Prostate cancer is a growing threat to Asian men's health [1]. Although the rate of incidence of prostate cancer is far greater in Western cultures (120 per 100,000 in Northern America) than in East Asian cultures (less than 10 per 100,000 in Asia) [2], when Asians migrate to Western countries, their rate of prostate cancer incidence increases. This finding supports the idea that lifestyle, diet, environmental, and genetic factors promote the development of prostate cancer [3,4]. This observation has prompted studies to identify dietary components, such as soy, a staple of the Asian diet, that may have anticancer properties. High soy intake may be one of the reasons Asians have a low risk of prostate cancer. Soy foods have been postulated to reduce the risk of several chronic diseases, including coronary artery disease, osteoporosis, and cancer. Moreover, the amount of soy taken in the diet is inversely proportional to the risk of prostate cancer [5-7]. The increasing burden of prostate cancer screening and treatment has made primary prevention an attractive strategy to decrease the incidence and slow the progression of this disease [8].

Chemoprevention is a prophylactic method that uses nontoxic natural or synthetic compounds to reverse, inhibit, or prevent the development of cancer by impeding specific molecular steps in the carcinogenic pathway. Prostate cancer has all the attributes of an ideal target disease for chemoprevention, including a long latency, high incidence, ample tumor marker availability, and identifiable preneoplastic lesions. Polyphenols, such as genistein, daidzein, equol, and curcumin (which are found in soy and the Indian spice, turmeric) are known to modulate multiple intracellular signaling pathways, including cellular proliferation, apoptosis, inflammation, and androgen receptor (AR) signaling, all of which have been implicated in cancer development and progression. These features make polyphenols promising chemopreventive agents (Fig. 1) [9,10].

Maintaining the integrity of the genome is fundamental to warding off cancer. Central to this process is the ability of cells to accurately recognize and correctly repair DNA damage in a timely manner to ensure the regulated and orderly progression of cells through the cell cycle. DNA damage caused by oxidative stress, chemical agents, or ultraviolet light triggers the DNA damage response (DDR). Recently, evidence has emerged that the DDR is one of the earliest events capable of thwarting the multistep progression of human epithelial carcinomas to invasive malignancy [11,12]. Agents that can activate the DDR are now appreciated as having potent cancer-preventive properties [13].

This review focuses on soy isoflavones and curcumin as candidate functional food factors that may be used for the chemoprevention of prostate cancer, especially emphasizing their effects on the DDR.

Recently, evidence has emerged that the DDR is one of the earliest events that impedes the multistep progression of human epithelial carcinomas to invasive malignancy. DNA damage can be due to a variety of factors, such as telomere dysfunction or oncogene-induced replication stress [11,12]. The signaling pathways activated during the DDR have three critical goals: 1) halting cell cycle progression and division to prevent transfer of DNA damage to progeny cells; 2) increasing the accessibility of damage sites to (and engagement of) the DNA damage repair machinery, and 3) triggering apoptosis to exterminate cells whose damaged DNA cannot successfully be repaired [79].

The early precursor lesions commonly express markers of an activated DDR [11,12]. These markers include phosphorylated kinases (ataxia-telangiectasia-mutated kinase [ATM] and checkpoint kinase2 [Chk2]), phosphorylated histone H2AX, and phosphorylated p53. Such activation of the DDR network leads to senescence or death of oncogene-transformed cells that delays or prevents cancer progression. Epithelial cells within premalignant lesions with markers of senescence maintain an intact response to cellular stress and are less likely to develop subsequent tumors. However, the DDR is not only invoked but also dysfunctional at an early stage in the development of neoplasia. Markers of double-strand breaks, such as nuclear γH2AX foci (a histone phosphorylation event that occurs on chromatin surrounding a double-strand break), are markedly elevated in some precancerous lesions [80,81]. One hypothesis proposes that the original cause of these effects is oncogene activation [81]. The activation of oncogenes such as MYC and RAS stimulates the firing of multiple replication forks as part of a proliferative program. For precancerous lesions to progress to mature tumors, it is thought that critical double-strand break (DSB) signal transduction and cell cycle checkpoint proteins, such as ATM, ataxia telangiectasis Rad3-related (ATR), and the master "gatekeeper" protein p53, must become inactivated. With these DDR components rendered dysfunctional, collapsed forks are not effectively repaired, and cells proceed through the cell cycle with DNA lesions intact, thus increasing the chance of mutagenesis [80,81]. The 370 kDa Ser/Thr kinase ATM has begun to emerge as a central DNA damage checkpoint against cancer predisposition [82]. ATM is a member of the phosphoinositide 3-kinase-related protein kinase family to which the master regulator of cell growth and metabolism, the mTOR pathway, also belongs. ATM is a well-known primary regulator of the cellular response to DNA DSBs. Simultaneously, a number of studies have recently established that oxidative stress also activates ATM, even in the absence of DSBs. In response to oxidative stress, ATM is phosphorylated at Ser-1981, which results in phosphorylation of its substrates, including p53, the master controller of DNA metabolic stresses, and AMP-activated protein kinase-α (AMPKα), the key sensor of fuel and energy status [83].

Type 2 diabetes has been associated with elevated levels of DNA damage and with the decreased efficacy of DNA repair [83]. This can contribute to genomic instability in persons with type 2 diabetes and, consequently, to cancer promotion and progression. Indeed, cancer risk in type 2 diabetic patients is high. However, recent studies have shown that metformin significantly diminishes the risk of developing cancer in type 2 diabetic patients [84]. One causal linkage between metformin's mechanism of action and metformin's cancer preventative effects might be the activation of the DDR. Metformin promotes activation of ATM and ATM targets such as the protein kinase Chk2 [13].

We recently reported that soy isoflavones and curcumin activate the DDR in LNCaP cells by inducing phosphorylation of ATM, histone H2AX, Chk2, and p53, which leads to apoptosis (Fig. 2). Combined treatment with isoflavones and curcumin conveys an additive effect. Interestingly, testosterone augments activation of the DDR as well as PARP cleavage induced by curcumin that is dependent on the AR. Thus, testosterone given in combination with polyphenol may have suppressive effects on the progression of prostate cancer [41]. Similarly, resveratrol, a polyphenol found in berries, nuts, and red wine, has been shown to activate the DDR pathways in ovarian carcinoma cells [85]. Because the DDR is the major innate tumor suppressor barrier in early human tumorigenesis, selective activation of DDR surveillance mechanisms by polyphenols may directly contribute to cancer-preventive effects (Fig. 3) [86].

Identifying the key proteins involved in carcinogenesis is an essential prerequisite to establishing an effective chemoprevention strategy. Soy isoflavones and curcumin can suppress not only the proliferation of both androgen-dependent and androgen-independent prostate cancer cell lines, but also that of xenografts by interfering with ARs, the cell cycle, activities of protein kinases, and apoptosis of prostate cancer cells. Furthermore, soy isoflavones and curcumin exert DDR effects in androgen-dependent prostate cancer cells. This provides a rationale for the clinical application of curcumin and isoflavones for the chemoprevention of prostate cancer.

To translate the in vitro efficacy of dietary agents in the prevention of cancer to clinical use, attention should be given to defining physiologically relevant concentrations and chronic exposure times under in vivo conditions. Indeed, it may not be practical to predict the chemopreventive effect of a single functional food factor. Rather, increased focus on the synergistic effect of treatment with combined functional food factors or multiple nutrients or food will yield a plausible approach to measuring the chemopreventive effect. On the basis of the epidemiologic and molecular evidence, the nutraceutical approach to cancer chemoprevention warrants further study.