Resveratrol-related compounds: Potential for cancer and beyond

Introduction

Resveratrol (RV) is a stilbenoid first isolated in 1939 from the traditional medicine plant Veratrum grandiflorum and also present in various foods such as grapes, apples, pistachios, plums and peanuts, earning it a place of choice among nutraceuticals (Zhang et al., 2021). From the two isomeric forms of RV, the trans-version is considered more biologically active (Kuršvietienė et al., 2016). Despite its low natural solubility in water, RV shows relatively high absorption (over 70%) after oral consumption (Vitrac et al., 2003; Walle et al., 2004), however its bioavailability is considered to be below 1% (Walle, 2011). RV is among the most actively studied natural compounds, as underlined by the number of RV-related entries recorded in the international clinical trial database (https://www.clinicaltrials.gov) covering a wide range of applications. This variety of biological effects can be linked to the diverse cellular pathways activated by RV, as the compound interacts with different cellular components and exerts multiple biological activities, including antioxidant (de la Lastra and Villegas, 2007; Xia et al., 2017), anti-inflammatory (Meng et al., 2021; Magrone et al., 2019), anti-microbial (Bostanghadiri et al., 2017), anti-proliferative (Stivala et al., 2001; Savio et al., 2016; Maccario et al., 2012) properties. RV is predominantly associated with antioxidant activity, an effect linked to the presence in its structure of three hydroxyl groups (Kuršvietienė et al., 2016; Stivala et al., 2001), as the molecule acts as scavenger of free radicals by increasing the intracellular concentration of antioxidant enzymes including SOD (superoxide dismutase), catalase, glutathione reductase and glutathione peroxidase (Yen et al., 2003; Ramprasath and Jones, 2010). It has however been proposed that RV could display a pro-oxidant activity, which could be responsible for lipid peroxidation and DNA damage (de la Lastra and Villegas, 2007). RV is also able to modulate several signalling pathways involved in inflammation, including AP-1, COX and NF-κB leading to an anti-inflammatory response (Meng et al., 2021). Crucially, RV is considered a potent activator of the NAD-dependent deacetylase enzyme Sirtuin 1 (SIRT1), a pleiotropic regulator of gene expression and silencing with particular relevance to cancer development (Yi and Luo, 2010; Choupani et al., 2018).

Possible Anti-Cancer Applications

RV has been taken up as anti-cancer molecule following numerous studies demonstrating its anti-tumoral profile, through combined effects on cancer cell proliferation, tumour microenvironment and angiogenesis (reviewed in (Naujokat and McKee, 2020)). RV is considered a chemopreventive agent, acting in the three major stages of carcinogenesis (Fig. 1).

Figure 1: RV anti-cancer effects.

In particular, RV is involved in the regulation of phase I and II enzymes and in the scavenging of ROS, blocking the initiation stage of carcinogenesis (Ko et al., 2017). RV has been observed to inhibit cell proliferation, arrest the replication cycle, and induce apoptosis and autophagy (Salehi et al., 2018) in several in vitro cancer models such as HT1080 fibrosarcoma and MCF7 breast adenocarcinoma (Stivala et al., 2001; Savio et al., 2016; Maccario et al., 2012). SIRT1 being a major mediator of RV effects, the ability of RV to upregulate SIRT1 in cancer cells is thought to induce in turn the degradation of β-catenin, supporting anti-cancer activities (Jung et al., 2013; Firestein et al., 2008). The ability of RV to inhibit the growth of cancerous cells is associated with well-documented therapeutic effects on the tumour environment including inhibition of angiogenesis and matrix metalloproteases (MMPs), modulation of epithelial-to-mesenchymal transition (EMT), and inhibition of invasion and metastasis (Belleri et al., 2008; Rauf et al., 2018). The compound was also shown to downregulate the phosphorylation and acetylation of NF-κB, impairing tumour proliferation, invasion and metastasis. In ovarian cancer cell lines, Tino et al. (2016) demonstrated that RV treatment inhibited cell growth by decreasing NF-κB levels and its downstream gene vascular endothelial growth factor (VEGF), which contributes to angiogenesis.

Its direct and indirect anti-tumour properties, combined with the aforementioned antioxidant and anti-inflammatory effects, hold clear potential for the use of RV in the clinic. Although clinical evaluation of the molecule is not without challenges (Ren et al., 2021), some clinical trials have investigated the use of RV in cancer patients, in multiple myeloma, breast and colorectal cancer (Berman et al., 2017). While treatment of colorectal cancer patients with RV or grape powder showed partly reduced tumour proliferation and increased cleaved caspase-3 levels in malignant hepatic metastases (Howells et al., 2011), results to date are not fully consistent across models, as it did yield adverse effects in the multiple myeloma trial (Berman et al., 2017). Preclinical observations have shown steadier benefits using RV, proposed as a chemosensitizer in complement to conventional chemotherapy (Harikumar et al., 2010). This approach trialled by applying RV in combination with doxorubicin (DOX) in breast (Jin et al., 2019), ovarian (Tino et al., 2016) and colorectal (Buhrmann et al., 2016) cancer cell models, was observed to inhibit proliferation, metastasis and chemoresistance. RV could thus potentiate chemotherapy and lower the necessary drug doses, consequently reducing the detrimental effects in patients from oxidative stress, lipid peroxidation, inflammation, apoptosis and autophagy (Yang et al., 2022).

Diverse Effects on Stem Cell Populations

Beside this possible role in cancer, RV have been linked to increased longevity and resistance to age-induced degeneration (Bonkowski and Sinclair, 2016), contributing to its promotion as a multifaceted anti-ageing compound attracting much commercial interest. The effect of RV on stem cell populations, responsible for the long term maintenance of organs and tissue throughout the lifetime, has been investigated in a range of cellular models and linked to its ability to activate Sirtuins (Stefani et al., 2007; Catalgol et al., 2012).

RV was reported to promote self-renewal in undifferentiated embryonic stem cell (ESC) cultures, in both mouse and human models, and reduce apoptotic markers (Li et al., 2017; Safaeinejad et al., 2017, 2018). Consequently, RV is among the additives trialled to facilitate cellular reprogramming for the production of induced pluripotent stem cells (iPSC) (Chen et al., 2011; Ding et al., 2013), presumed to act on the SIRT1-SOX2 axis. Application of RV at various concentrations yielded diverse outcomes on adult stem cell populations, in particular lower concentrations were reported to increase the proliferative ability of mesenchymal progenitors (Yoon et al., 2014; Yuan et al., 2012), with a similar effect on neuroprogenitor also limited to lower doses (Kumar et al., 2016). With regards to differentiation response, low dose RV applied to pancreatic stem cells improved β-cell formation (Xu et al., 2017), while RV added to endothelial progenitors at 20 μM supported their differentiation (Campagnolo et al., 2015). In differentiating mesenchymal stem cell (MSC) cultures, RV was consistently observed to promote osteogenesis (Moon et al., 2020; Dai et al., 2007; Wang et al., 2019; Song et al., 2022) at doses up to 1 μM (reviewed in (Safaeinejad et al., 2018)), warranting its incorporation in tissue engineering products for localised release to promote bone repair (Wei et al., 2021). RV added to mouse mesenchymal progenitors also caused inhibition of the adipogenic response (Zhou et al., 2015; Li et al., 2016) through Sirt1 (Jang et al., 2017), although some conflicting reports have observed the opposite effect in some mouse (Hu et al., 2015) and in human progenitors (Caldarelli et al., 2015). The publication of such discordant results further underlines the likelihood of RV acting in a dose-, time- and species- dependent manner, already evidenced in certain stem cell models (Safaeinejad et al., 2018; Peltz et al., 2012).

Outstanding Issues & Perspectives

The basis of this apparent discrepancy in the differentiation response to RV has been linked to a biphasic dose-response profile (Borriello et al., 2013; reviewed in (Calabrese et al., 2010)), which might hinder general comparisons across models and studies. The fact that RV’s beneficial effects may depend on reaching a specific in vivo concentration, points to the need for a better controlled pharmacological profile to achieve the desired effects (Scott et al., 2012; Cai et al., 2015). Better RV bioavailability is under active investigation (Chimento et al., 2019), including via alternative formulations (Howells et al., 2011; Tripathi et al., 2018), nano-encapsulation to assist the delivery and release (Santos et al., 2019) and chemical analogues including hydroxylated (Piotrowska et al., 2012) or methylated (Kapetanovic et al., 2011) derivatives such as pterostilbene showing superior bioavailability in vivo. One derivative in particular, trans-4,4′-dihydroxystilbene or DHS has shown promising biological characteristics. Produced as a synthetic new compound, its chemical structure (Fig. 2) was originally optimised to replicate the trans bicyclic/phenolic stilbene backbone of RV, based on the correlation previously observed between structure and activity (Stivala et al., 2001). DHS was subsequently also identified as a natural derivative (Torres et al., 2003), and found to be a potent antioxidant and anti-proliferative stilbene, superior to RV in vitro (Maccario et al., 2012; Savio et al., 2009).

Figure 2: Chemical structure of RV (trans-3,5,4'-trihydroxystilbene) and DHS (trans-4,4’-dihydroxystilbene). Image created using the design tool from https://chem-space.com.

DHS is active at a lower concentration compared to RV, and shows a different mechanism of action. In particular, DHS modified the cell cycle in the G1 phase, whereas RV induces a block at the beginning of the S phase, involving different DNA polymerases (Savio et al., 2009). Strictly related to its structure, DHS is more potent than RV in inhibiting neoplastic transformation of murine fibroblasts, as well as the proliferation and invasion of breast cancer cells (Maccario et al., 2012). In vivo, a murine lung cancer model was used to show that tumour volume and cell proliferation were significantly inhibited by DHS, and this is related to the reduction of angiogenesis (Savio et al., 2016). In addition, liver metastatic lesions were significantly reduced by DHS treatment, an observation that was confirmed in a zebrafish tumour model (Savio et al., 2016) and in a separate colon cancer model (Kimura et al., 2020). These early results underline the potential of DHS as an alternative RV derivative for treatment of cancer and metastasis. More work is underway to explore its biological effects on other cell types and broader therapeutic applications.

Acknowledgement: We thank colleagues from the Department of Molecular Medicine for their support.

Availability of Data and Materials: Not applicable.

Author Contribution: The authors confirm contribution to the paper as follows: Manuscript preparation: M. Savio, V. Minoia, V. Sottile; Critical review of the manuscript: P. Fulghieri, LA. Stivala. All authors reviewed and approved the final version of the manuscript.

Ethics Approval: Not applicable.

Funding Statement:This work is supported by a Grant from the Italian Ministry of Education, University and Research (MUR) to the Department of Molecular Medicine of the University of Pavia under the Initiative ‘Dipartimenti di Eccellenza (2018–2022)’.

Conflicts of Interest:The authors declare that they have no conflicts of interest to report regarding the present study.

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