Polyphenols constitute a major class of phytochemicals showing favorable effects on various pathologic conditions. They are plant-derived metabolites mainly originating from the acetate–malonate and shikimate biosynthetic pathways and they mostly exist as glycosides or are conjugated with other moieties (e.g., amines, carboxylic acids, lipids, and other phenols) ^[1][2][1,2]. Natural polyphenols include flavonoids and nonflavonoid compounds (e.g., phenolic acids and their esters, stilbenoids, and curcuminoids) [3].

Several studies have highlighted the relationships between dietary polyphenols and lower incidences of cancer, chronic heart diseases, and neurodegenerative syndromes ^[4][5][6][7][4,5,6,7]. The Mediterranean diet is associated with a reduced risk of cardiovascular disease, thanks to an adequate intake of olive oil, red wine, and anthocyanin-containing fruits and vegetables ^[8][9][8,9]. Other beneficial health effects, such as anti-inflammatory, antioxidant, antiallergic, antithrombotic, and antiviral activities, are related to dietary polyphenol intake ^[10][11][12][10,11,12]. Increasing lines of evidence have shown a relationship between some of the aforementioned diseases and oxidative stress resulting from the generation of reactive oxygen (ROS) and nitrogen species (RNS) [13], but no natural antioxidant has been approved so far for any therapeutic indication, except for the nutrient content claims for dietary supplements and conventional foods.

2. Protective Effects of Polyphenols against Adverse Effects of Antitumor Therapies

2.1. Polyphenolic Adjuvants in Anticancer Therapeutic Interventions

In a study conducted on MCF-7 cells (human breast cancer), ellagic acid was proven to (i) increase cell death, (ii) reduce cells’ capacity to form colonies, and (iii) accumulate cells in the sub-G1 (apoptotic) phase after gamma radiation treatment ^[14][50]. The effects were significantly higher for the combined treatment compared to the ellagic acid or irradiation treatment alone, thereby demonstrating the ability of ellagic acid to radio-sensitize MCF-7 cells. Interestingly, ellagic acid showed radio-protective effects on normal murine cell line in vitro. Fractions from wine extracts, mainly containing procyanidins, catechins, and flavonols, have shown an antiproliferative effect on PC3 cells (prostate cancer) in a dose-dependent manner ^[15][51]. These fractions induced autophagy on the same cell line, thus corroborating the potential to prevent the disease. In a recent in vitro study ^[16][52], ovarian cell lines were treated with oleuropein (a phenolic compound present in the fruits and leaves of olive trees). In particular, the authors showed that after using oleuropein to treat A2780 and A2780 cisplatin resistance cell lines, the expression of p21 and p53 increased, while the expression of Bcl-2 decreased. As a result, oleuropein was able to induce apoptosis, reduce cell proliferation, and reduce resistance to cisplatin in ovarian cell lines. Hydroxytyrosol, the product of oleuropein hydrolysis, is an effective anti-inflammatory and antioxidant polyphenol. It is able to reduce the nephrotoxicity from cisplatin by inhibiting chemokine-like factor 1 (CKLF1) involved in inflammation pathways and to induce anti-oxidative stress and anti-apoptosis activities in the kidneys of mice ^[17][53]. Honey contains a mixture of different active compounds (Figure 1), including coumaric acids (7–9), caffeic acid (10), ferulic acid (11), eugenol (12), and flavonoids, such as quercetin, apigenin, chrysin (13), pinocembrin (14), pinobanksin (15), and naringin (16) in different percentages depending on the floral source and geographical origins. An increasing amount of evidence has attributed a potential chemopreventive activity to honey ^[18][54]. In fact, multi-floral honey prevented the formation of breast cancer induced by 7,12-dimethylbenz(a)anthracene (DMBA) in a rat model ^[19][55]. Moreover, an increased level of bone marrow lymphocytes and peritoneal macrophages in mice suggested the activation of the immune system ^[20][56]. Oral mucositis (OM), which is one of the most common side effects of chemotherapy, could be reduced by honey, thanks to its capacity to increase the immune system response ^[21][57]. This effect was confirmed by a double-blind randomized clinical trial in which the patients affected by OM after chemotherapy were treated with betamethasone, honey, and a combination of honey and coffee ^[22][58]. Patients with head and neck cancer treated with radiotherapy showed a reduction in oral side effects (xerostomia) after consuming thyme honey ^[23][59], and manuka honey and talk honey induced a reduction in liver and kidney toxicity via cisplatin in rats ^[24][60]. This organ-protective effect could be due to honey’s free-radical scavenging as well as anti-inflammatory and anti-apoptotic activities. These data suggest the protective effect of honey and its promising application. To induce the same protective effect on oral mucosa, a clinical trial (NCT05994638, 2023) ^[25][61] is starting to recruit patients receiving a polyphenol-rich aerosol for minimizing side effects in patients after radiation therapy. A group of 10 patients with head and neck cancer who have undergone radiotherapy will orally receive an aerosol constituted of polyphenol-rich plant extracts, hyaluronic acid, Cetraria islandica, and vitamin B3 for one month. Another clinical trial (NCT06017661, 2023) ^[26][62] is using a standard commercial product, ‘nutridrink’, enriched with a preparation of plant extracts rich in polyphenolic compounds as support for recovering patients undergoing gastrointestinal tumor resection. In a recent patent (CN111447940; 2020) ^[27][63], quercetin and its analogues were used to provide novel compositions and methods for the treatment of radiation-induced bystander effects (RIBEs) resulting from radiation exposure. Moreover, in a recruiting clinical study (NCT05984888, 2023) ^[28][64], some patients affected by breast cancer were treated with the MIND (Mediterranean Intervention for Neurodegenerative Delay), with the aim of protecting the brain from the toxic side effects of chemotherapy. The MIND is a diet with anti-inflammatory nutrients (e.g., omega-3 polyunsaturated fatty acids (PUFAs), carotenoids, B-vitamins, and polyphenols) which may help alleviate negative cognitive outcomes from cancer treatments. Another clinical trial (NCT02195960, 2023) ^[29][65] seeks to evaluate the effects of polyphenol-rich food supplementation against the toxic side effects of breast cancer radiotherapy.

2.2. Activity against ROS-Mediated Effects of Chemotherapeutics

Anthracyclines are anticancer antibiotics characterized by an anthraquinone moiety branched with an amino sugar at C-7. Doxorubicin (17) and daunorubicin (18) (Figure 2), isolated from the bacteria Streptomyces peucetius, were the earliest drugs of this family that entered clinical practice for cancer treatment ^[30][66]. Daunorubicin is effective in acute lymphocytic and myeloid leukemia, while doxorubicin is a component of polypharmacological protocols for treating solid tumors (e.g., breast cancer, soft tissue sarcomas, and aggressive lymphomas). Even though it is a common chemotherapeutic, the clinical use of doxorubicin is limited by its dose-dependent cardiac toxicity, which may lead to severe and irreversible forms of cardiomyopathy ^[31][32][67,68]. Indeed, anthracyclines can induce the early onset of progressive chronic cardiotoxicity, usually within one year of treatment ^[33][69]. Cardiomyopathy may persist or advance even after the discontinuation of therapy ^[34][70]. The mechanistic explanation for iatrogenic cardiotoxicity lies in the overproduction of ROS. Doxorubicin quinone can be reversibly reduced to semiquinone, an unstable metabolite whose futile redox cycle within mitochondria leads to ROS overload, especially the superoxide radical anion O₂∙⁻. As shown in Figure 5, the reduction in doxorubicin quinone (C ring) to semiquinone is catalyzed by NADH-dependent enzymes. The semiquinone in turn donates a single electron to O₂, thereby generating O₂∙⁻ and recycling itself to quinone. Superoxide dismutase 2 (SOD2) catalyzes the transformation of O₂∙⁻ in H₂O₂, which can be detoxified by catalase or glutathione (GSH) peroxidase in the presence of GSH or converted into the highly reactive hydroxyl radical (HO) in the presence of endogenous Fe²⁺ through the Fenton reaction. The highly reactive HO^∙ can in turn generate lipid radicals and other ROS. In addition to ROS, the RNS peroxynitrite (ONOO⁻) is generated in cardiomyocytes following doxorubicin administration, most likely due to the reaction between the O₂∙⁻ generated from mitochondria and nitric oxide (NO) ^[35][71]. In addition, iron ions (Fe²⁺/Fe³⁺) have been shown to play a crucial role in this process. Fe³⁺ is able to react with hydrogen peroxide to yield reactive hydroperoxyl radicals (HOO) and to form chelates with the C11-C12 β-hydroxycarbonyl system of doxorubicin (Figure 2) ^[36][72]. Iron accumulates in cardiomyocytes during doxorubicin treatment, probably because of its capability to interfere with the main iron-transporting and iron-binding proteins ^[37][73]. In preclinical and clinical studies of anthracycline-induced cardiotoxicity, iron chelators, such as dexrazoxane, showed promise ^[38][74]. Other molecules, such as amifostine and mesna for example, have also been evaluated as cardioprotective auxiliary agents in preclinical studies ^[39][75].

2.2.1. Preclinical Findings

Ellagic acid (19, Figure 3) is a product of the hydrolysis of ellagitannins. Recent pharmacological studies have demonstrated that 19 acts as a free-radical scavenger, with several health benefits, such as anti-inflammatory, antihepatotoxic, antisteatosic, anticholestatic, antifibrogenic, antidiabetic, hypolipidemic, and antiatherosclerotic effects ^[40][41][76,77]. Moreover, ellagic acid has been proven to inhibit type-B monoamine oxidase (MAO-B) ^[42][78], thereby protecting rat brains from 6-hydroxydopamine-induced neuroinflammation in a model of Parkinson’s disease ^[43][79] and preventing scopolamine- and diazepam-induced cognitive impairments ^[44][80]. In male Wistar rats, orally administered 19 was proven to attenuate the doxorubicin-induced oxidative process in myocardial tissue ^[45][81]. Gallic acid, a potent free-radical scavenger ^[46][82], is a product of the hydrolysis of gallotannins. Doxorubicin-treated albino rats developed severe alopecia, and their fur became scruffy ^[47][83]. A 60% mortality rate was observed in the doxorubicin group, whereas in animals treated with gallic acid orally administered at doses of 15 mg/kg and 30 mg/kg, the mortality rate decreased to 30% and 15%, respectively. Gallic acid showed effectiveness in the functional recovery of the heart, with a significant reduction in cardiac injury, which may be related to its antioxidant properties ^[48][84]. Medicinal uses of turmeric (Curcuma longa L., Zingiberaceae) arise from its content of volatile oil and curcuminoids (Figure 3, 20–22) ^[49][85]. It has been reported that turmeric has anti-inflammatory, hepatoprotective, antiviral, and anticancer activities, and it might have neuroprotective effects ^[50][51][86,87]. Recently, the medicinal chemistry of curcumin has been reviewed in depth, and new research developments on curcuminoids have been widely discussed ^[52][88]. Extensive investigations over the past quarter century, including over a hundred clinical studies of curcuminoids against several diseases, have addressed the pharmacokinetics, safety, and efficacy of turmeric ^[53][89]. The administration of a single dose of doxorubicin to a group of male rats was compared with a group receiving doxorubicin and an alcoholic extract of C. longa L. via an oral gavage. Compared to the controls, the doxorubicin-treated animals showed a 50% increase in mortality. In rats co-treated with turmeric extracts, not only was the mortality rate significantly diminished, but the heart weight and heart/bodyweight ratio significantly increased. Turmeric was proven to protect animals against acute doxorubicin-induced cardiotoxicity, ameliorate cardiac enzymes, and modulate the pathways triggering cardiac apoptosis, decreased levels of GSH, and the overproduction of oxidant radicals ^[54][90].

2.2.2. Evaluation of Clinical Studies

The flavonoid 7-mono-O-(β-hydroxyethyl)rutoside (monoHER) (23, Figure 3), a semi-synthetic derivative of rutin (24) bearing rutinose (α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranose) as the disaccharide moiety, has been shown to protect mice against doxorubicin-induced cardiotoxicity without adverse effects at a very high dose (500 mg/kg) ^[55][91]. Based on these results, clinical trials were performed to evaluate its protective effects in cancer patients. MonoHER, administered intravenously at a 1500 mg/m² dose 60 min before doxorubicin was administered, was evaluated through an endomyocardial biopsy, but the benefits observed in these preclinical studies were not confirmed ^[56][92]. These conflicting results might be attributable to interspecies differences in ADME (absorption, distribution, metabolism, and excretion). However, the antitumor activity of doxorubicin appeared to greatly improve, even displaying a partial remission of metastatic soft-tissue sarcoma in some patients. These results are somehow in agreement with the potentiating anti-proliferative effects observed in vitro for a number of flavonoids ^[57][93]. Another noteworthy clinically investigated polyphenol is salidroside (i.e., tyrosol glucoside, 25) found in Rhodiola rosea and used in traditional Tibetan medicine. Salidroside (Figure 3), along with the less active rosavin 26 (a cinnamyl alcohol glycoside bearing α-l-arabinopyranosyl-α-d-glucopyranoside as the disaccharide moiety), was reported to play a role in reducing mitochondrial-generated ROS and apoptosis signaling ^[58][94]. Pretreatment with salidroside appears to significantly reduce in vitro both ROS and mitochondrial superoxide overproduction ^[59][95] as well as to arrest the cell cycle and apoptosis in human breast cancer cells ^[60][96]. Furthermore, 25 showed antioxidant-related cardiovascular protection ^[61][97]. These results led to clinical studies to assess its effectiveness in protecting against cardiac dysfunctions induced by epirubicin in sixty patients with histologically confirmed breast cancer. In this trial, all the patients had a scheduled cumulative epirubicin dose of 400 mg/m². Although the oral co-administration of 25 and epirubicin was well tolerated in all of the patients, no significant differences in the protection from epirubicin-induced cardiotoxic effects were found compared to the placebo groups, once again suggesting that most likely the poor bioavailability of the polyphenolic phytochemicals in humans is a major factor limiting its clinical application ^[62][98].

2.3. Bioavailability Issues

A main hurdle to the therapeutic application of polyphenols is their poor bioavailability. Despite their antioxidant, antiphlogistic, and anticancer pharmacological activities, which may synergistically cooperate in antitumor chemotherapy, polyphenols show poor bioavailability, which strongly limits their efficacy. Several factors, such as low solubility/permeability, photochemical isomerization, auto-oxidation, and hepatic/intestinal rapid metabolic processes, just to name the main ones, negatively affect their bioavailability and in fact represent major obstacles to their therapeutic use. Nanodelivery systems may have the potential to improve their therapeutic efficacy. While the reader may refer to recent, more exhaustive reviews on these topics ^[4][10][4,10], herein rwesearchers would like to draw attention to some promising applications in CNS diseases ^[63][46] or in cancer prevention and therapy ^[64][99]. For example, numerous studies have proven that curcumin (20) is chemically and metabolically unstable and thereby poorly bioavailable ^[52][88]. A spectroscopic analysis revealed that a major degradation product (27) is formed by the autoxidation of 20 ^[65][100], whereas three minor degradation products, namely vanillin (28), ferulic acid (29), and the ketone product 30, are generated via a solvolysis reaction in an aqueous alkaline buffer ^[66][101] (Figure 4). Pharmaceutical nanotechnologies may implement efficient delivery systems aimed at improving the bioavailability of polyphenols ^[67][102].