**4. Chemo preventative strategies against cancer**

A number of chemo preventative compounds have been proposed to reduce the risk of tumorigenesis (**Table 2**). A chemoprevention agent that blocks the very first step of tumorigenesis would be best. The next sections will discuss various pathways which can be targeted to potentially prevent cancer.

### **4.1 Inflammation**

Dysregulation of cell proliferation and apoptosis evasion are major determinants of the evolution of neoplasia and tumor growth, the hallmarks of cancer (Hanahan and Weinberg 2000). As tumors move to a progressed state and possibly metastasis, it is generally accepted that there is further induction of genetic and genomic alterations which has been synonymous with an increase in DNA mutations and further loss of homeostasis primarily

Bilateral prophylactic mastectomy (removal of healthy breasts) and prophylactic salpingooophorectomy (removal of healthy fallopian tubes and ovaries) do not, however, offer a guarantee against developing cancer. Because not all at-risk tissue can be removed by these procedures, some women have developed breast cancer, ovarian cancer, or primary

Additionally, there are instances where despite strict lifestyles, cancer unfortunately will still develop. In these situations where prevention has failed, the next effective strategy is early detection of disease, which can improve the chance of beating cancer. Regular screening for cancer increases the chance of catching the disease early, while it is still treatable. Screening does not, however, change the risk of developing cancer. For example, breast cancer can be screened by mammography and clinical breast exams. Studies are currently under way to test the effectiveness of other breast cancer screening methods, such as magnetic resonance imaging (MRI), in women with BRCA1 or BRCA2 mutations. For ovarian cancer, surveillance methods include transvaginal ultrasound, blood tests for CA– 125 antigen, and clinical exams. Similarly, prostate cancer screening includes assaying prostate specific antigen (PSA) levels and digital rectal exam for lumps in the prostate. High PSA levels and lumps may be indicative of cancer but infection and inflammation may falsely elevate PSA levels as well. Routine colonoscopy to look for early signs of cancer is recommended at age 50 or earlier if there is a family history of colorectal cancer, a personal history of inflammatory bowel disease, or other risk factors. These strategies help in

The most effective steps to curb cancer are low-cost and low-tech. For example, giving up smoking and losing weight can drastically reduce the chances of developing cancer. Smoking has long been known to be a risk factor while obesity has more recently been recognized as one. Together they account for roughly half of all cancer cases (Ott et al. 2011, Brand et al. 2011, Land et al. 2011, Li et al. 2011a, Boniol and Autier 2010, Giovannucci et al. 2010, Gotay 2010, Khan et al. 2010, Teucher et al. 2009). Since these habits are easier said than done, policies that make unhealthy lifestyle choices difficult and expensive while making healthier ones easier and cheaper will be a step in the right direction. In addition, a number of clinical compounds have also been proposed to reduce the risk of carcinogenesis.

A number of chemo preventative compounds have been proposed to reduce the risk of tumorigenesis (**Table 2**). A chemoprevention agent that blocks the very first step of tumorigenesis would be best. The next sections will discuss various pathways which can be

Dysregulation of cell proliferation and apoptosis evasion are major determinants of the evolution of neoplasia and tumor growth, the hallmarks of cancer (Hanahan and Weinberg 2000). As tumors move to a progressed state and possibly metastasis, it is generally accepted that there is further induction of genetic and genomic alterations which has been synonymous with an increase in DNA mutations and further loss of homeostasis primarily

peritoneal carcinomatosis even after prophylactic surgery.

diagnosing cancer at its early stages.

These are discussed in detail below.

targeted to potentially prevent cancer.

**4.1 Inflammation** 

**4. Chemo preventative strategies against cancer** 


Table 2. Chemo preventative drugs currently approved by the FDA.

cholesterol management, has been shown to disrupt the growth and proliferation of cancer cells such as prostate cancer (Kochuparambil et al. 2011). This has been verified in clinical trials as well where the use of statin drugs was linked with a reduced risk of advanced,

Other small molecules, such as metformin and tamoxifen, demonstrate anti-tumor activity against breast cancer (Goodwin, Ligibel and Stambolic 2009, Jiralerspong et al. 2009, Osborne 1998). Raloxifene and tamoxifen have been shown to cut down the risk of estrogenreceptor positive breast cancers by as much as 50% (Vogel et al. 2006). Tamoxifen, a selective estrogen receptor modulator, has demonstrated benefit when used alone as well as in combination with chemotherapy to treat advanced breast cancer. It reduces circulating insulin-like growth factor-1, inhibits angiogenesis, and induces apoptosis (Li et al. 2009). It is also efficacious in reducing tumor recurrence and prolonging survival when administered as postoperative adjuvant therapy in stages I and II disease. In a randomized breast cancer prevention clinical trial to evaluate the worth of taking tamoxifen for the prevention of breast cancer in women considered to be at increased risk for the disease, tamoxifen prevented the appearance of a substantial number of breast cancers (Fisher et al. 1998). Tamoxifen administered daily for at least 5 years prevented invasive breast cancer in women at increased risk (Fisher et al. 1998). Women who took tamoxifen also had fewer diagnoses of noninvasive breast tumors, such as lobular carcinoma in situ. The study found that though tamoxifen reduced the occurrence of estrogen receptor-positive tumors, it had no effect on the occurrence of estrogen receptor-negative tumors (Fisher et al. 2005). Tamoxifen is available in the United States for the reduction of breast cancer incidence in

Raloxifene, another selective estrogen receptor modulator, has successfully been tested for the treatment and prevention of osteoporosis. Raloxifene hydrochloride is a selective estrogen receptor modulator that binds to estrogen receptors to competitively block estrogen-induced DNA transcription (Grese et al. 1997, Brzozowski et al. 1997). An evaluation of breast cancer incidence in women treated with raloxifene for the prevention of osteoporosis showed a 75% decrease in invasive breast cancer, and, as with tamoxifen, only the estrogen receptor positive disease is reduced (Martino et al. 2004, Cummings et al. 1999). These data emphasize the fact that these drugs target the estrogen receptor-mediated growth mechanism. These data validate the original hypothesis that a non-steroidal antiestrogen in the same class as tamoxifen could be used not only to prevent osteoporosis but

Similar to other cancers, prostate cancer chemoprevention involves the use of natural and synthetic agents that inhibit or reverse the development of precancerous lesions or delay progression of these lesions to invasive disease. Since androgens are involved in the development of prostate cancer, they are an obvious chemotherapeutic target. Finasteride, an inhibitor of 5α-reductase, inhibits the conversion of testosterone to dihydrotestosterone, the primary androgen in the prostate (Thompson et al. 2003). A phase III trial for prostate cancer prevention, the Prostate Cancer Prevention Trial using the drug finasteride,

especially metastatic or fatal, prostate cancer (Platz et al. 2006).

high-risk premenopausal and postmenopausal women.

also to prevent breast cancer as a beneficial side effect.

**4.3 Androgen signaling** 

**4.2 Estrogen signaling** 

via inflammation-based pathways (Colotta et al. 2009, Solinas et al. 2010, Klein and Glazer 2010). Inflammatory chemokines and cytokines such as *CCL2*, *CCL18,* and others have been implicated in such processes (Chen et al. 2011, Bonecchi, Locati and Mantovani 2011, Redon et al. 2010). It has been suggested that the tumor surrounding may contribute to tumor proliferation. Tumors have the ability to alter their stroma and support the development of both tumor cells and non-malignant cells (Polyak, Haviv and Campbell 2009). The tumor eventually escapes from the host immune system via activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells (Schreiber, Old and Smyth 2011). The ability to block tumor escape hinges on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Monitoring the change(s) in the tumor stroma such as those occurring in the mesenchymal stem cells within tumor stroma via molecular and cellular profiles as the tumor progresses allows for identification of cell or protein targets for cancer prevention and therapy (Karnoub et al. 2007). Increasingly, cancer treatments are being modified to include tumor surrounding as a therapeutic target, since the non-malignant cells are more genetically stable and less likely to evolve into drug resistant phenotypes. For example, aspirin inhibits COX-1, while Celebrex inhibits COX-2 (Chan, Ogino and Fuchs 2007, Harris et al. 2005, Cooper et al. 2010, Ghosh et al. 2010, Harris 2007, Koehne and Dubois 2004, Reddy 2007, Reddy and Rao 2005, Smith et al. 1998). COX-1 is produced in tissues throughout the body, and is known to mediate the production of prostaglandins, chemical messengers that control a number of physiological functions, such as lowering blood pressure, regulating body temperature and controlling inflammation (Kundu and Fulton 2002, Smith et al. 1998, Pereira, Medeiros and Dinis-Ribeiro 2009). COX-2, on the other hand, is strictly regulated and tends to spike during inflammation and other stress (Cesario, Rocca and Rutella 2011). Abundance of COX-2 has been linked to the growth and proliferation of cancerous and pre-cancerous cells (Cesario et al. 2011, Khan et al. 2011). Inhibiting the COX pathways can alter cancerous and precancerous cells by decreasing angiogenesis and cell growth (Banu et al. 2007, Half, Sun and Sinicrope 2007, Ishizaki et al. 2006, Sheng et al. 1997, Suh et al. 2009, Tuynman et al. 2008, Zhang et al. 2009). In addition, COX inhibition enhances apoptosis and enables the immune system to recognize and target the cells for destruction (Hida et al. 2000, Ding, Tong and Adrian 2000, Hsu et al. 2000, Souza et al. 2000). While COX-2 inhibitors are still a promising drug for chemoprevention, they have not been approved as a standard chemo preventative agent yet. This is, in part, due to increased risk of stroke, gastrointestinal bleeding, and heart attack following administration of these agents (Marnett 2009, Menter, Schilsky and DuBois 2010, Psaty and Furberg 2005). Nevertheless, a number of clinical trials evaluating the clinical efficacy of aspirin in decreasing the risk of colon, lung, prostate and brain cancer are currently in progress (Rothwell et al. 2011). Five year follow up data suggests that aspirin dramatically reduces the risk of death from solid tumors and gastrointestinal cancers. The latent period before an effect on deaths was about 5 years for esophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and esophageal cancer, benefit was confined to adenocarcinomas. Benefit was unrelated to aspirin dose as long as the administered dose was 75 mg or upwards. Benefit was unrelated to sex or smoking, but increased with age (Rothwell et al. 2011).

Emerging research suggests that other systemic anti-inflammatory drugs may have antitumorigenic potential as well. For example, statins, which were initially developed for

via inflammation-based pathways (Colotta et al. 2009, Solinas et al. 2010, Klein and Glazer 2010). Inflammatory chemokines and cytokines such as *CCL2*, *CCL18,* and others have been implicated in such processes (Chen et al. 2011, Bonecchi, Locati and Mantovani 2011, Redon et al. 2010). It has been suggested that the tumor surrounding may contribute to tumor proliferation. Tumors have the ability to alter their stroma and support the development of both tumor cells and non-malignant cells (Polyak, Haviv and Campbell 2009). The tumor eventually escapes from the host immune system via activation of one or several molecular mechanisms that lead to inhibition of immune cell functions or to apoptosis of anti-tumor effector cells (Schreiber, Old and Smyth 2011). The ability to block tumor escape hinges on a better understanding of cellular and molecular pathways operating in the tumor microenvironment. Monitoring the change(s) in the tumor stroma such as those occurring in the mesenchymal stem cells within tumor stroma via molecular and cellular profiles as the tumor progresses allows for identification of cell or protein targets for cancer prevention and therapy (Karnoub et al. 2007). Increasingly, cancer treatments are being modified to include tumor surrounding as a therapeutic target, since the non-malignant cells are more genetically stable and less likely to evolve into drug resistant phenotypes. For example, aspirin inhibits COX-1, while Celebrex inhibits COX-2 (Chan, Ogino and Fuchs 2007, Harris et al. 2005, Cooper et al. 2010, Ghosh et al. 2010, Harris 2007, Koehne and Dubois 2004, Reddy 2007, Reddy and Rao 2005, Smith et al. 1998). COX-1 is produced in tissues throughout the body, and is known to mediate the production of prostaglandins, chemical messengers that control a number of physiological functions, such as lowering blood pressure, regulating body temperature and controlling inflammation (Kundu and Fulton 2002, Smith et al. 1998, Pereira, Medeiros and Dinis-Ribeiro 2009). COX-2, on the other hand, is strictly regulated and tends to spike during inflammation and other stress (Cesario, Rocca and Rutella 2011). Abundance of COX-2 has been linked to the growth and proliferation of cancerous and pre-cancerous cells (Cesario et al. 2011, Khan et al. 2011). Inhibiting the COX pathways can alter cancerous and precancerous cells by decreasing angiogenesis and cell growth (Banu et al. 2007, Half, Sun and Sinicrope 2007, Ishizaki et al. 2006, Sheng et al. 1997, Suh et al. 2009, Tuynman et al. 2008, Zhang et al. 2009). In addition, COX inhibition enhances apoptosis and enables the immune system to recognize and target the cells for destruction (Hida et al. 2000, Ding, Tong and Adrian 2000, Hsu et al. 2000, Souza et al. 2000). While COX-2 inhibitors are still a promising drug for chemoprevention, they have not been approved as a standard chemo preventative agent yet. This is, in part, due to increased risk of stroke, gastrointestinal bleeding, and heart attack following administration of these agents (Marnett 2009, Menter, Schilsky and DuBois 2010, Psaty and Furberg 2005). Nevertheless, a number of clinical trials evaluating the clinical efficacy of aspirin in decreasing the risk of colon, lung, prostate and brain cancer are currently in progress (Rothwell et al. 2011). Five year follow up data suggests that aspirin dramatically reduces the risk of death from solid tumors and gastrointestinal cancers. The latent period before an effect on deaths was about 5 years for esophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and esophageal cancer, benefit was confined to adenocarcinomas. Benefit was unrelated to aspirin dose as long as the administered dose was 75 mg or upwards. Benefit was unrelated to sex or

smoking, but increased with age (Rothwell et al. 2011).

Emerging research suggests that other systemic anti-inflammatory drugs may have antitumorigenic potential as well. For example, statins, which were initially developed for cholesterol management, has been shown to disrupt the growth and proliferation of cancer cells such as prostate cancer (Kochuparambil et al. 2011). This has been verified in clinical trials as well where the use of statin drugs was linked with a reduced risk of advanced, especially metastatic or fatal, prostate cancer (Platz et al. 2006).

#### **4.2 Estrogen signaling**

Other small molecules, such as metformin and tamoxifen, demonstrate anti-tumor activity against breast cancer (Goodwin, Ligibel and Stambolic 2009, Jiralerspong et al. 2009, Osborne 1998). Raloxifene and tamoxifen have been shown to cut down the risk of estrogenreceptor positive breast cancers by as much as 50% (Vogel et al. 2006). Tamoxifen, a selective estrogen receptor modulator, has demonstrated benefit when used alone as well as in combination with chemotherapy to treat advanced breast cancer. It reduces circulating insulin-like growth factor-1, inhibits angiogenesis, and induces apoptosis (Li et al. 2009). It is also efficacious in reducing tumor recurrence and prolonging survival when administered as postoperative adjuvant therapy in stages I and II disease. In a randomized breast cancer prevention clinical trial to evaluate the worth of taking tamoxifen for the prevention of breast cancer in women considered to be at increased risk for the disease, tamoxifen prevented the appearance of a substantial number of breast cancers (Fisher et al. 1998). Tamoxifen administered daily for at least 5 years prevented invasive breast cancer in women at increased risk (Fisher et al. 1998). Women who took tamoxifen also had fewer diagnoses of noninvasive breast tumors, such as lobular carcinoma in situ. The study found that though tamoxifen reduced the occurrence of estrogen receptor-positive tumors, it had no effect on the occurrence of estrogen receptor-negative tumors (Fisher et al. 2005). Tamoxifen is available in the United States for the reduction of breast cancer incidence in high-risk premenopausal and postmenopausal women.

Raloxifene, another selective estrogen receptor modulator, has successfully been tested for the treatment and prevention of osteoporosis. Raloxifene hydrochloride is a selective estrogen receptor modulator that binds to estrogen receptors to competitively block estrogen-induced DNA transcription (Grese et al. 1997, Brzozowski et al. 1997). An evaluation of breast cancer incidence in women treated with raloxifene for the prevention of osteoporosis showed a 75% decrease in invasive breast cancer, and, as with tamoxifen, only the estrogen receptor positive disease is reduced (Martino et al. 2004, Cummings et al. 1999). These data emphasize the fact that these drugs target the estrogen receptor-mediated growth mechanism. These data validate the original hypothesis that a non-steroidal antiestrogen in the same class as tamoxifen could be used not only to prevent osteoporosis but also to prevent breast cancer as a beneficial side effect.

#### **4.3 Androgen signaling**

Similar to other cancers, prostate cancer chemoprevention involves the use of natural and synthetic agents that inhibit or reverse the development of precancerous lesions or delay progression of these lesions to invasive disease. Since androgens are involved in the development of prostate cancer, they are an obvious chemotherapeutic target. Finasteride, an inhibitor of 5α-reductase, inhibits the conversion of testosterone to dihydrotestosterone, the primary androgen in the prostate (Thompson et al. 2003). A phase III trial for prostate cancer prevention, the Prostate Cancer Prevention Trial using the drug finasteride,

Finally, calcium may also improve signaling within cells and cause tumor cells to differentiate and undergo cell death (Varani 2011, Roberts-Thomson, Curry and Monteith

Retinoids such as all-trans retinoic acid and 9-cis retinoic acid are derivatives of vitamin A that play a pivotal role in a diverse group of biologic processes including cellular proliferation, differentiation, apoptosis, and development (Sporn and Roberts 1983). Retinoic acids have been studied intensively for their anticancer effects, which are exerted through a wide range of mechanisms. All-trans-retinoic acid-based differentiation therapy which slows proliferation and induces differentiation is utilized in acute promyelocytic leukemia (Reichman et al. 1997). Relapse of this subtype of leukemia is often associated with acquired resistance to retinoid maturation induction. In addition to leukemia, retinoids have been shown to be efficacious in the prevention of breast, cervical, neural, and hematological

hTERT up-regulation has long been known as a key element in tumorigenesis, vital to the immortality of cancer cells. Treatment with the retinoid 9cUAB30, a synthetic analog of 9 cis-retinoic acid, leads to downregulation of hTERT expression, decrease in telomerase activity, and induction of apoptosis of leukemic cells (Love et al. 2008). The compound has also demonstrated beneficial effects against breast cancer (Hansen et al. 2007). These findings strongly support the use of 9cUAB30 as a chemo preventative agent. A first in human pharmacokinetic study with this compound was recently completed and further

A number of other compounds have shown promise based on anti-cancer effects and low toxicity. With most solid-tumor cancers, the biggest threat is not the tumor itself but its ability to metastasize. Genistein, a soy isoflavone has been promising in preventing metastasis of prostate cancer by preventing the activation of the focal adhesion kinase and decreasing the levels of matrix metalloproteinase-2 (MMP-2) (Li et al. 2006, Huang et al.

Curcumin, a molecule derived from turmeric, has potential anti-cancer activity as well (Wilken et al. 2011). Curcumin inhibits proliferation and induces apoptosis in cancer cells via suppression of the AKT pathway (Wong et al. 2011, Sun et al. 2010, Duarte et al. 2010, Saini et al. 2011, Prakobwong et al. 2011, Zanotto-Filho et al. 2011, Sreekanth et al. 2011). Moreover, it decreases cell growth via inactivation of NF-κB, preventing DNA binding, nuclear translocation, and p65 phosphorylation. Curcumin also suppresses activation of STAT-3 as indicated by decreased phosphorylation and inhibition of JAK1 phosphorylation (Rajasingh et al. 2006, Zhang et al. 2010, Saydmohammed, Joseph and Syed 2010, Bill et al. 2010). Moreover, curcumin induces expression of peroxisome proliferator activated receptor gamma and upregulates death receptors, DR4 and DR5. Curcumin also inhibits expression of cell survival proteins such as Bcl-2, Bcl-xl, XIAP, cFLIP, cIAP-1, cIAP-2, and survivin, and proteins linked to cell proliferation, such as cyclin D1 and c-Myc (Bava et al. 2010, Glienke et al. 2010, Prakobwong et al. 2011, Watson et al. 2009, Fossey et al. 2011). The growth

2005, Kumi-Diaka et al. 2010, El Touny and Banerjee 2009, Xu et al. 2009).

cancers (Casillas et al. 2003, Choi et al. 2000, Ding et al. 2002, Sanborn et al. 2000).

2011, Fedirko et al. 2009, Peterlik, Grant and Cross 2009).

**4.5 Retinoids** 

research is currently underway.

**4.6 Potential chemo preventative agents** 

suggested that this chemopreventive agent can reduce the risk of developing prostate cancer (Thompson et al. 2003). In this clinical trial, 18,882 men 55 years of age or older with a normal digital rectal examination and a prostate-specific antigen level of 3.0 ng per milliliter or lower were randomly assigned to treatment with Finasteride (5 mg per day) or placebo for seven years. The primary end point was the prevalence of prostate cancer during the seven years of the study and a 24% reduction in incidence of prostate cancer was observed in the treatment arm. However, the incidence of high-grade tumors was higher in men receiving finasteride compared to those on placebo (Thompson et al. 2003).

#### **4.4 Vitamin D**

Another molecule that has shown great chemopreventive potential is vitamin D. Vitamin D promotes the differentiation and apoptosis of cancer cells, slowing down their proliferation. It has been previously reported that Vitamin D has anti-proliferative effects in prostate cancer and mechanism of action involves nuclear exclusion of cyclin dependent kinase 2 (CDK2) and increase in p27 levels, an inhibitor of CDK2. This results in G1 cell cycle arrest of tumor cells (Yang and Burnstein 2003, Yang et al. 2002). Supplemental vitamin D intake or synthesis of vitamin D has the potential to reduce the incidence and death rates of colon, breast, prostate, and ovarian cancers (Manson, Mayne and Clinton 2011). A number of studies have established the association between vitamin D and its metabolites and cancer. It has long been observed that cancer rates were lower among people living in southern latitudes compared to similar groups in northern latitudes. Long-term studies have confirmed the efficacy of moderate intake of vitamin D in reducing cancer risk and, when administered with calcium, in reducing the incidence of fractures. Calcitriol, the hormonally active form of vitamin D, is being actively evaluated in clinical trials as an anti-cancer agent (Crescioli et al. 2004, Scher et al. 2011). Besides anti-proliferative, pro-apoptotic, and prodifferentiating actions on various malignant cells and decreasing tumor growth in vivo, calcitriol also exhibits several anti-inflammatory effects including suppression of prostaglandin action, inhibition of p38 stress kinase signaling, and the subsequent production of pro-inflammatory cytokines and inhibition of NF-κB signaling (Krishnan et al. 2011). Calcitriol also decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis in breast cancer, both by a direct transcriptional repression and indirectly by reducing prostaglandins, which are major stimulators of aromatase transcription (Diaz et al. 2009, Swami et al. 2011, Zanatta et al. 2011, Krishnan et al. 2009). Other important effects include the suppression of tumor angiogenesis, invasion, and metastasis (Krishnan and Feldman 2010, Krishnan and Feldman 2009, So et al. 2010, Krishnan et al. 2010, Chung et al. 2009, Ma, Trump and Johnson 2010). These calcitriol actions provide a basis for its potential use in cancer therapy and chemoprevention.

As mentioned above, calcium supplementation has great anti-tumorigenic potential as well (Lappe et al. 2007). Multiple theories exist on the mechanism of anti-tumor activity of calcium. Calcium binds to bile acids and fatty acids in the gastrointestinal tract to form insoluble complexes known as calcium soaps. This reduces the ability of the acids to damage cells in the lining of the colon and stimulate cell proliferation to repair the damage (Newmark, Wargovich and Bruce 1984, Pence 1993, Suzuki and Mitsuoka 1992, Wargovich, Lynch and Levin 1991). Calcium may also act directly to reduce cell proliferation in the lining of the colon or cause proliferating colon cells to undergo differentiation, which, in turn, leads to a reduction in cell proliferation (Boyce and Ham 1983, Hennings et al. 1980). Finally, calcium may also improve signaling within cells and cause tumor cells to differentiate and undergo cell death (Varani 2011, Roberts-Thomson, Curry and Monteith 2011, Fedirko et al. 2009, Peterlik, Grant and Cross 2009).

#### **4.5 Retinoids**

80 Cancer Prevention – From Mechanisms to Translational Benefits

suggested that this chemopreventive agent can reduce the risk of developing prostate cancer (Thompson et al. 2003). In this clinical trial, 18,882 men 55 years of age or older with a normal digital rectal examination and a prostate-specific antigen level of 3.0 ng per milliliter or lower were randomly assigned to treatment with Finasteride (5 mg per day) or placebo for seven years. The primary end point was the prevalence of prostate cancer during the seven years of the study and a 24% reduction in incidence of prostate cancer was observed in the treatment arm. However, the incidence of high-grade tumors was higher in men

Another molecule that has shown great chemopreventive potential is vitamin D. Vitamin D promotes the differentiation and apoptosis of cancer cells, slowing down their proliferation. It has been previously reported that Vitamin D has anti-proliferative effects in prostate cancer and mechanism of action involves nuclear exclusion of cyclin dependent kinase 2 (CDK2) and increase in p27 levels, an inhibitor of CDK2. This results in G1 cell cycle arrest of tumor cells (Yang and Burnstein 2003, Yang et al. 2002). Supplemental vitamin D intake or synthesis of vitamin D has the potential to reduce the incidence and death rates of colon, breast, prostate, and ovarian cancers (Manson, Mayne and Clinton 2011). A number of studies have established the association between vitamin D and its metabolites and cancer. It has long been observed that cancer rates were lower among people living in southern latitudes compared to similar groups in northern latitudes. Long-term studies have confirmed the efficacy of moderate intake of vitamin D in reducing cancer risk and, when administered with calcium, in reducing the incidence of fractures. Calcitriol, the hormonally active form of vitamin D, is being actively evaluated in clinical trials as an anti-cancer agent (Crescioli et al. 2004, Scher et al. 2011). Besides anti-proliferative, pro-apoptotic, and prodifferentiating actions on various malignant cells and decreasing tumor growth in vivo, calcitriol also exhibits several anti-inflammatory effects including suppression of prostaglandin action, inhibition of p38 stress kinase signaling, and the subsequent production of pro-inflammatory cytokines and inhibition of NF-κB signaling (Krishnan et al. 2011). Calcitriol also decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis in breast cancer, both by a direct transcriptional repression and indirectly by reducing prostaglandins, which are major stimulators of aromatase transcription (Diaz et al. 2009, Swami et al. 2011, Zanatta et al. 2011, Krishnan et al. 2009). Other important effects include the suppression of tumor angiogenesis, invasion, and metastasis (Krishnan and Feldman 2010, Krishnan and Feldman 2009, So et al. 2010, Krishnan et al. 2010, Chung et al. 2009, Ma, Trump and Johnson 2010). These calcitriol actions provide a basis for its potential

As mentioned above, calcium supplementation has great anti-tumorigenic potential as well (Lappe et al. 2007). Multiple theories exist on the mechanism of anti-tumor activity of calcium. Calcium binds to bile acids and fatty acids in the gastrointestinal tract to form insoluble complexes known as calcium soaps. This reduces the ability of the acids to damage cells in the lining of the colon and stimulate cell proliferation to repair the damage (Newmark, Wargovich and Bruce 1984, Pence 1993, Suzuki and Mitsuoka 1992, Wargovich, Lynch and Levin 1991). Calcium may also act directly to reduce cell proliferation in the lining of the colon or cause proliferating colon cells to undergo differentiation, which, in turn, leads to a reduction in cell proliferation (Boyce and Ham 1983, Hennings et al. 1980).

receiving finasteride compared to those on placebo (Thompson et al. 2003).

**4.4 Vitamin D** 

use in cancer therapy and chemoprevention.

Retinoids such as all-trans retinoic acid and 9-cis retinoic acid are derivatives of vitamin A that play a pivotal role in a diverse group of biologic processes including cellular proliferation, differentiation, apoptosis, and development (Sporn and Roberts 1983). Retinoic acids have been studied intensively for their anticancer effects, which are exerted through a wide range of mechanisms. All-trans-retinoic acid-based differentiation therapy which slows proliferation and induces differentiation is utilized in acute promyelocytic leukemia (Reichman et al. 1997). Relapse of this subtype of leukemia is often associated with acquired resistance to retinoid maturation induction. In addition to leukemia, retinoids have been shown to be efficacious in the prevention of breast, cervical, neural, and hematological cancers (Casillas et al. 2003, Choi et al. 2000, Ding et al. 2002, Sanborn et al. 2000).

hTERT up-regulation has long been known as a key element in tumorigenesis, vital to the immortality of cancer cells. Treatment with the retinoid 9cUAB30, a synthetic analog of 9 cis-retinoic acid, leads to downregulation of hTERT expression, decrease in telomerase activity, and induction of apoptosis of leukemic cells (Love et al. 2008). The compound has also demonstrated beneficial effects against breast cancer (Hansen et al. 2007). These findings strongly support the use of 9cUAB30 as a chemo preventative agent. A first in human pharmacokinetic study with this compound was recently completed and further research is currently underway.

#### **4.6 Potential chemo preventative agents**

A number of other compounds have shown promise based on anti-cancer effects and low toxicity. With most solid-tumor cancers, the biggest threat is not the tumor itself but its ability to metastasize. Genistein, a soy isoflavone has been promising in preventing metastasis of prostate cancer by preventing the activation of the focal adhesion kinase and decreasing the levels of matrix metalloproteinase-2 (MMP-2) (Li et al. 2006, Huang et al. 2005, Kumi-Diaka et al. 2010, El Touny and Banerjee 2009, Xu et al. 2009).

Curcumin, a molecule derived from turmeric, has potential anti-cancer activity as well (Wilken et al. 2011). Curcumin inhibits proliferation and induces apoptosis in cancer cells via suppression of the AKT pathway (Wong et al. 2011, Sun et al. 2010, Duarte et al. 2010, Saini et al. 2011, Prakobwong et al. 2011, Zanotto-Filho et al. 2011, Sreekanth et al. 2011). Moreover, it decreases cell growth via inactivation of NF-κB, preventing DNA binding, nuclear translocation, and p65 phosphorylation. Curcumin also suppresses activation of STAT-3 as indicated by decreased phosphorylation and inhibition of JAK1 phosphorylation (Rajasingh et al. 2006, Zhang et al. 2010, Saydmohammed, Joseph and Syed 2010, Bill et al. 2010). Moreover, curcumin induces expression of peroxisome proliferator activated receptor gamma and upregulates death receptors, DR4 and DR5. Curcumin also inhibits expression of cell survival proteins such as Bcl-2, Bcl-xl, XIAP, cFLIP, cIAP-1, cIAP-2, and survivin, and proteins linked to cell proliferation, such as cyclin D1 and c-Myc (Bava et al. 2010, Glienke et al. 2010, Prakobwong et al. 2011, Watson et al. 2009, Fossey et al. 2011). The growth

 DC-Vax Prostate Onyvax-P

CYT004-MelQbG10

GVAX leukemia

IMA901IMA910

Ii-Key/HER2/neu cancer vaccine

NeuVax

 Lucanix IDM-2101 Stimuvax GV1001

 DC-Vax Brain HSPPC-96 Oncophage

CDX-110

GV1001

Vaginal HPV vaccine (Gardasil and Cervarix) Vulvar HPV vaccine (Gardasil and Cervarix) Anal HPV vaccine (Gardasil and Cervarix) Penile HPV vaccine (Gardasil and Cervarix) Oropharyngeal HPV vaccine (Gardasil and Cervarix)

Table 3. Preventive and therapeutic cancer vaccines either in clinical trial or approved for

MAGE-A3 antigen-specific cancer immunotherapeutic

 M-vax Uvidem M3TK

**Type Cancer Vaccine**

Prostate Provenge

Melanoma Oncophage

Leukemia GRNVAC1

Bladder Bexidem Colorectal Collidem

Breast INGN 225

Lung INGN 225

Brain Oncophage

Pancreatic GVAX pancreatic

Renal IMA901IMA910

**Preventive** Cervical HPV vaccine (Gardasil and Cervarix)

Ovarian CVac

Lymphoma Biovax ID

Liver GV1001

Liver Hepatitis B

clinical use.

Colorectal MUC1 - poly-ICLC

**Therapeutic** Kidney Oncophage

inhibitory effects of curcumin are enhanced in the IKK deficient cells, the enzyme required for NF-κB activation (Prakobwong et al. 2011). Thus, curcumin mediates its antiproliferative and apoptotic effects through activation of multiple cell signaling pathways, and thus its anti-tumor activity is under active research. Curcumin blocks a number of targets involved in tumor initiation, promotion, and progression, and is considered a promising chemopreventive agent. Thus, among others, a phase II trial of curcuminoids' effect on cellular proliferation, apoptosis and COX-2 expression in the colorectal mucosa of subjects with recently resected sporadic adenomatous polyps is currently ongoing. Further research is warranted to evaluate the efficacy of cucumin in other cancers.
