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Sbaffone, M.;  Ruggieri, M.;  Sebastiano, M.;  Mackay, A.R.;  Zelli, V.;  Farina, A.R.;  Cappabianca, L.A. Role of Nutraceuticals in Neuroblastoma. Encyclopedia. Available online: (accessed on 06 December 2023).
Sbaffone M,  Ruggieri M,  Sebastiano M,  Mackay AR,  Zelli V,  Farina AR, et al. Role of Nutraceuticals in Neuroblastoma. Encyclopedia. Available at: Accessed December 06, 2023.
Sbaffone, Maddalena, Marianna Ruggieri, Michela Sebastiano, Andrew Reay Mackay, Veronica Zelli, Antonietta Rosella Farina, Lucia Annamaria Cappabianca. "Role of Nutraceuticals in Neuroblastoma" Encyclopedia, (accessed December 06, 2023).
Sbaffone, M.,  Ruggieri, M.,  Sebastiano, M.,  Mackay, A.R.,  Zelli, V.,  Farina, A.R., & Cappabianca, L.A.(2022, November 21). Role of Nutraceuticals in Neuroblastoma. In Encyclopedia.
Sbaffone, Maddalena, et al. "Role of Nutraceuticals in Neuroblastoma." Encyclopedia. Web. 21 November, 2022.
Role of Nutraceuticals in Neuroblastoma

Neuroblastoma (NB) is a highly malignant embryonic extracranial solid tumor that arises from sympathoadrenal neuroblasts of neural crest origin. In addition to genetic factors, NB has been linked to maternal exposure to a variety of substances during pregnancy. Recent interest in the potential of nutrients to prevent cancer and reduce malignancy has resulted in the identification of several nutraceuticals including resveratrol, curcumin, and molecular components of garlic, which together with certain vitamins may help to prevent NB development. As NBs arise during fetal development and progress during early childhood, specific NB inhibiting nutraceuticals and vitamins could enhance the preventative influence of maternal nutrition and breast feeding on the development and early progression of NB.

nutraceuticals neuroblastoma therapy

1. Neuroblastoma

Neuroblastoma (NBs) arise from sympathoadrenal progenitor cells of neural crest origin that normally give rise to the sympathetic ganglia, sympathetic neurons, and adrenal chromaffin cells [1][2][3][4]. NB cells do not respond to differentiation signals and are blocked in a de-differentiated, stress-resistant proliferating state [5]. This state is facilitated by activated oncogenes including MYCN, which is amplified in approximately 20% of primary NBs and carries poor prognosis [6][7]; the hypoxia-regulated oncogenic alternative TrkAIII splice variant of the neurotrophin receptor tropomyosin-related kinase A (TrkA), which exhibits spontaneous intracellular activation and is expressed in advanced stage, relapsed, and metastatic NBs [8][9], aberrant neurotrophin receptor TrkB expression [10], and oncogenic ALK activation [11], to name a few.

2. Nutraceuticals and Their Role in Neuroblastoma

The term “nutraceutical” was coined in 1989 by Stephen De Felice, who defined a nutraceutical as a “food, or parts of a food, that provides medical or health benefits, including the prevention and/or treatment of a disease”. Nowadays, nutraceuticals are considered to be natural molecular dietary alternatives to pharmaceuticals that provide physiological benefits [12]. Several nutraceuticals have been shown to exhibit anticancer properties including the inhibition of tumor cell invasion and metastatic progression [13], without detrimentally affecting normal cells [14]. Due to their biological anti-cancer activities, interest is increasing in the potential use of nutraceutical supplements in association with conventional treatments for both cancer prevention and anti-cancer therapy. Nutraceuticals exhibiting inhibitory activity in NB models in vitro and in vivo are listed in Table 1.
The absorption of nutrients required for fetal growth, development, and health originate from maternal nutrition and arrive at the fetus via the placenta. Both mother and fetus, therefore, are in potential danger of experiencing micronutrition deficiency during the period of gestation due to fetal growth requirements. For this reason, maternal nutrient supplementation is frequently prescribed in order to offset these potentially adverse outcomes for both mother and child, should micronutrient levels fall below a critical level. These supplements contain all of the most important components for the healthy development of the fetus [41].

2.1. Curcumin

The natural polyphenol curcumin (diferuloylmethane) is the most important nutraceutical component extracted from the rhizome of native Indian plant turmeric (Curcuma longa) [42], commonly used for its characteristic color and flavor in curries and mustards [43][44]. Tumeric preparations contain carbohydrates, proteins, essential oils, fat, minerals, curcuminoids, and traces of vitamins [43]. The curcuminoids include curcumin, dimethoxycurumin, and bis-dimethoxycurcumin, of which curcumin is the most abundant [42]. Curcumin exists in tautomeric bis-keto and enolate forms, and at acid and neutral pH, is mainly in a hydrogen donating bis-keto form while at basic pH, it is mainly in enolic form [45]. The therapeutic potential of curcumin stems from reports of anticancer [46], anti-inflammatory [47][48], antioxidant [49], and antimicrobial activity [50]. Curcumin’s anti-cancer properties include the inhibition of tumor promotion, tumor-associated angiogenesis, and tumor growth [51]. However, curcumin exhibits poor bioavailability due to low absorption and rapid metabolism, and is rapidly eliminated from tissues and blood, regardless of the administration route [52]. Co-administration with adjuvants and nano-formulations have been developed to overcome these problems [53].
In NB models, curcumin inhibits MYCN-amplified NB cell proliferation and induces P53-dependent apoptosis [15]. Curcumin also promotes NB cell apoptosis by upregulating phosphatase and tensin homolog (PTEN) expression, decreasing phosphorylated Akt levels and increasing Foxo3a nuclear translocation, resulting in pro-apoptotic p27, Bim, and Fas-L expression [16]. In addition, curcumin reduces HSP60 expression in NB cells, which is involved in pathogenesis and progression and reduces HSP60 S-nitrosylation, increasing the folding capacity, and implicating HSP60 in curcumin anti-cancer activity [17]. Curcumin also inhibits NB cell migration [14], motility factor autotaxin (Atx) expression in MYCN-amplified and non-amplified NB cells [18], and matrix metalloproteinase-2 (MMP-2) expression and activates the MMP inhibitor TIMP-1 [19], which together characterize curcumin as a potent inhibitor of NB cell migration and invasion.

2.2. Resveratrol

The polyphenolic stilbene phytoalexin resveratrol (3,5,4′-trihydroxystilbene) is produced in damaged plants and is abundant in grapes, wine, peanuts, tea, and some berries [54][55]. Red grapes are a principal source of resveratrol, and resveratrol concentrations in red wine range from 1.5 to 3 mg L-1 [56]. Resveratrol exists in cis and trans forms, and trans-resveratrol is the more stable and abundant isoform [55]. The majority of studies have focused on the biological properties of trans-resveratrol [57]. The beneficial properties of dietary resveratrol include antioxidant, cardio-protective, and chemo-protective activity. In addition, resveratrol exhibits anti-inflammatory, antiviral, neuroprotective [58], and anti-cancer activity. Resveratrol exhibits tumorigenesis inhibitory activity in vitro and in vivo that is consistent with a cancer preventing function [59][60], and could be used in combination with standard chemotherapy because of its antioxidant and anti-inflammatory properties [60].
In NB models, resveratrol is cytotoxic to NB cells and induces NB cell apoptosis associated with caspase 3 activation. Resveratrol promotes cell cycle arrest in S phase, probably by downregulating p21 and upregulating cyclin E expression, and arrests NB growth and increases survival in a mouse NB model [20]. Resveratrol also promotes mitochondrial permeability, resulting in mitochondrial cytochrome c and Smac/DIABLO release, resulting in apoptosis through the intrinsic pathway [21]. Resveratrol also inhibits proliferation and induces apoptosis in NB B65 cells through a SIRT1 independent mechanism, consistent with p53 activation and the inhibition of oncogenic signal transduction [22]. The antioxidant activity of resveratrol prevents ROS production and suppresses intra-mitochondrial activation of the oncogenic alternative TrkAIII splice variant in NB cells under conditions of ER stress, reducing stress-resistance, cell survival, and protective glycolytic metabolic adaptation [23].
The combined activity of resveratrol and immune-cytokines has also been investigated in a mouse NB model. Treatment with immune-cytokines alone arrested NB progression, which progressed after the cessation of treatment. Treatment with resveratrol alone resulted in primary tumor regression, but relapse with metastatic progression following the cessation of treatment. In contrast, treatment with resveratrol and immuno-cytokines resulted in primary tumor regression, long-term survival in 61% of mice, and the absence of metastatic progression [61]. This illustrates the need to further evaluate the NB inhibitory effects of resveratrol in combination with other drugs.

2.3. Garlic Compounds

Garlic (Allium sativum L. Fam. Liliacee) is a native plant of middle Asia, the beneficial effects of which have been known for over 5000 years. In ancient times, garlic was used by many populations, such as the Chinese, Israelis, Greeks, Egyptians to cure hemorrhoids, rheumatism, cough, skin disease, fever, and other diseases [62][63]. Today, garlic is known for its beneficial properties as an antioxidant [64], antibacterial agent [65], and for its anti-hypertensive [66] and anti-cancer properties [67]. Of the more than 2000 bioactive molecules present in garlic, the medicinal properties of garlic have largely been attributed to molecular organosulfur compounds [68][69], of which alliin is the most interesting.
In chopped or crushed garlic, the non-proteinogenic amino acid alliin is converted into allicin by the release of alliinase, and is then rapidly transformed into ajoene, diallyl sulfide (DAS), and diallyl disulfide (DADS) [62]. Garlic also contains smaller amounts of biologically active g-glutamyl-S-allylcysteine (GSAC), S-methylcysteine sulfoxide (methiin), S- trans-1-propenylcysteine sulfoxide, and S-2-carboxypro-pylglutathione and S-allylcysteine (SAC) [70].
However, the antitumoral effects of many molecular garlic components have not been studied. Allicin induces apoptosis and inhibits proliferation in NB cells by downregulating ornithine decarboxylase (ODC1), a direct transcriptional target of the metastasis promoting oncogenes c-MYC and MYCN [24]. When combined with cyclophosphamide, allicin exhibits greater anti-tumor activity than cyclophosphamide alone in a mouse NB model [70]. The antitumoral effects of the garlic component SAC has also been evaluated in NB cells. SAC promotes apoptosis by inducing mitochondrial permeability and inhibits cell growth [25]. The allicin metabolite DADS induces mitochondrial apoptosis and inhibits proliferation in SH-SY5Y NB cells [26], and the pro-oxidant ROS producing activity of DADS also leads to cytoskeletal impairment, cell cycle arrest in G2/M, apoptosis, protein phosphatase 1 (PP1) activation, and subsequent Tau dephosphorylation [27]. DADS-induced ROS production, however, activates peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC1α), which exhibits both cancer promoting and anti-cancer activity, and in NB cells induces mitochondrial biogenesis with anti-apoptotic effects, consistent with NB promoting potential [28]. The activity of DADS in NB, therefore, should be better understood.

2.4. Vitamin A and Retinoids

Vitamin A is an essential liposoluble micronutrient, the precursors of which are the provitamin A forms β-carotene e β-canthaxanthin. Forms of Vitamin A include all-trans-retinol, retinal, and retinoic acid (RA), collectively known as retinoids [71][72]. Humans do not synthesize retinoids and are, therefore, dependent upon dietary vitamin A [73]. Following intestinal absorption, retinol is transported by chylomicrons to the liver, which is the primary retinol (retinyl esters) storage site. Retinol is subsequently exported via retinol-binding proteins (RBPs) via the bloodstream to target tissues [71][74].
Vitamin A is essential for physiological processes such as sight, cutaneous integrity, immune system function, reproduction, and fetal development (organogenesis) [75] and has pleiotropic functions due to its biologically active isoforms. Vitamin A deficiency or excess is associated with characteristic symptoms and diseases., including night-blindness and corneal ulcers. Excess vitamin A causes osteosclerosis and teratogenic effects including organ malformation and altered organogenesis [76]. Vitamin A concentration, therefore, must be maintained within a strict range [77]. Vitamin A supplementation is commonly combined in multiple micronutrient integration and rarely alone [41].
Retinoids, as cancer preventing and anti-cancer agents, have been evaluated in NB as apoptosis inducers and pro-differentiation agents [72]. All-trans retinoic acid differentiates NB cells in vitro [29] and promotes neuritogenesis consistent with NB cell neural differentiation [78][79]. RA binds nuclear retinoic acid receptors (RARs) and retinoid X receptor (RXR), resulting in the transcription of retinoic acid responsive target genes [76]. Furthermore, retinoids also activate the transcription factor IRF1, a tumor suppressor involved in activating the tumor-selective death ligand TRAIL, leading to apoptosis through the extrinsic apoptotic pathway [80].
Retinoids (particularly 13-cis-RA) are used in high-risk NB as apoptosis and differentiation inducing agents in maintenance therapy for minimal residual disease [81]. Furthermore, the stereoisomer 9-cis-RA has been shown to induce greater differentiation in NB amplified NMYC cells [31]. However, despite its anti-NB activity in a human NB rat xenograft model, 9-cis-RA exhibits higher cytotoxicity, lower bioavailability, and a short half-life, limiting clinical use [30].

2.5. Green Tea Polyphenols

Green tea is a preparation obtained from the dried leaves of the plant Camellia sinensis, which contains high levels of the ubiquitous plant polyphenol catechins and expounds numerous health benefits [82][83]. Green tea polyphenols include epicatechin, epigallocatechin (EGC), epicatechin-3-gallate, and epigallocatechin-3-gallate (EGCG) [83], of which EGCG is the most abundant anti-cancer component [33] . EGCG has been characterized as a potential growth inhibitor in several types of cancer including NB [82], and in SH-SY5Y NB cells induces apoptosis through caspase and calpain activation [32]. In a BE (2)-C NB cell tumor sphere model of high-risk NB, EGCG prevents the formation of tumor-initiating cells, which are considered to be responsible for tumor relapse and therapeutic resistance [33]. EGCG, furthermore, has been shown to improve the anti-tumor efficacy of the rexinoid, 6-OH-11-O-hydroxyphenanthrene [34]. EGCG, however, regulates many signaling pathways and, therefore requires further investigation in order to fully understand the mechanisms through which it exerts its anti-cancer activity [33].

2.6. Other Compounds

With respect to other nutraceutical molecules with potential anti-NB activity (see Table 1), berberine (BBR) is a natural alkaloid present in the rhizomes and roots of several plants including Captis chinensis, Hydrastis canadensis, Berberis aquifolium, Berberis aristata, and Berberis vulgaris. In NB in vitro and in vivo models, treatment with BBR leads to a reduction in tumor growth and regulates both differentiation and stemness [40][84]. In addition, BBR induces p53-dependent apoptosis in human SK-N-SH and SK-N-MC NB cell lines [38]. The in vitro cytotoxicity of BBR in cancer cells has also been reported to be enhanced when combined with arsenic trioxide (As2O3), a chemotherapeutic drug approved for the treatment of relapsed NB. BBR combined with As2O3 induces the apoptosis of SH-SY5Y NB cells by increasing the production of ROS and promoting the fragmentation of DNA, resulting in caspase activation and cell death [39].
The natural alkaloid caffeine, present in coffee, cocoa, tea, cola, guarana, and mate plants, is another potential NB inhibitory nutraceutical. At high concentrations, caffeine has been shown to induce apoptosis in SK-N-MC NB cells via a capase-3 dependent mechanism [37].


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