Carbohydrates
Given the hypothesis that insulin is a growth factor for PCa, it has been hypothesized that reducing carbohydrates and thus lowering serum insulin may slow PCa growth [
3]. Indeed, in animal models, either a no-carbohydrate ketogenic diet (NCKD) [
4,
5] or a low-carbohydrate diet (20% kcal as carbohydrate) has favorable effects on slowing prostate tumor growth [
6,
7]. In human studies, one study found that high intake of refined carbohydrates was associated with increased risk of PCa [
7]. In addition to the amount of carbohydrates, type of carbohydrates may impact on PCa but research has been inconclusive.
The potential to reduce PCa risk and progression via impacting carbohydrate metabolism is actively being investigated with Metformin. Metformin reduced PCa cell proliferation and delayed progression
in vitro and
in vivo, respectively [
8-
10] and reduced incident risk and mortality in humans [
11-
13]. Two single arm clinical trials also showed a positive effect of metformin in affecting markers of PCa proliferation and progression [
14,
15]. However, other retrospective cohort studies have not supported an effect of metformin on recurrence or incident risk of PCa [
16-
22].
Despite the potential for reducing either total or simple carbohydrates in benefiting PCa control, evidence is lacking from randomized controlled trials (RCT). Two randomized trials are on-going examining the impact of a low-carbohydrate diet (approximately 5% kcal) on the PSA doubling time among PCa patients post radical prostatectomy (NCT01763944) and on glycemic response among patients initiating androgen deprivation therapy (ADT) (NCT00932672 ). Findings from these trials will shed light on the effect of carbohydrate intake on markers of PCa progression and the role of reduced carbohydrate intake on offsetting the side effects of ADT.
Fat
Research findings examining fat consumption with PCa risk or progression are conflicting. Both the total absolute intake [
47] of dietary fat and the relative fatty acid composition may independently relate to PCa initiation and/or progression. While animal studies repeatedly show that reducing dietary fat intake slows tumor growth [
48-
50] and high fat diets, especially animal fat and corn oil increase PCa progression [
51], human data are less consistent. Case–control studies and cohort studies have shown either no association between total fat consumption and PCa risk [
52-
55] or an inverse association between fat intake and PCa survival, particularly among men with localized PCa [
47]. In addition, a cross-sectional study showed that fat intake expressed as percent of total calorie intake was positively associated with PSA levels in 13,594 men without PCa [
56].
Given these conflicting data, it is possible that the
type of fatty acid [
56] rather than total amount may play an important role in PCa development and progression. A study found plasma saturated fatty acids to be positively associated with PCa risk in a prospective cohort of 14,514 men of the Melbourne Collaborative Cohort Study [
57]. In addition, another study found that eating more plant-based fat was associated with reduced PCa risk [
58]. These studies support the current dietary guideline of eating less animal-based fat and more plant-based fat.
The data regarding omega-6 (w-6) and omega-3 (w-3) polyunsaturated fatty acid (PUFA) consumption and PCa risk are also conflicting. While there are data to support a link between increased w-6 PUFA intake (mainly derived from corn oil) and risk of overall and high-grade PCa [
57,
59], not all data support such a link [
60]. In fact, a greater polyunsaturated fat intake was associated with a lower all cause mortality among men with nonmetastatic PCa in the Health Professionals Follow-up study [
58]. The postulated mechanism linking w-6 PUFAs and PCa risk is the conversion of arachidonic acid (w-6 PUFA) to eicosanoids (prostaglandin E-2, hydroxyeicosatetraenoic acids and epoxyeicosatrienoic acids) leading to inflammation and cellular growth [
61]. Conversely, w-3 PUFAs, which are found primarily in cold water oily fish, may slow growth of PCa through a number of mechanisms [
61-
63]. In a study of 48 men with low risk PCa under active surveillance, repeat biopsy in six months showed that prostate tissue w-3 fatty acids, especially eicosapentaenoic acid (EPA), may protect against PCa progression [
64].
In vitro and animal studies suggest that w-3 PUFAs induce anti-inflammatory, pro-apoptotic, anti-proliferative and anti-angiogenic pathways [
65,
66]. Moreover, a mouse study comparing various types of fat found that only the fish oil diet (that is, omega-3 based diet) slowed PCa growth relative to other dietary fats [
67]. In regards to human data, a phase II randomized trial showed that a low-fat diet with w-3 supplementation four to six weeks prior to radical prostatectomy decreased PCa proliferation and cell cycle progression (CCP) score [
62,
68]. A low-fat fish oil diet resulted in decreased 15(S)-hydroxyeicosatetraenoic acid levels and lowered CCP score relative to a Western diet [
69]. The potential benefits of omega-3 fatty acids from fish are supported by epidemiological literature showing that w-3 fatty acid intake was inversely associated with fatal PCa risk [
70,
71]. Despite the promise of omega-3 fatty acids, not all studies agree. Supplementing 2 g alpha-linolenic acid (ALA) per day for 40 months in 1,622 men with PSA <4 ng/ml did not change their PSA [
72]. However, another study found that a high blood serum n-3 PUFA and docosapentaenoic acid (DPA) was associated with reduced total PCa risk while high serum EPA and docosahexaenoic acid (DHA) was possibly associated with increased high-grade PCa risk [
73]. Further research is required to understand better the role of omega-3 PUFAs in PCa prevention or treatment.
Vitamins and minerals
Herein we will review the recent data on vitamins A, B complex, C, D, E, and K and selenium. In the two large clinical trials: the Carotene and Retinol Efficacy Trial (CARET; PCa was a secondary outcome) and the National Institutes of Health-American Association of Retired Persons (NIH-AARP) Diet and Health prospective cohort study, excessive multivitamin supplementation was associated with a
higher risk of developing aggressive PCa, particularly among those taking individual β-carotene supplements [
85,
86]. Similarly, high serum β-carotene levels were associated with a higher risk for PCa among 997 Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor cohort [
87]. However, β-carotene supplement was not found to affect risk for lethal PCa during therapy [
88], or in the Danish prospective cohort study of 26,856 men [
89]. Circulating retinol also was not associated with PCa risk in a large case–control study [
90]. Thus, the association between vitamin A and PCa is still unclear.
Preclinical evidence suggests folate depletion may slow tumor growth, while supplementation has no effect on growth or progression, but may directly lead to epigenetic changes via increases in DNA methylation [
91]. Two meta-analyses also showed that circulating folate levels were positively associated with an increased risk of PCa [
92,
93], while dietary or supplemental folate had no effect on PCa risk [
94] in a cohort study with 58,279 men in the Netherlands [
95] and a case–control study in Italy and Switzerland [
96]. In fact, one study of a cohort of men undergoing radical prostatectomy at several Veterans Administration facilities across the US even showed that higher serum folate levels were associated with lower PSA and, thus, lower risk for biochemical failure [
97]. Another study using data from the 2007 to 2010 National Health and Nutrition Examination Survey showed that a higher folate status may be protective against elevated PSA levels among 3,293 men, 40-years old and older, without diagnosed PCa [
98]. It was suggested that folate may play a dual role in prostate carcinogenesis and, thus, the complex relationship between folate and PCa awaits further investigation [
99].
Despite the potential role of vitamin C (ascorbic acid) as an antioxidant in anticancer therapy, trials examining dietary intake or supplementation of vitamin C are few. A RCT showed no effect of vitamin C intake on PCa risk [
89]. Furthermore, vitamin C at high doses may act more as a pro-oxidant than antioxidant, complicating the research design and interpretation.
The primary active form of vitamin D, 1,25 dihydroxyvitamin D3 (calcitriol) aids in proper bone formation, induces differentiation of some immune cells, and inhibits pro-tumor pathways, such as proliferation and angiogenesis, and has been suggested to benefit PCa risk [
100]; however, findings continue to be inconclusive. More recent studies found that increased serum vitamin D levels were associated with
decreased PCa risk [
101,
102]. Further, supplementing vitamin D may slow PCa progression or induce apoptosis in PCa cells [
103-
105]. Other studies, however, reported either no impact of vitamin D supplement on PSA [
106] or no effect of vitamin D status on PCa risk [
107,
108]. Some studies contrarily reported that a lower vitamin D status was associated with a lower PCa risk in older men [
109], or a higher serum vitamin D was associated with a higher PCa risk [
110,
111]. A study even suggested that a ‘U’ shaped relationship may exist between vitamin D status and PCa and the optimal range of circulating vitamin D for PCa prevention may be narrow [
112]. This is consistent with the findings for other nutrients that a greater intake of a favorable nutrient may not always be better.
A recent study showed that the association between vitamin D and PCa was modulated by vitamin D-binding protein [
113] which may have partially explained the previous inconsistent findings. Further, a meta-analysis investigating the association between Vitamin D receptor (VDR) polymorphisms (BsmI and FokI) and PCa risk reported no relationship with PCa risk [
114]. Thus, the role of vitamin D in PCa remains unclear.
In a large randomized trial with a total of 14,641 US male physicians ≥50-years old, participants randomly received 400 IU of vitamin E every other day for an overall mean of 10.3 (13.8) years. Vitamin E supplementation had no immediate or long-term effects on the risk of total cancers or PCa [
115]. However, a moderate dose of vitamin E supplement (50 mg or about 75 IU) resulted in lower PCa risk among 29,133 Finnish male smokers [
116]. Multiple preclinical studies suggest vitamin E slows tumor growth, partly due to inhibiting DNA synthesis and inducing apoptotic pathways [
117]. Unfortunately, human studies have been less than supportive. Two observational studies (the Cancer Prevention Study II Nutrition Cohort and the NIH-AARP Diet and Health Study) both showed no association between vitamin E supplementation and PCa risk [
118,
119]. However, a higher serum α-tocopherol but not the γ-tocopherol level was associated with decreased risk of PCa [
120,
121] and the association may be modified by genetic variations in vitamin E related genes [
122]. On the contrary, a prospective randomized trial, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), showed vitamin E supplementation significantly
increased PCa risk [
123] and that a higher plasma α-tocopherol level may interact with selenium supplements to increase high grade PCa risk [
124]. This finding is consistent with a case-cohort study of 1,739 cases and 3,117 controls that showed vitamin E increased PCa risk among those with low selenium status but not those with high selenium status [
125]. Thus, more research is needed to examine the association between vitamin E and PCa and the dose effect and interaction with other nutrients should be considered.
Vitamin K has been hypothesized to help prevent PCa by reducing bioavailable calcium. Preclinical studies show the combination of vitamins C and K have potent anti-tumor activity
in vitro and act as chemo- and radiosensitizers
in vivo [
126]. To date, few studies have investigated this, although one study using the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort found an inverse relationship between vitamin K (as menaquinones) intake and PCa incidence [
127].
Little to no preclinical studies have been conducted to examine the role of calcium with PCa. Retrospective and meta-analyses suggest increased or reduced PCa risk with increased calcium intake, while others suggest no association [
128,
129]. Another study suggests a ‘U’-shaped association, where very low calcium levels
or supplementation are both associated with PCa [
130].
Selenium, on the other hand, has been hypothesized to prevent PCa. While
in vitro studies suggested that selenium inhibited angiogenesis and proliferation while inducing apoptosis [
131], results from SELECT showed no benefit of selenium alone or in combination with vitamin E for PCa chemoprevention [
123]. Further, selenium supplementation did not benefit men with low selenium status but increased the risk of high-grade PCa among men with high selenium status in a randomly selected cohort of 1,739 cases with high-grade (Gleason 7–10) PCa and 3,117 controls [
125]. A prospective Netherlands Cohort Study, which included 58,279 men, 55- to 69-years old, also showed that toenail selenium was associated with a reduced risk of advanced PCa [
132]. Further research is needed to clarify the role of selenium with PCa.