3.1.1 Prostate cancer

PCa regarded as male cancer, has been considered the second most prevalent cancer in men; more than 1.2 million diagnosed cases of PCa was reported in 2018, worldwide.⁷⁵

Unfortunately, investigations into nut intake and PCa incidence are limited and have emerged with discrepant reports. The Netherlands Cohort Study (2019) on 58,279 men aged 55–69 years exhibited no remarkable correlation between the consumption of peanuts, other tree nuts, and total nuts and advanced, nonadvanced, and total PCa. However, consumption of peanut butter was observed to have a direct relationship with the risk of nonadvanced PCa.²⁹

Peanuts and walnuts have been also considered as the most prominent sources of phytosterols that inhibit proliferation of PCa cells in vitro.⁴³ Findings of a cross-national study on PCa mortality (i.e., PCa deaths per 100,000 males aged 45–74 years old) between 1985 and 1989 in 59 countries have exhibited a negative correlation between PCa-related mortality and the calories supplied from nuts and seed oils.⁵⁵

Population-based studies performed in Canada⁵⁶ to make an adequate expectation for dietary intake using a dietary history reported a remarkable attenuation (31%) in the risk of PCa. However, this finding was true for total nuts, seeds and legumes, and their individual effects were not differentiated.

Wang and co-workers claimed that a significant correlation was not observed between the consumption of nuts and PCa incidence or its related mortality. Overall mortality was remarkably reduced (34%) when nuts were frequently consumed (five or more times per week) after PCa diagnosis. They confirmed PCa diagnosis with medical records and pathology reports. Deaths were also identified using family reports and National Death Index searches.⁵⁷

The dietary supplementation with α-tocopherol has been reported to be markedly associated with the reduced incidence of PCa. In other words, higher levels of serum α-tocopherol was well associated with a decreased risk of PCa.^{76, 77}

A recent ecological study including 170 countries, that assessed the link between dietary factors and PCa, demonstrated inverse associations between the consumption of seeds and nuts and the incidence (β −0.7, p < 0.001), prevalence (β −2.1, p < 0.001), and mortality (β −0.1, p = 0.02) rates of PCa.⁵⁸

Vaioulis et al. studied the possible effects of the Mediterranean diet on PCa in a Greek population consisting of 279 healthy men and 431 patients suffering from PCa. The patient group was selected after prostate biopsy of the participants who had a PSA level ≥4 ng/mL or a positive digital examination, or a lesion suspicious for malignancy in the transanal ultrasound examination. Although they did not find a significant association between the dietary patterns and the incidence of PCa, daily intake of nuts (odds ratio [OR]: 0.63), white meat (OR: 0.59), whole grains (OR: 0.55), and dairy products (OR: 0.64) was higher in the healthy group. In addition, consumption of nuts with a frequency of less than once a week was correlated with the increased prevalence of PCa (OR: 1.8).⁵⁹

Different studies on the association of PCa and nut consumption show inconsistent results, either a nonsignificant or a protective association. However, several epidemiological studies have demonstrated that metabolic syndrome might increase PCa risk and reduce survival.^78-80 Accordingly, consumption of a nut-supplemented diet aiming a healthy body mass index, might improve quality of life and consequently, increase survival.⁸¹

Regarding the mechanism of the possible association of nut consumption and PCa cancer, it can be attributed to the hormone-mediated nature of this cancer.⁵⁵ It has been reported that phytoestrogens, especially isoflavonoids and lignans, as well as other polyphenols, phytosterols, and even some fatty acids, which are abundant in nuts modify hormonal mechanisms or conduct antiestrogenic activity. Hence, these compounds of nuts may contribute to the prevention of hormone-dependent cancers.^{33, 34, 82-84} Moreover, omega-3 fatty acids have shown inhibitory effects on the growth of tumors in prostate.^{85, 86}

3.1.2 Bladder cancer

Nuts are a good source of vitamin E. Vitamin E has exhibited intracellular antioxidant properties.⁸⁷ α-Tocopherol, as the most abundant and active form of vitamin E in humans, is also able to enhance immune response, in addition to the modulation of gene expression, and inhibition of cell proliferation, and adhesion.⁸⁸

Wang and colleagues performed a meta-analysis on 20 observational studies alongside the reported data from 7693 BC cases and suggested that intake of vitamin E was remarkably associated with the decreased risk of BC.⁸⁹ Lin et al. also demonstrated an inverse association between the intake of vitamin E and BC risk.⁹⁰

Several in vitro studies have confirmed that ellagic acid which is contained in nuts has antiproliferative and cytotoxic effects on BC cell lines.^91-93 Ellagic acid can improve the antitumor property of mitomycin C in several types of human BC cell lines. Claudia and colleagues observed that ellagic acid found in nuts causes a considerable reduction in the proliferation rate, infiltrative behavior, and tumor-associated angiogenesis of human BC xenografts. Accordingly, they proposed this polyphenol for the adjunct therapy of BC.⁹⁴

In a work study on 113 patients with BC and control sample (n = 292), the association between nut consumption and BC was investigated. It was found that intake of nuts was related with the reduced BC risk by 76% (OR, 0.24; 95% confidence interval [CI], 0.12–0.48).⁶⁰

However, the results of another study on the data of the Health Professionals Follow-up Study (1986–2018), the Nurses' Health Study (1980–2014), and the Nurses' Health Study II (1991–2015) showed that frequent nut consumption had no significant relation with the risk of BC.⁶¹

3.2.1 Pancreas cancer

PC is regarded as the fourth leading cause of death associated with cancer, worldwide. Also, it has been evidenced that the PC incidence in developed countries is continuously elevating.⁹⁵

It has been demonstrated that elevated levels of baseline plasma insulin and C-peptide are significantly correlated with the increased risk of subsequent PC.⁶² Unsaturated fatty acids, magnesium, and fiber from nuts have been reported to be able to improve insulin sensitivity.⁹⁶

Bao et al. investigated the association between nut consumption and the risk of PC with prospective following 75,680 women in the Nurses' Health Study. After adjusting for relevant variables, they found that the participants who consumed a nut serving size of 28 g twice or more per week, experienced a considerably lower risk of PC (RR, 0.65; 95% CI, 0.47–0.92; P for trend = 0.007) in comparison to nonconsumers.¹¹

In the follow-up phase (20.3 years) of the Netherlands Cohort Study (with 120,852 participants), 583 incident PC cases, including 349 microscopically confirmed PC (MCPC) cases were reported. Multivariable case–cohort analyses of these PC cases by Nieuwenhuis and van den Brandt in 2018 showed a nonlinear dose–response relation between the intake of tree nuts and the incidence of MCPC. Consumption of peanut butter was also associated to a significantly decreased risk of MCPC in men while unclear relation was found in women.⁹⁷ In a meta-analysis study in 2020, subgroup analyses of the association between specific types of cancer and nut consumption revealed an inverse association for PC.⁹⁸

Zhao and co-workers reported that ellagic acid had the capability to exert in vivo therapeutic effects against PC.⁶³ Ellagic acid has also been demonstrated to inhibit nuclear factor kappa B in PC cells and induce apoptosis.⁹⁹

However, a population-based case-control study conducted in the Netherlands in 1991 showed no positive relationship between PC and nuts intake.¹⁰⁰

3.2.2 Colon cancer

CC is one of the most prevalent solid tumors and is considered as a primary cause of cancer-related mortality, worldwide.¹⁰¹ In most cases, CC achieves a better prognosis if immediately diagnosed at the initiation phase, and in this case, the 5-year overall survival rate of the patient can be up to 80%–90%.¹⁰² Some population-based studies have proposed that 90% of mortality caused by large bowel cancer are due to the high intake of saturated fat and red meat which elevate the risk of CC.^{103, 104}

A study on the mice model of CC indicated that walnut consumption suppressed colon carcinogenesis.¹⁰⁵

The inhibitory effects of phytosterols, phytic acid, and resveratrol on CC have been well supported by both in vitro and in vivo studies.^{64, 106} Peanut is a well-known source of phytosterols,⁴³ phytic acid,⁴³ and resveratrol.⁶⁵ β-Sitosterol, as the main component accounting for approximately 80%,⁴³ possesses protective effects against CC and inhibits the proliferation of HT-29 CC cells.¹⁰⁷

A peptide fraction which was gained by the chymotrypsin-based hydrolysis of walnut protein has been reported to inhibit the survival of HT-29 and MDA-MB231 CC cells. This inhibitory effect was attributed to the antioxidant activity of the hydrolysate.¹⁹

Koh and co-workers conducted an in vivo study on mice model of CC and found that the phenolic extract of walnut was able to ameliorate colitis-associated CC via inhibiting nuclear factor kappa B signaling in intestinal epithelial cells.¹⁰⁸

To study the metabolites formed during the fermentation of nuts in the human digestion system, Lux et al. prepared fermentation supernatants from the dietary fiber of macadamias, almonds, hazelnuts, walnuts, and pistachios and investigated their effects on the growth of HT29 cell line. They observed that all of the prepared fermentation supernatants, except that of pistachio, significantly decreased the growth of HT29 cells.¹⁰⁹

3.2.3 Colorectal cancer

Etiological evidence indicated that over 85% cases of CRC are well-correlated with environmental factors,¹¹⁰ in particular dietary factors.¹¹¹

In men and women, CRC has been reported to be the third and second most frequent cancer types, respectively.¹¹² Despite several well-defined risk factors such as age, familial history, and genetic inherited defects, CRC prevalence has been found to be higher in subjects suffering from obesity,^{113, 114} metabolic dysregulation,¹¹⁵ insulin resistance,¹¹⁶ and/or type-2 diabetes mellitus.^117-121 Cirillo et al. have reported 13 miRNAs as potential molecular links between metabolic alterations related to obesity and CRC onset and development.¹¹⁴ According to the hyperinsulinemia hypothesis, elevated levels of insulin and free IGF-1 lead to the promoted proliferation of colon cells and survival of transformed cells, which ultimately result in CRC.¹¹⁸ Since the consumption of nuts can remarkably improve insulin resistance,⁶⁶ lower weight gain,¹²² and decrease the risk of type-2 diabetes mellitus,¹²³ intake of nuts may also attenuate the risk of developing CRC.

Findings of a research by Nagel et al. showed that walnut intake significantly inhibited the development of CRC in a mice model via suppressing angiogenesis.⁶⁷

Additionally, some epidemiological studies have linked the intake of methionine and folate, which are found in abundance in nuts, to a decreased risk of CRC and colorectal adenomas. The possible corresponding mechanism, especially the effects of genetic polymorphisms, has been also investigated.^{27, 124}

Yeh's research group performed a study on 11,917 women and 12,026 men aging 30–65 years in Tai population and demonstrated that regular intake of either peanut or its products was able to reduce CRC risk in women, due to its antiproliferative effects.⁶⁸

Wu and co-workers surveyed 30,708 participants in a meta-analysis review and reported a significant association between the consumption of nuts and reduced risk of CRC.¹²⁵

Recently, another meta-analysis of observational studies on the effects of phytochemically rich diets and CRC risk has confirmed the finding of Wu et al. Borgas and co-workers reported a significant association between higher consumption of dietary nuts and decreased risk of CRC.¹²⁶ However, they observed a significant heterogeneity that made it difficult to achieve a reliable conclusion based on currently available data.

Analyzing the data of the Netherlands Cohort Study (with 120,852 participants), Nieuwenhuis and co-workers found nonlinear associations between the consumption of nuts and peanut butter and decreased risk of rectal cancer in women. However, borderline significant nonlinear relations were observed for men who consumed nuts. Surprisingly, the intake of peanut butter was observed to be related to a raised risk of CRC that did not progress via the serrated neoplasia pathway in men.¹²⁷

3.3.1 Breast cancer

BrC is known as the main cause of cancer deaths in women, globally. Different risk factors have been identified for BrC, including age, breast density, reproductive history, lactation, genetic factors, hormone levels or use, lifestyle-related factors, and diet.^{69, 128, 129} While some of these factors are not modifiable, dietary patterns and lifestyles can be modified to prevent BrC development.^{70, 71}

Consumption of nuts, including peanuts, walnuts, and almonds have been reported to decrease the risk of BrC by two to three folds.^{20, 43} Also, Bao et al. reported similar effects of nut consumption on the development of BrC.¹¹ Jacobs et al. investigated the effects of the consumption of nuts and seeds on 396 South-African women with BrC and found that the stratification of estrogen receptor-positive was inversely associated with the risk of the disease.⁷²

In another study on 97 patients with BrC and 104 healthy control women, protective effects of peanuts, almonds, and walnuts for the inhibition of BrC development was observed.¹³⁰

The results of a population-based case-control study on 350 Iranian women with pathologically confirmed BrC showed an inverse association between the intake of nuts (walnut, almond, hazelnut, and peanut) and the odds of BrC.¹³¹

Berkey and co-workers studied the combined effects of adolescent alcohol use and nut consumption on the risk of benign breast disease in young women, using the data of a prospective cohort study on 9031 females aged between 9 and 15 years (at baseline). As a main result, it was found that nut consumption mitigated the risk of the disease in high-school females, who drank.¹³²

Ellagic acid, which exists in nuts, has been demonstrated to exert therapeutic effects against BrC in an in vivo study.¹³³ Peanuts are a well-known source of phytosterols, especially β-sitosterol, which have a protective role against BrC, as shown in an in vitro study.⁴³

However, two investigations revealed no positive correlation between BrC and the intake of nuts.^{100, 134}

3.3.2 Cervical cancer

CeC, which is potentially preventable,¹³⁵ is the second most frequent cancer type in women, worldwide.¹³⁶ In developing countries, CeC is considered the most frequent female genital tract malignancy.^{137, 138} Approximately 500,000 newly diagnosed cases and 273,000 deaths due to CeC are reported per year. Eighty-five percent of these deaths are occurred in developing countries.¹³⁶

Nuts may be good anticancer candidates for CeC because they contain numerous substances with potential anticarcinogenic activity. A cross-sectional study in Shanxi, China showed an association between the dietary intake of nuts and the reduced risk of cervical intraepithelial neoplasia grade 2 or higher while controlling for human papillomavirus infection.⁷³

Burin and co-workers investigated the effects of the oil of pecan nut on cervical squamous cancer cells (SiHa) using MTT assay and reported IC₅₀ of 16.46 μg/mL and selectivity index of 0.75.⁷⁴

In addition, different constituents of nuts have been demonstrated to be effective against CeC. In a study on 20,000 women aged <65 years in Yangqu County, a significant association between low levels of serum folate and the risk of cervical intraepithelial neoplasia progression was observed.¹³⁹

Phenolics, quercetin, and resveratrol are compounds that regulate immunological activity and inflammatory response. These compounds have been reported to be remarkably involved in prostaglandins and proinflammatory cytokines generation that further intervene with inflammatory responses.^{32, 36} This mechanism might be paramount important in tumors displaying a pattern of chronic inflammation, including CeC.³²

Juglone which is found in different parts of plants in the Juglandaceae family particularly the black walnut, has interesting anticancer effects against human CeC.^{39, 140-142} For instance, Lu and colleagues studied the possible regulatory effects of juglone on the apoptosis of CeC cells, and the related molecular mechanism. They observed that Juglone induced the expression of apoptotic molecules in mitochondrial and death receptor pathways via JNK/c-Jun activation pathway and further apoptosis of the CeC cells.³⁹

In addition, Zhang and his research team reported that treatment of Hela cells with juglone resulted in some typical morphological changes in apoptotic body formation. The early apoptotic Hela cells detected using Annexin V-FITC were 5.23%, 7.95%, 10.69%, and 20.92% in response to 12.5, 25, 50, and 100 µmol/L of juglone, respectively. Bcl-2 expression was significantly downregulated while Bax expression was remarkably upregulated, in response to various concentrations of juglone after 24-h treatment. These events were alongside with the activation of caspases-3, -8, and -9, as well as PARP (polymerase) cleavage. According to these findings Zhang et al. proposed juglone as a good candidate for the treatment of HeLa cells.¹⁴⁰

In another study, Zhang and colleagues surveyed the effects of juglone on the proliferation of SiHa cells. They demonstrated that Juglone was able to significantly induce the apoptosis of the cells and remarkably inhibit their proliferation.¹⁴¹

Zhang and co-workers also studied the effects of Juglone on human CeC Caski cells and reported that Juglone considerably prevented the proliferation of the cells and simultaneously elevated apoptosis in the Caski cells.¹⁴²