226,227].

Regarding OS, the efficacy of quercetin in enhancing CDDP sensitivity has been demonstrated by Zhang et al. in 143B cells [208]. miR-217 is a tumor suppressor which inhibits cell proliferation and metastasis in OS. Its over-expression could reverse CDDP chemoresistance in lung cancer cells [228]. Expression of miR-217 was upregulated after quercetin and/or CDDP treatment, while its target Kirsten rat sarcoma virus (KRAS) was downregulated both at mRNA and protein levels, thus suggesting an involvement of the miR-217-KRAS axis in the QUE-improved sensitivity of CDDP [208]. Quercetin has also been shown to be effective in boosting the anticancer activity of MTX on SaOS-2 cancer cells. A decline in MTX IC50 value was observed from 13.7 ng/ml to 8.45 ng/ml in the presence of quercetin. Moreover, the mRNA expression outcomes indicated that the combination therapy significantly up-regulates the tumor suppressor genes, such as p53, CBX7, and CYLD, and declines anti-apoptotic genes BCL-2 and miR-223, which can lead to proliferation, inhibition and apoptosis inducement [229].

Taken together, these findings provide experimental evidence of the effectiveness of quercetin in treating OS in human cell lines. On the other hand, further research including clinical trials are needed to support the future development of quercetin as an effective and safe candidate agent for the prevention and/or therapy of OS.

6.2.2. Galangin

Galangin (3,5,7-trihydroxyflavone) (Figure 4) is another plant flavonol from the flavonoid group of polyphenols. It is primarily extracted from the rhizome of Alpinia officinarum, which has been used as a herbal medicine in Asia for decades. Studies have shown that galangin has anti-inflammatory [230], antibacterial [231] and antiviral [232] activities in vitro. Currently, its antitumor properties are subject of attention. Studies have shown that galangin suppresses the proliferation and functions of various tumor cells [233,234,235]. However, research on galangin’s effects on OS specifically is limited (Table 2). In a study conducted by Yang et al. [236], exposure to galangin significantly suppressed MG-63 and U2OS cells by inhibiting their proliferation and invasion and triggering their apoptosis, in a concentration-dependent manner. The underlying mechanism was associated with the suppression of PI3K and its downstream regulators, cyclin D1 and MMP-2/9, and upregulation of p27Kip1, caspase-3, and caspase-8 [236]. Other evidence indicated that, in addition to effectively attenuating cell proliferation, incubation of MG-63 and U2OS cells with galangin increased dose dependently the expression levels of several markers for osteogenic differentiation such as, Col I, ALP, OPN, OCN and the transcription factor Runx2. Galangin could also attenuate OS growth in vivo, in the xenograft mouse model [237]. There are several cytokines that control bone formation, among which TGF-β1 has been proven to be fundamental in osteoblastic differentiation and bone matrix synthesis, through Smads-dependent signaling [238]. TGF-β1 secretion and the phosphorylation of Smad2 and Smad3 were triggered in a dose-dependent manner after galangin treatment, clearly indicating that galangin-mediated cell differentiation was dependent on its selective activation of the TGF-β1/Smad2/3 signaling pathway [237].

6.5. Catechins

Catechins, which are considered as readily applicable and safe phytochemicals [254], are the major bioactive constituent in green tea polyphenols. Their basic structure consists of a flavan-3-ol unit with a catechol (1,2-dihydroxybenzene) moiety. There are different types of green tea catechins (GTC), including epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), and epigallocatechin gallate (EGCG), among others. These variations occur due to the number and position of hydroxyl groups attached to the flavan-3-ol structure. The arrangement of hydroxyl groups determines the distinct properties and potential health benefits of each catechin [255]. EGCG is the most abundant and biologically active catechin [256]. Its chemical structure is reported in Figure 4. Based on decades of research, EGCG has received considerable attention due to its inhibitory activities against carcinogenesis at all stages, i.e. initiation, promotion and progression [257,258]. Other catechins, such as ECG and EGC, have been shown to have similar, albeit lower, activities in numerous studies [259,260]. However, in humans, plasma bioavailability of GTCs is very low, which has been in part attributed to their oxidation, metabolism and efflux [261]. The low bioavailability and absorption of GTCs are considered to be the major reason behind the differing effects between in vitro and in vivo studies. In fact, extensive studies on the improvement of GTC bioavailability should help in this regard [261].

The bone strength mainly relies on selenium (Se), calcium, and vitamin (K and D) contents. Se deficiency is associated with the risk of developing multiple cancers including OS [262]. To minimize the risk associated with Se deficiency, its doping with hydroxyapatite (HAp) can be an effective approach which may potentially reduce the growth of OS cells. Currently, HAp has received considerable attention in reconstructive surgeries, orthodontic, and three-dimensional printing of scaffolds, owing to its high bioactive and osteoconductive properties [263,264]. Owing to the known antitumor properties of catechins, a recent study by Khan et al. aimed to develop catechin-modified Se-doped HAp nanocomposites (CC/Se-HAp) for potential application in OS therapy [265]. Cell toxicity analysis showed that CC/Se-HAp were rapidly internalized into the MNNG/HOS cells and improved anticancer activity compared to Se-doped HAp nanocomposite, by inducing ROS-mediated apoptosis through the activation of caspase-3 pathway [265]. This suggests that CC/Se-HAp nanoparticles possess the potential for the targeted treatment of OS. Further studies on the anti-OS properties of catechins have mainly focused on EGCG (Table 2). This green tea polyphenol can effectively inhibit the tumor characteristics of OS cells (i.e., 143B, MG-63, U2OS and SaOS-2), including proliferation, migration, and apoptosis [266,267,268]. Moreover, it protects local bone tissue from destruction and prevents lung metastasis of tumor cells [267,268]. These effects may occur by regulating the activity of the Wnt/β-catenin pathway, as demonstrated by cell and animal experiments [268]. Additional EGCG targets have been identified. In MG-63 and U2OS, the inhibitory activity of EGCG treatment has been partially associated with the upregulation of miR-1, one of the miRNAs critically involved in the pathogenesis and progression of human OS [267]. Moreover, combined administration of EGCG and IL-1 receptor antagonist (IL-1Ra) efficiently downregulated IL-1-induced IL-6 and IL-8 release from U2OS cells. This treatment approach also reduced the secretion of invasiveness-promoting MMP-2 and pro-angiogenic VEGF, without affecting the metabolic response and caspase-3 activity [266]. EGCG has also been shown to act as a chemosensitizer for DOX in OS models. The synergistic interaction between EGCG and DOX has been shown to be mediated by SOX2 overlapping transcript (SOX2OT), which contributes to suppress OS via autophagy and stemness inhibition ([269], p. 7).

Table 2. Effects of flavonoids on osteosarcoma. Downward arrows represent downregulation or reduction. Upward arrows represent upregulation or increase.

Table 2. Effects of flavonoids on osteosarcoma. Downward arrows represent downregulation or reduction. Upward arrows represent upregulation or increase.

Phytoestrogen	Cell Line/ in vivo model	Concentrations	Combined treatment	Molecular Mechanism	Observed Effects	References
Genistein	U2OS	1µM		ER-mediated down-regulation of EGFR	↑ differentiation ↑ apoptosis ↑ cell cycle arrest	[156]
	MG-63	2.5 – 30 μmol/L		↑ matrix vesicles, ↑ ALP activity	↑differentiation ↑mineralized bone noduli ↓ proliferation	[160]
	MG-63, SaOS-2	10 – 30 µM		↓ PTK, ↑ ER	↓ synthesis and secretion of GAGs/PGs	[164]
	MG-63	40 – 80 µM		↑ PPARγ pathway	↑cell cycle arrest ↓ proliferation	[166]
	SaOS-2, MG-63	1 – 100 µM	calcitriol 10 nM for 48 h	↑ SGPL1, VDR, ERβ	↑ calcitriol sensitivity ↓ proliferation ↓ extracellular acidification ↓ mitochondrial respiration	[167]
	MG-63, U2OS	10 - 100 μmol/L	gemcitabine 0.5 µmol/l for 72 h	↓ Akt/NF-κB pathway	↑ gemcitabine sensitivity ↑ apoptosis	[270]
Daidzein	U2OS	1 µM		ER-mediated down-regulation of EGFR	↑ differentiation ↑ apoptosis ↑cell cycle arrest	[156]
	143B, U2OS xenograft mouse model	10 - 500 μmol/L 20 mg/kg every 2 days		↓ Src-ERK pathway	↑ apoptosis ↑ cell cycle arrest ↓ migration ↓ tumour weights	[179]
Biochanin A	MG-63, U2OS	5 - 30 μg/mL	DOX 1μg/mL for 24 h	↑ caspase-3/9, ↑ Bax: Bcl-2/Bcl-XL ratio	↑ DOX sensitivity ↓ proliferation ↑ apoptosis	[185]
	MG-63, U2OS	5 - 80 μM		↓ PCNA, cyclin D1, Bcl-2, ↑ Bax, caspase-3; ↓ MMP-9, N-cadherin, ↑ E-cadherin	↑ cell cycle arrest ↑ apoptosis ↓ migration, invation	[186]
Formononetin	U2OS, tumor-bearing nude mice	20 - 80 μM, 80 mg/kg/d		↓ Bcl-2, miR-375, ↑ Bax	↑ apoptosis ↓ tumour weights	[193]
	U2OS	5 - 100 μM		↑ caspase-3 and Bax, ↓ Bcl-2 ↓ ERK and PI3K/AKT pathway	↑ apoptosis	[192]
	MG-63	15 - 45 μM		↑ miR-214-3p/PTEN pathway	↓ proliferation ↑ apoptosis	[194]
	tumor-bearing nude mice	25-100mg/kg/d		↓ ESR1, p53, ERBB2	↓ tumour weights	[196]
Quercetin	MG-63	20 - 320 μM		↑ cytochrome C, caspase-3/9, Bax, ↓ Bcl-2	↑ apoptosis	[209]
	HOS, ATCC 1543	10 - 1000 µM		↓ cyclin D1, ↑ caspase-3, cleaved PARP	↑ cell cycle arrest ↓ proliferation ↑ apoptosis	[212]
	U2OS/MTX300	10 - 50 µM		↑ cytochrome C, caspase-3, Bax, cleaved PARP; ↓Bcl-2, Akt	↑ apoptosis ↓ proliferation	[214]
	143B	10 - 100 µM		↑ caspase-3, cleaved PARP	↑ cell cycle arrest ↑ apoptosis ↓ adhesion ↓ migration	[207]
	MG-63	50 - 200 µM		↑ LC3B-II/LC3B-I ratio, ↓ ROS - NUPR1 pathway	↑ autophagy	[218]
	HOS, MG-63, tumor-bearing nude mice	20 - 100 µM 25-100 mg/kg/d		↓ HIF-1α, VEGF, MMP-2/9	↓ migration, invasion ↓ tumor growth	[210]
	U2OS, SaOS-2			↓PTHR1	↓ proliferation ↓ adhesion ↓ migration, invasion	[211]
	143B	5 μM	CDDP 5 μM for 24 h	↑ miR-217- KRAS axis	↑ CDDP sensitivity ↓ proliferation ↓ migration, invasion	[208]
	SaOS-2	10 - 200 μM	MTX 10-200 μM for 48 h	↑ p53, CBX7, CYLD, ↓ Bcl-2, miR-223	↑ MTX sensitivity ↓ proliferation ↑ apoptosis	[229]
Galangin	MG-63, U2OS	5 - 300 µM		↓ PI3K/Akt pathway ↓ cyclin D1, MMP-2/9, ↑ p27Kip1, caspase-3/8	↓ proliferation ↑ apoptosis ↓ invasion	[236]
	MG-63, U2OS tumor xenograft mouse	25 - 100 μM 50, 100 mg/kg/d		↑ TGF-β1/Smad2/3 pathway ↑Col I, ALP, OPN, OCN	↑ differentiation ↓ tumor growth	[237]
Apigenin	U2OS tumor xenograft mouse	50 - 200 μM 2 mg/kg every 3 days		↑ caspase-3/8/9, BAX, AIF	↑ apoptosis ↓ tumor growth	[243]
	U2OS, MG-63	20 - 100 μg/ml		↓ Wnt/β-catenin pathway	↓ proliferation ↓ invasion	[244]
Naringenin	HOS, U2OS	100 - 500 μM		↑ ROS-Mediated ER Stress	↑ autophagy ↑ apoptosis	[253]
EGCG	MG-63, 143B, SaOS-2 tumor-bearing nude mice	10 - 50 μM 10 - 40 mg/kg every 2 days		↓ Wnt/β-catenin pathway	↓ proliferation ↓ migration, invasion ↓ tumor growth	[268]
	MG-63, U2OS tumor-bearing nude mice	0.0125 - 0.1 g/L 30 mg/kg/d		↑ miR-1	↓ proliferation ↓ tumor growth	[267]
	U2OS	5 - 50 μM	IL-1Ra1 ng/ml	↓ MMP-2, VEGF ↓ IL-6/8	↓ proliferation ↓ invasion	[266]
	U2OS, SaOS-2	20 μg/ml	DOX 1 - 2.5 μM	↓ SOX2OT	↑ autophagy	[269], p. 7

7. Anti-Osteosarcoma Effects of Non-Flavonoids

7.1. Stilbenes

7.1.1. Resveratrol

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a powerful nutritional polyphenol found in more than 70 plant species and is especially abundant in food products such as red grapes (up to 14 mg/L) and derived products, peanuts, mulberries and soy [35,271]. Resveratrol is a phytoalexin. These chemicals are characterized by their low molecular weight and their ability to inhibit the progress of infections and other adverse stressful conditions for the plants [272]. Resveratrol is characterized by a stilbene structure which consists of two phenolic rings bonded together by a double styrene bond, which is responsible for the isometric cis- and trans-forms of resveratrol (Figure 5). The trans-isomer appears to be the more predominant and stable natural form [273]. There are many synthetic and natural analogues of resveratrol, as well as adducts, derivatives, and conjugates, including glucosides [274]. In red and white grape juice, resveratrol exists mostly as polydatin, its glycosidic form (see next section). Red grape juices contain significant amounts of trans-polydatin, followed by cis-polydatin and trans-resveratrol. These compounds are considered to be the primary compounds responsible for the health benefits associated with wine consumption [271].

Figure 5. Downregulation of various pathways involved in the anti-OS activity of the stilbenes, resveratrol and its glycosidic form polydatin.

Figure 5. Downregulation of various pathways involved in the anti-OS activity of the stilbenes, resveratrol and its glycosidic form polydatin.

Resveratrol is commonly used as a nutraceutical in the management of high cholesterol, cancer, heart disease, as well as many other pathological conditions [275,276,277]. Its chemopreventive and anticancer effects, have been documented by in vivo and clinical studies in a wide variety of tumor cell types, highlighting its role in diverse cellular events associated with all stages of carcinogenesis, i.e., tumor initiation, promotion, and progression [8,278,279,280,281]. Unlike other phytoestrogens which bind ERβ with higher affinity, resveratrol binds ERα and ERβ with comparable affinity, but with 7,000-fold lower affinity than estradiol, acting as mixed agonist/antagonist [53]. Many lines of compelling data indicate that the effects of resveratrol on the survival of estrogen-related cancer cells might rely on ER-dependent mechanisms [282,283].

Regarding the bone microenvironment, resveratrol has been shown to have multiple bioactivities including antioxidative, anti-inflammatory, estrogen-like and proliferative properties that can influence bone metabolism [107,284]. In particular, in normal osteoblasts and osteoclasts, it regulates cell proliferation, cellular senescence and apoptosis, and inflammation processes, reducing the activity of NF-B and MAPK, and also acts through an epigenetic control, modulating the expression and activity of sirtuin-1 (SIRT-1), which is capable of increasing osteoblast survival and differentiation [285].

A body of studies on the effect of resveratrol on OS demonstrated a strong suppression of the cell viability, self-renewal ability and tumorigenesis of OS cells, whereas no significant inhibition effect on normal osteoblasts was observed [286,287,288,289,290,291]. However, the underlying mechanisms of action of resveratrol on OS cells have only been partially defined (Table 3). The Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway is involved in different biological processes such as immunity, cell division, cell death, and tumor formation [292]. Aberrantly activated JAK2/STAT3 is frequently detected in many cancer diseases that are usually refractory to standard chemotherapy [292]. Studies have demonstrated a critical role of STAT3 signaling in the persistence of cancer stem cells (CSCs) [293], which is a primary cause of tumor relapse and metastasis [294]. Peng et al. [289], investigated the underlying molecular mechanism of resveratrol activity against OS CSCs, reporting that resveratrol treatment inhibited tumorigenesis ability by decreasing the synthesis of cytokines such as IL-6, IFN-γ, TNF-α and Oncostatin M, and preventing JAK2/STAT3 signaling pathway, which was consistent with the decline of the CSC marker CD133. On the other hand, exogenous STAT3 activation had the opposite effect and could abrogate the effect of resveratrol on CSCs, suggesting that resveratrol may be a promising therapeutic agent for OS management [289].

Additional studies have reported a correlation between resveratrol activity and the canonical Wnt/β-catenin cascade [288,295]. Aberrant activation of the Wnt-β-catenin signaling pathway plays a critical role in OS pathogenesis, which makes the Wnt/β-catenin pathway a hot topic in OS research [103,104,245]. Nevertheless, the development of therapeutic agents specifically targeting the aberrant Wnt activation in OS cells is still in its infancy. Exploring the effects of the resveratrol treatment against U2OS cells, Xie and coworkers found that the antitumor effects of resveratrol occurred through suppressing the activity of the Wnt/β-catenin pathway and the expression of related genes such as, c-myc, cyclin D1, MMP-2 and MMP-9 [295].

Moreover, resveratrol was able to up-regulate the expression level of Connexin 43 (Cx43) and E-cadherin [295], two important mediators of cell-cell adhesion which are critical in tumor progression [188,296]. The association between the anti-OS effect of resveratrol and the Wnt signaling was further demonstrated by Zou et al. [288].

Using β-catenin as a drug target, they performed a high content screening of botanical extracts to identify potential drugs against the human MG-63 OS cell line. β-catenin is a pivotal member of the canonical Wnt signaling pathway with the dual functions of regulating the coordination of cell-cell adhesion and gene transcription [297]. Aberrant expression of β-catenin activates numerous downstream target genes of the Wnt signaling pathway, a number of which are associated with cancer progression [298,299]. In a total of 14 botanical extracts assessed, resveratrol markedly downregulated the expression of β-catenin and significantly inhibited MG-63 cell proliferation [288].

OS is characterized by a high metastatic potential which is associated with a high death rate [83,100]. Proteinase enzymes, such as cathepsins, MMPs, and PA, are involved in many steps of tumor metastasis, including tumor invasion, migration, host immune escape, angiogenesis, and tumor growth [300]. MMPs, especially MMP-2 and MMP-9, are usually over-expressed in a wide range of human cancer types, including OS, providing a potential therapeutic target [102]. Based on in vitro, in vivo, and clinical evidence, Yang and coauthors showed that resveratrol can suppress the metastatic potential of human OS cells (i.e., HOS, MG-63, U2OS, Saos-2, and 143B) through transcriptional and epigenetic regulation of MMP-2, by respectively inhibiting cAMP CREB-DNA-binding activity and upregulating miR-328, which was initiated by the inhibition of the p38 MAPK/JNK pathways. Consistently, suppression of miR-328 significantly relieved MMP-2 and motility inhibition imposed by resveratrol treatment [301]. The proliferation, invasion and metastasis of tumor cells, as well as tumor relapse, are strongly correlated with the interactions of several factors, in which angiogenesis is a prerequisite. During this process, VEGF functions as the most significant vascular endothelial stimulating factor [302,303]. According to Liu et al. [304], resveratrol exerts a time and dose-dependent inhibition of OS cell invasion capabilities and proliferation, which is mediated by the downregulation of VEGF expression [304].

Recently, De Luca and colleagues [291] made a series of important observations on different human OS cell lines (i.e. MG-63, SaOS-2, KHOS, U2OS). They found that resveratrol was involved in the pAKT and caspase-3 pathway, causing cell growth inhibition and increase in apoptosis. Moreover, a significant increase in osteoblastic differentiation genes, such as osterix (Osx), OPN, ALP, Col I alpha 1, and OCN, was observed, suggesting that resveratrol may act as an inducer of differentiation, which is known to make OS cells more vulnerable to the action of chemotherapeutic agents [305]. Furthermore, they highlighted an epigenetic action of resveratrol on the promoters of interleukins IL-6 and IL-8, whose role in tumor progression is a well-described process in several cancer models [306,307]. The epigenetic change induced the reduction of the secretion of interleukins IL-6 and IL-8, which further explained the inhibitory effects of resveratrol on OS cellular growth and motility. In line with data previously reported [286], the OS cell lines examined, which represent the various typical characteristics of OS, responded in a variable manner to resveratrol treatment. This explained why by calculating the IC50 of resveratrol, different values were obtained, i.e. around 120 µM for MG-63 and SaOS-2 and around 60 µM for KHOS and U2OS treatment [291].

Strong evidence from breast, gastric, and prostate cancer cells subjected to combined treatment with resveratrol–DOX or resveratrol–CDDP has shown a synergistic behavior of resveratrol towards chemotherapeutic agents [308,309,310]. According to De Luca et al., the cotreatment of resveratrol with DOX and CDDP increased their cytotoxic effect on OS cells, suggesting that resveratrol might be a promising therapeutic adjuvant agent for OS cell treatment [291].

7.1.2. Polydatin

Polydatin (3, 4′, 5-trihydroxystibene-3-β-mono-D-glucoside), also known as piceid, is a naturally occurring glucoside derivative of resveratrol, in which the glucoside group linked to position C-3 replaces the hydroxyl group [311,312] (Figure 5).

Polydatin was first extracted from the roots of Polygonum cuspidatum (Polygonaceae), which have a long history of use in traditional Chinese and Japanese medicines, but it also exists in a variety of other sources including dietary plants such as grape, peanut, berries and chocolate [312]. The trans form of polydatin is well known for its high therapeutic potential in a variety of medical domains, for example infection, inflammation, cardiovascular disorders and aging-related diseases such as osteoporosis [313,314,315,316]. The Chinese FDA has approved polydatin for multiple phase II clinical trials, mainly for anti-shock applications [317].

Glucose substitution gives polydatin a more hydrophilic character than resveratrol, resulting in a significantly increased bioavailability and higher health-promoting/disease-modifying activities [318,319]. Furthermore, comparative studies of polydatin and resveratrol regarding antioxidative effects in vivo have revealed a better antioxidant activity of polydatin than resveratrol [311,320]. Polydatin has been recognized as a potent anticancer agent, with the ability to regulate various signaling pathways involved in the progression of several kinds of cancers [321,322]. It is mainly involved in cell cycle regulation, apoptosis, autophagy, signaling pathways, EMT, inhibition of inflammation and metastasis, and regulation of enzymes related to oxidative stress [323,324].

Moreover, recent studies by Mele et al. demonstrated that polydatin exerts a significant cytotoxic effect on cancer cells by Glucose-6-phosphate dehydrogenase inhibition, a rate-limiting enzyme in the pentose phosphate pathway which is altered in different malignant tumors [325]. A beneficial role of polydatin was also documented in prevention and treatment of OS. In an early study, Xu et al. evaluated the anti-OS activity of polydatin in human OS cell lines (i.e., 143B and MG-63). Polydatin dose-dependently inhibited proliferation by suppressing the β-catenin signaling and promoted apoptosis via upregulated expressions of Bax/Bcl-2 and caspase-3 in OS cells [326].

Polydatin also induced apoptosis via different mechanisms such as reducing the expression/phosphorylation of STAT3 and increasing the expression of autophagy-related genes (Atg12, Atg14, BECN1, PIC3K3), thereby triggering autophagic cell death in MG-63 cells [327]. Further studies reported the efficacy of polydatin in drug-resistant models of OS [328,329]. The therapeutic effect of polydatin against DOX-resistant OS, in vitro and in a MG-63/DOX xenograft model, occurs via the oncogene Taurine upregulated gene 1 (TUG1) mediated suppression of Akt signaling, which promotes apoptosis and prevents cell proliferation [329]. Additionally, polydatin enhances the chemosensitivity to the antineoplastic agent paclitaxel of U2OS and MG-63 cells and their paclitaxel-resistant variants, suppressing cell growth and migration and inducing cell-cycle arrest in the S phase [328]. Interestingly, a recent work investigated the role accomplished by polydatin, alone or after radiation therapy, in the osteogenic differentiation of SaOS-2 and MG-63 [330].

As mentioned above, the osteogenic differentiation has a role in the pathogenesis of OS considering that OS tumors deregulate the signaling pathways associated with osteogenic differentiation by arresting the cells as undifferentiated precursors [112].

In combination with radiotherapy, the pretreatment with polydatin promoted a radiosensitizing effect on OS cancer cells as demonstrated by the increased mineralization and osteogenic markers levels. The differentiation process was paralleled by the activation of the Wnt-β-catenin pathway and cell cycle arrest in S-phase. Additionally, the secretion of sphingolipid, ceramides, and their metabolites were analyzed by mass spectrometry in OS treated cells. In past years, evidence has accumulated demonstrating that 2′-hydroxy ceramide/sphingolipids have distinct biological functions to regulate various cellular processes and cell differentiation by binding to specific target proteins [331].

Moreover, Sphingosine-1-phosphate has been reported to inhibit osteoclast formation and mineralization [332]. MS analysis demonstrated that polydatin-induced osteogenic differentiation was mediated by an increased expression and secretion of ceramides and sphingolipids and pretreatment with polydatin sensitized OS cells to ionizing radiation, suggesting that polydatin, in combination with radiotherapy, can consolidate the response to therapy of OS cells [330].

Various novel drug delivery systems, including nanoparticles [333], liposomes [334], micelles [335], quantum dots [336] and polymeric nanocapsules [337] have been designed to enhance polydatin pharmacodynamics and pharmacokinetics [338]. Polycaprolactone (PCL) is a biodegradable hydrophobic polyester used to obtain clinically applicable implantable nanostructures [339]. In their study, Lama and coworkers demonstrated that PCL nanofibers complexed to polydatin supported the adhesion and promoted the osteogenic differentiation in both SaOS-2 cells and bone MSCs, providing evidence of the osteogenic capacity of polydatin to create a biomimetic, innovative and patented scaffold for both anticancer and regenerative purposes [340].

7.2. Lignans

In contrast to other types of phytoestrogens, lignan-type phytoestrogens have rarely been studied, although they are widely distributed in the plant kingdom. Cereals, grains, berries, and garlic are good dietary sources of lignans [32]. The plant lignans may occur in the form of aglycones and glycosides. After consummation, they can be converted by gut bacteria to form enterolignans (enterodiol and enterolactone), also known as “mammalian lignans”, which have a variety of biologic activities, including tissue-specific ER activation, and anti-inflammatory and apoptotic effects, that may influence disease risk in humans [341].

The effects of enterodiol and enterolactone on the viability and differentiation of MG-63 cells have been examined. Data suggested that both enterolactone and enterodiol have biphasic effects on cell proliferation, ALP activity and transcriptional levels of osteonectin (ON) and Col I, showing induction at low doses and inhibition at high doses.

The dose-dependent effects have been linked to the estrogenic and antiestrogenic properties of estrogen-like molecules as well as their ability to induce multiple signaling transduction [342].

Table 3. Effects of non-flavonoids on osteosarcoma. Downward arrows represent downregulation or reduction. Upward arrows represent upregulation or increase.

Table 3. Effects of non-flavonoids on osteosarcoma. Downward arrows represent downregulation or reduction. Upward arrows represent upregulation or increase.

Phytoestrogen	Cell Line/ in vivo model	Concentrations	Combined treatment	Molecular Mechanism	Observed Effects	References
Resveratrol	MNNG/HOS, MG-63 tumor xenograft mouse	10 - 40 μM 100 mg/kg/d		↑caspase-3, Bax, cleaved PARP, ↓ Bcl-2, Bcl-xL; ↓ cytokines ↓ JAK2/STAT3 pathway	↑ apoptosis ↓ CSCs survival ↓ tumor growth	[289]
	U2OS	6 - 24 μg/ml		↓ Wnt/β-catenin pathway ↓ β-catenin, c-myc, cyclin D1, ↓MMP-2/9 ↑ Cx43, E-cadherin	↓ proliferation ↑ apoptosis ↓ migration, invasion	[295]
	MG-63	10 - 40 µg/ml		↓ β-catenin signaling	↓ proliferation	[288]
	HOS, MG-63, U2OS, SaOS-2, 143B HOS orthotopic graft model	25 - 200 μM 40, 100-mg/kg/d		↓ p38 MAPK/JNK pathways ↓ CREB, ↓ MMP-2, ↑ miR-328	↓ migration, invasion, adhesion ↓ tumor growth, metastasis	[301]
	U2OS	10 - 40 μM		↓ VEGF		[304]
	MG-63, SaOS-2, KHOS, U2OS	50 -100 µM	DOX 0.1-10 µM or CDDP 0.2-2 µg/mL for 24 h	↓ pAKT, ↑ caspase-3 ↓ IL-6/8 ↑ Osx, OPN, ALP, Col I, OCN	↓ proliferation ↑ apoptosis ↑ differentiation ↑ DOX/CDDP sensitivity	[291]
Polydatin	143B, MG-63	1 - 100 µM		↓ β-catenin signaling ↑ Bax/Bcl-2, caspase-3	↓ proliferation ↑ apoptosis	[326]
	MG-63	10 -160 µM		↓ STAT3 signaling	↑ apoptosis, ↑ autophagy	[327,328]
Polydatin	SaOS-2/ DOX, MG-63/DO xMG-63/ DOX xenograft model	50 - 250 μM 150 mg/kg/d		↓ TUG1/Akt signaling	↓ proliferation ↑ apoptosis ↓ tumor growth	[329]
	U2OS, MG-63		paclitaxel		↓ proliferation ↓ migration ↑cell-cycle arrest	[328]
	SaOS-2	1 - 150 μM	ionizing radiation	↓ Wnt/β-catenin pathway ↑ lipid metabolite secretion	↑ differentiation ↑cell-cycle arrest ↑radiation sensitivity	[330]
Enterodiol, Enterolactone	MG-63	0.1–10 mg/ml		↑ALP activity ↑ ON, Col I	↓ proliferation ↑ differentiation	[342]

8. Conclusions and Perspectives

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