Polyphenols in cancer prevention: New insights (Review)

Abstract

BC is the second most frequent type of cancer worldwide; in particular, among women, it is considered the most commonly diagnosed type of cancer, constituting approximately 25% of all diagnosed tumors (7). The risk of developing BC is affected by non‑modifiable factors, including age and genotype, as well as modifiable factors, such as smoking, alcohol, nutrition and occupational exposure (40). It has been observed that obesity, a sedentary lifestyle and unhealthy diet are known to increase the mortality rate of BC survivors. As the same risk factors are common to cardiovascular diseases, the risk of cardiovascular diseases is also higher among BC survivors. Consequently, the implementation of a healthy diet rich in unrefined cereal, fresh fruit and vegetables could also indirectly improve the outcome of BC survivors by reducing body weight. The nutrients present in a typical Mediterranean diet have shown a positive impact on the biomarkers of inflammation, DNA damage, oxidative stress and genetic alterations, all factors that can influence BC outcomes. In addition, several studies have reported that a high adherence to MD is associated with a lower risk of the incidence of BC in post‑menopausal women (41). A prospective cohort study conducted in the Mediterranean included 10,713 middle‑aged, Spanish female university graduates and revealed an inverse association between the total polyphenol intake and the risk of BC for post‑menopausal women (42). The intake of polyphenols from food or as a food supplement for the prevention of BC is actually controversial, as only high concentrations are able to inhibit the proliferation of ERα and ERα+ BC cells, while lower concentrations can even stimulate the growth of ERα+ cells (43). One of the polyphenols studied for its inhibitory effects on BC is carnosol. An in vivo study demonstrated that this compound can reduce the proliferation of BC cell lines (MDA‑MB‑231) and can significantly inhibit invasion and metastasis both in vitro and in vivo; in particular, it has been shown that carnosol exerts its effect against BC through the downregulation of MMP‑9 activity and expression, and by the inhibition of the STAT3 signaling pathway through the ROS‑dependent proteasome degradation of the STAT3 protein (44). The antioxidant properties of RES, a natural component of plants such as peanuts, cocoa, grapes, berries and red wine, are attributed to its polyphenolic stilbene structure. RES and its analogues have been classified as phytoestrogens able to bind estrogen receptor, and the results of investigations in ER‑positive subtypes strongly suggest their use in hormone anticancer therapy. In fact, the majority of authors agree on the ability of RES to modulate ERα and p53 expression in ER‑positive BC: It inhibits the expression of major cell cycle‑related genes, through the downregulation of ERα mRNA transcription. Recently, a membrane receptor site for RES on an integrin has been revealed in both ER‑positive and ER‑negative BC subtypes: Upon binding of RES with this receptor, the p53‑dependent induction of apoptosis occurs (45).Therefore, RES and other stilbene derivatives would elicit significant cytotoxic and pro‑apoptotic effects in ER‑negative and ‘triple‑negative’ breast cancer (TNBC) cells, lacking receptors for estrogens, progesterone and human epidermal growth factor. While the potential effects against BC of RES and other polyphenols such as curcumin (CUR), genistein, quercetin and silibinin have been widely investigated, interest towards the potential anticancer activity of luteolin is more recent. The mechanisms considered to be responsible for the cancer preventive activity of luteolin are reduced DNA alterations, antioxidant, anti‑inflammatory and antiestrogenic action. Moreover, pro‑apoptotic (e.g., by inhibiting PI3K/Akt and inducing FOXO3a activation) and chemosensitizing (mainly through JNK activation) effect may confer it a therapeutic potential. Luteolin inhibits BC cell survival, proliferation and migration and reduces angiogenesis, by modulating multiple signaling pathways and miRNAs (46). EGCG and oleuropein (OLE) have been suggested as potential supplements against BC. Zan et al demonstrated that EGCG blocked cell cycle progression at the G2/M phase in MCF‑7. EGCG also induced apoptosis by inhibiting miR‑25 expression and increasing PARP and pro‑caspase expression (47). Oleuropein (OLE), a natural polyphenol, has also shown potential apoptotic and anti‑invasive effects on MCF‑7 cells. In fact, OLE reduced neoplastic cell invasiveness and viability and at the same time induced apoptosis in MCF‑7 cancer cells (48); in particular, OLE acts on cancer control by epigenetic mechanism, such as the inhibition of histone deacetylase (HDAC) (49). Finally, an in vitro study reported the anti‑proliferative and cytotoxic effects of a polyphenol complex (catechin and lysine, 1:2) in BC cell lines. In particular, it was shown that this complex acts by interfering with glucose uptake and lactate production by tumor cells. It exerts selective anti‑migratory (mediated by JAK2/STAT3 and Wnt pathway inhibition) and pro‑apoptotic effects in breast, pancreatic and colorectal cancer cell lines (50). Nonetheless, epidemiological studies on flavonoids and BC have some limitations: Study design, a low sample size, variable doses of flavonoid intake and BC subtype are the most common (51).