**4.2 ENOX2 cloning and tissue distribution**

396 Cancer Prevention – From Mechanisms to Translational Benefits

cancer, the indications might be as much as 5 to 7 years before clinical symptoms based on the development time estimated for breast as well as lung cancer expression between a

Fig. 6. Interpretive diagram to illustrate the various stages of cancer progression (estimated to require as long as 20 y) beginning with a cancer-causing event (initiation) through

Cells in tissues and organs are continuously subjected to oxidative stress and free radicals as well as other potential cancer initiating events on a daily basis (Kryston et al., 2011). Cells normally withstand these attacks but some result in cancer causing events to initiate the rather long (est. 20 y) development phase prior to clinical symptoms (Fig. 6). Our hypothesis is that ENOX proteins being critical to the unregulated growth of cancer will be shed into sera well in advance of clinical symptoms as the rationale for the proposed early detection strategy. The essential role of ENOX2 in unregulated cancer growth provides the basis for

Early detection coupled with early intervention as diagrammed in Figure 1 raises the possibility of an important paradigm shift in cancer management toward early diagnosis and treatment options vastly different from those currently employed to deal primarily with advanced cancer. Consequently, the treatment of cancer might evolve from a primarily acute to a more chronic setting with monitoring and less invasive treatments. Reducing surgery, radiation and chemotherapy, as well as shortened hospital stays based on less invasive and less costly interventions afforded by very early detection would be expected to

have a significant impact on reducing health care costs world wide.

development of a clinically defined malignancy.

**4. Discussion 4.1 Significance** 

early intervention.

cancer causing event and clinically evident disease (Weinberg, 2007).

ENOX2 was expression cloned (Chueh et al., 2002) (Genbank Accession No. AF207881) using a monoclonal antibody that recognizes only a common ENOX2 epitope near the cancer drug-binding site (Cho et al., 2002) and from which the pan ENOX2 scFv recombinant antibody was derived (Kim, 2011). This binding site contains a conserved 5 amino acid (EMTEE) motif (Table 2). Based on biochemical (drug inhibition of activity) and immunological evidence, this EEMTE drug binding motif in Exon 5 appears to be common to all ENOX2 forms and absent from the amino acid sequence of the constitutive ENOX1 proteins characteristic of both cancer and non-cancer cells.

The presence of ENOX2 proteins in sera of cancer patients represents an origin due to shedding from the patient's cancer (Wilkinson et al., 1996). The presence of the ENOX2 proteins has been demonstrated in a number of human tumor tissues and xenografts (mammary carcinoma, prostate cancer, neuroblastoma, colon carcinoma, and melanoma). However, serum analysis indicates a much broader association with cancer. ENOX2 proteins are ectoproteins reversibly bound at the outer leaflet of the plasma membrane (Morré, l995). As is characteristic of other examples of ectoproteins (sialyl and galactosyl transferases, dipeptidylamino peptidase IV, etc.), the ENOX2 proteins are shed, appearing in soluble form in conditioned media of cultured cells and in patient sera (Wilkinson et al., 1996; Morré et al., 1997). The ENOX2 transcript variants from sera exhibit the same degree of drug responsiveness as do the membrane-associated forms (Morré and Reust, 1997; Morré et al., 1997). With sera from more than 200 breast cancer patients, the majority (ca. 196), were found to exhibit the drug-responsive activity. In contrast, no drug-responsive activities were found with sera from healthy volunteers or sera from patients with diseases other than cancer (cardiac, arthritis and other inflammatory diseases, gastric ulceration, emphysema, various non-malignant blood disorders). As such the antitumor drug-responsive ENOX2 activities represent novel cell surface properties potentially associated with most, if not all, forms of human cancer to confirm their appropriateness as appropriate biomarkers for serum or plasma detection and diagnosis of cancer. ENOX2 proteins are robust and highly resistant to heat and protein degradation which enhances their utility as non-invasive markers for cancer detection and diagnosis (Morré and Morré, 2003a).

ENOX2 proteins are absent or present at levels below the limits of detection (less than 10 picomoles/ml of serum) from sera of healthy volunteers or patients with diseases other than cancer. Circulating ENOX2 has been detected based on drug response of ENOX activity of sera of more than 500 cancer patients representing all major forms of human cancer including leukemias and lymphomas (Morré and Reust, l997; Morré et al., l997).

Early Detection: An Opportunity for Cancer Prevention Through Early Intervention 399

replaced by EGCg-free media, even after 8 h, cancer cells in vivo resume normal rates of growth. Similarly, normal rates of growth are resumed as EGCg is cleared from the culture medium and/or metabolized. Even in cell culture, the EGCg may not survive in the media for more that a few h at nanomolar concentrations. The cancer cells in vitro must be inhibited from growing for at least 48 and perhaps up to 72 h in order for apoptosis to be

Feasibility of an efficacious dosing schedule is indicated from studies with rats (Janle et al., 2008). The results from the animal study are consistent with epidemiological studies in humans and animal experiments where cancer benefit has been ascribed to drinking at least 10 cups of green tea per day without adverse effects (Fujiki, l999; Nakachi et al., 2000). Green tea polyphenols are absorbed after oral administration and reach their highest plasma levels after about l to 2 h after dosing both in rats (Unno and Takeo, l995; Zhu et al., 2000; Janle et al., 2008) and in humans (Warden et al., 200l). In the rat, the levels of EGCg reached of 12.3 nmoles/ml in plasma (12.3 µmolar) 60 min after a single oral administration of 500 mg/kg body weight of EGCg (Nakagawa, l997), which is more than l00 times the effective dose to stop the growth of tumor cells. The studies by Yang (l997) show that the concentration of

EGCg in the blood after 2-3 cups of green tea reached a maximum of about 0.6 µM.

In human studies of ingested catechins, 0.2% of the ingested EGCg and 0.2% to l.3% of ingested (-)-epigallocatechin (EGC) were found in plasma 90 min after ingestion (Nakagawa et al. 1997). Van het Hof et al. (1999) determined the half life for plasma levels of individuals drinking 8 cups of tea per day for 3 days to be 4.8 h for green tea and 6.9 h for black tea. After ingestion of green tea by human volunteers, Cmax values were observed 1.4 to 2.4 h after injection with a half life of 5 to 5.5 h (Yang et al., 1998). These observations provided the rational basis for dosing at regular intervals of 4 h with the Capsol-T product. Formulated for sustained release, the expectation is that two 500 mg capsules of 50% material per day, one in the morning and one in the evening will prove to be sufficient.

Tea catechins especially EGCg in combination with *Capsicum* have been characterized as specific ENOX2 inhibitors inducing apoptotic cell death in cancer but not in non-cancer cells (Morré et al., 2000; Chueh et al., 2004; Morré et al., 2009a). Safety and efficacy are well documented (Cooper et al., 2005). Safety has been the subject of a series of reports dealing with genotoxic, acute, dermal, sub-chronic short-term, teratogenic and reproductive assays (e.g. Isbrucker et al., 2006a,b,c). Capsol-T is both caffeine- and vitamin K-free and free of herbicide, pesticide and/or heavy metal residues. Tea as a food form is generally recognized as safe by the U.S. Food and Drug Administration (National

Oral green tea extracts have been studied in human cancer patients. Pisters et al. (2001) did a phase 1 study with a commercially available but not decaffeinated green tea source given 1 or 3 times daily for 4 weeks to 6 months Doses of 0.5 to 5.05 g/m2 per day and l.0-2.2 g/m2 three times per day were tested in 49 cancer patients. The maximum tolerated dose of 4.22 g/m2 was limited primarily by caffeine levels easily avoided with decaffeinated green tea. In a series of open label sequential trials with Capsol-T summarized by Morré and Morré (2006), 36% of participants with advanced cancer reported significant prolongation of life and/or remained alive at the time of the analysis. Another 32 reported improvement while the remaining 32% experienced a normal course of their disease. Most in the last category were diagnosed very late in the development of their disease such that an inability even to

induced by EGCg in a majority of the cancer cells present.

Cancer Institute Fact Sheet).

### **4.3 Very early detection and diagnosis is unique to ENOX2 transcript variants**

Many cancers are detected only after clinical symptoms present and often after the cancer has spread leaving chemotherapy as perhaps the only resource for treatment. Tomographic or x-ray methods may detect before clinical symptoms present but only after a tumor mass has already formed. There appear to be few, if any, on-going indications of opportunities either for early cancer detection or for early intervention. Various genomic, transcriptomic and/or proteomic analyses, while of potential utility for tissue analyses of biopsy material, have thus far failed to provide new and reliable non-invasive serum indicators of cancer occurrence (Goncalves and Bertucci, 2011) despite continued promise offered by circulating microRNAs (Wu et al., 2011). A relatively small percentage of all cancers can be attributed to predisposing genes such as *BRACA1, BRACA2* and less frequently *p53* and *PTEN* (Lee et al., 2010) for 5 to 10% of all breast cancers. While indicative of cancer risk, predisposing genes do not necessarily signal cancer presence.

#### **4.4 Early intervention strategy based on green tea-** *Capsicum* **synergies**

The potential benefits of early detection will not be fully realized without some opportunity for early curative or preventive intervention. As an early intervention strategy, findings suggest that a decaffeinated green tea extract containing 98% tea catechins of which 40% are EGCg and a *Capsicum* powder in the ratio of 25 parts tea extract plus l part *Capsicum* powder, available on line as Capsol-T (www.Capsol-T.com) and under commercial development by Stratum Nutrition, a division of Novus International, St. Charles, Mo under the brand name TeaFense may induce apoptosis as a means to eliminate early stage cancer when only a small number of cells are present prior to development of clinical symptoms. The ENOX proteins are responsible for the increase in cell size following cell division. After cell division, a minimum cell size must be reached or cell division stops and after several days, the cells undergo programmed cell death (apoptosis). Cancer cells with blocked ENOX2 activity are not able to enlarge and are thus directed towards apoptosis. The growth inhibition is due mainly to cell cycle arrest in Gl (stage of cell division before DNA is replicated). EGCg inhibits growth of cancer cells in culture and in implanted tumors in mice (Li et al., 2010). The growth of implanted tumors was inhibited in a dose-dependent manner at doses of 0.l%, 0.3% and 0.5% in the diet.

Morré and Morré (2003b) have described synergy of decaffeinated green tea and a commercially available *Capsicum* preparations containing anti-cancer vanilloids (Capsibiol-T) at a ratio of 25:l which resulted in a 100-fold increase in killing of cultured cancer cell lines compared to green tea alone. The current food grade *Capsicum*-green tea product (Capsol-T) gives equivalent results. EGCg, when combined with other catechins also found in green tea, is superior to EGCg alone (Morré et al., 2003).

Evidence from laboratory studies with cancer cells in culture indicate that one 250 mg capsule of Capsol-T every 4 h is equivalent to drinking l6 cups of green tea every 4 h. The need for l capsule of Capsol-T every 4 h is predicated on pharmacokinetic information (Janle et al., 2008) and the knowledge that the inhibition of ENOX2 by Capsol-T is reversible (Morré et al., 2000). In order to have therapeutic efficacy in selective killing of cancer cells, findings with cultured cancer cells show that the catechins must be present in the culture medium at a level of about 100 nM and to inhibit ENOX2 continuously at that level for a period of 48 to 72 h (Morré et al., 2000). If EGCg, for example, is removed and

Many cancers are detected only after clinical symptoms present and often after the cancer has spread leaving chemotherapy as perhaps the only resource for treatment. Tomographic or x-ray methods may detect before clinical symptoms present but only after a tumor mass has already formed. There appear to be few, if any, on-going indications of opportunities either for early cancer detection or for early intervention. Various genomic, transcriptomic and/or proteomic analyses, while of potential utility for tissue analyses of biopsy material, have thus far failed to provide new and reliable non-invasive serum indicators of cancer occurrence (Goncalves and Bertucci, 2011) despite continued promise offered by circulating microRNAs (Wu et al., 2011). A relatively small percentage of all cancers can be attributed to predisposing genes such as *BRACA1, BRACA2* and less frequently *p53* and *PTEN* (Lee et al., 2010) for 5 to 10% of all breast cancers. While indicative of cancer risk, predisposing genes

The potential benefits of early detection will not be fully realized without some opportunity for early curative or preventive intervention. As an early intervention strategy, findings suggest that a decaffeinated green tea extract containing 98% tea catechins of which 40% are EGCg and a *Capsicum* powder in the ratio of 25 parts tea extract plus l part *Capsicum* powder, available on line as Capsol-T (www.Capsol-T.com) and under commercial development by Stratum Nutrition, a division of Novus International, St. Charles, Mo under the brand name TeaFense may induce apoptosis as a means to eliminate early stage cancer when only a small number of cells are present prior to development of clinical symptoms. The ENOX proteins are responsible for the increase in cell size following cell division. After cell division, a minimum cell size must be reached or cell division stops and after several days, the cells undergo programmed cell death (apoptosis). Cancer cells with blocked ENOX2 activity are not able to enlarge and are thus directed towards apoptosis. The growth inhibition is due mainly to cell cycle arrest in Gl (stage of cell division before DNA is replicated). EGCg inhibits growth of cancer cells in culture and in implanted tumors in mice (Li et al., 2010). The growth of implanted tumors was inhibited in a dose-dependent manner

Morré and Morré (2003b) have described synergy of decaffeinated green tea and a commercially available *Capsicum* preparations containing anti-cancer vanilloids (Capsibiol-T) at a ratio of 25:l which resulted in a 100-fold increase in killing of cultured cancer cell lines compared to green tea alone. The current food grade *Capsicum*-green tea product (Capsol-T) gives equivalent results. EGCg, when combined with other catechins also found in green

Evidence from laboratory studies with cancer cells in culture indicate that one 250 mg capsule of Capsol-T every 4 h is equivalent to drinking l6 cups of green tea every 4 h. The need for l capsule of Capsol-T every 4 h is predicated on pharmacokinetic information (Janle et al., 2008) and the knowledge that the inhibition of ENOX2 by Capsol-T is reversible (Morré et al., 2000). In order to have therapeutic efficacy in selective killing of cancer cells, findings with cultured cancer cells show that the catechins must be present in the culture medium at a level of about 100 nM and to inhibit ENOX2 continuously at that level for a period of 48 to 72 h (Morré et al., 2000). If EGCg, for example, is removed and

**4.3 Very early detection and diagnosis is unique to ENOX2 transcript variants** 

**4.4 Early intervention strategy based on green tea-** *Capsicum* **synergies** 

do not necessarily signal cancer presence.

at doses of 0.l%, 0.3% and 0.5% in the diet.

tea, is superior to EGCg alone (Morré et al., 2003).

replaced by EGCg-free media, even after 8 h, cancer cells in vivo resume normal rates of growth. Similarly, normal rates of growth are resumed as EGCg is cleared from the culture medium and/or metabolized. Even in cell culture, the EGCg may not survive in the media for more that a few h at nanomolar concentrations. The cancer cells in vitro must be inhibited from growing for at least 48 and perhaps up to 72 h in order for apoptosis to be induced by EGCg in a majority of the cancer cells present.

Feasibility of an efficacious dosing schedule is indicated from studies with rats (Janle et al., 2008). The results from the animal study are consistent with epidemiological studies in humans and animal experiments where cancer benefit has been ascribed to drinking at least 10 cups of green tea per day without adverse effects (Fujiki, l999; Nakachi et al., 2000). Green tea polyphenols are absorbed after oral administration and reach their highest plasma levels after about l to 2 h after dosing both in rats (Unno and Takeo, l995; Zhu et al., 2000; Janle et al., 2008) and in humans (Warden et al., 200l). In the rat, the levels of EGCg reached of 12.3 nmoles/ml in plasma (12.3 µmolar) 60 min after a single oral administration of 500 mg/kg body weight of EGCg (Nakagawa, l997), which is more than l00 times the effective dose to stop the growth of tumor cells. The studies by Yang (l997) show that the concentration of EGCg in the blood after 2-3 cups of green tea reached a maximum of about 0.6 µM.

In human studies of ingested catechins, 0.2% of the ingested EGCg and 0.2% to l.3% of ingested (-)-epigallocatechin (EGC) were found in plasma 90 min after ingestion (Nakagawa et al. 1997). Van het Hof et al. (1999) determined the half life for plasma levels of individuals drinking 8 cups of tea per day for 3 days to be 4.8 h for green tea and 6.9 h for black tea. After ingestion of green tea by human volunteers, Cmax values were observed 1.4 to 2.4 h after injection with a half life of 5 to 5.5 h (Yang et al., 1998). These observations provided the rational basis for dosing at regular intervals of 4 h with the Capsol-T product. Formulated for sustained release, the expectation is that two 500 mg capsules of 50% material per day, one in the morning and one in the evening will prove to be sufficient.

Tea catechins especially EGCg in combination with *Capsicum* have been characterized as specific ENOX2 inhibitors inducing apoptotic cell death in cancer but not in non-cancer cells (Morré et al., 2000; Chueh et al., 2004; Morré et al., 2009a). Safety and efficacy are well documented (Cooper et al., 2005). Safety has been the subject of a series of reports dealing with genotoxic, acute, dermal, sub-chronic short-term, teratogenic and reproductive assays (e.g. Isbrucker et al., 2006a,b,c). Capsol-T is both caffeine- and vitamin K-free and free of herbicide, pesticide and/or heavy metal residues. Tea as a food form is generally recognized as safe by the U.S. Food and Drug Administration (National Cancer Institute Fact Sheet).

Oral green tea extracts have been studied in human cancer patients. Pisters et al. (2001) did a phase 1 study with a commercially available but not decaffeinated green tea source given 1 or 3 times daily for 4 weeks to 6 months Doses of 0.5 to 5.05 g/m2 per day and l.0-2.2 g/m2 three times per day were tested in 49 cancer patients. The maximum tolerated dose of 4.22 g/m2 was limited primarily by caffeine levels easily avoided with decaffeinated green tea.

In a series of open label sequential trials with Capsol-T summarized by Morré and Morré (2006), 36% of participants with advanced cancer reported significant prolongation of life and/or remained alive at the time of the analysis. Another 32 reported improvement while the remaining 32% experienced a normal course of their disease. Most in the last category were diagnosed very late in the development of their disease such that an inability even to

Early Detection: An Opportunity for Cancer Prevention Through Early Intervention 401

Janle E, Morré DM, Morré DJ, Zhou Q, Chang H, Zhu Y: Pharmacokinetics of green tea

Kim C: Patent GB2442553B, Single chain pan ECTO-NOX variable region (ScFv) antibody,

Kryston TB, Georgiev A, Georgakilas AG: Role of oxidative stress and DNA damage in

Li GX, Chen YK, Hou Z, Xiao H, Jin H, Lu G, Lee MJ, Liu B, Guan F, Yang Z, Yu A, Yang CS:

Lee E, Park SK, Park B., Kim S-W, Lee MH, Ahn S-H, Son BH, Yoo K-Y, Kang D: Effect of

Morré DJ: NADH oxidase activity of HeLa plasma membranes inhibited by the antitumor

Morré DJ, Morré DM: Cell surface NADH oxidases (ECTO-NOX proteins) with roles in

Morré DJ, Morré DM: Synergistic *Capsicum*-tea mixtures with anticancer activity. J Pharm

Morré DJ, Morré DM: Catechin-vanilloid synergies with potential clinical applications in

Morré DJ, Reust T: A circulating form of NADH oxidase responsive to the antitumor

Morré DJ, Wilkinson FE, Kim C, Cho N, Lawrence J, Morré DM, McClure D: Antitumor

Morré DJ, Caldwell C, Mayorga A, Wu LY and Morré DM: NADH oxidase activity from

Morré DJ, Bridge A, Wu LY, Morré DM: Preferential inhibition by (-)-epigallocatechin-3-

Morré DJ, Morré DM, Sun H, Cooper R, Chang J, Janle EM: Tea catechin synergies in

Morré DJ, Geilen CC, Welch AM, Morré DM: Response of carcinoma in situ (actinic keratosis) to green tea concentrate plus *Capsicum*. J Dietary Suppl 6:385-389, 2009a. Morré DJ, Morré DM, Brightmore R: Omega-3 but not omega-6 unsaturated fatty acids

to sera from cancer patients. J Bioenerg Biomemb 29:281-289, 1997.

review and meta-analysis. Breast Cancer Res Treat 122:11-25, 2010.

external site. Biochim Biophys Acta 1240:201-208, 1995.

2008.

coding sequence and methods, 2011.

*in vitro*. Carcinogenesis 31:902-910, 2010.

Radic Res 37:795-808, 2003a.

cancer. Rejuv Res 9:45-55, 2006

Biochim Biophys Acta 1280:197-206, 1996.

culture. Biochem Pharmacol 60:937-946, 2000.

(ECTO-NOX). Pharmacol Toxicol 92:234-241, 2003.

constitutive ENOX1. J Dietary Suppl 7:154-158, 2009b.

Biochem Biophys 342: 224-230, 1997.

Pharm 55:987-994, 2003b.

human carcinogenesis. Mutat Res 711:193-201, 2011.

catechins in extract and sustained-release preparations. J Dietary Suppl 5:248-263,

Pro-oxidative activities and dose-response relationship of (-)-epigallocatechin-3 gallate in the inhibition of lung cancer cell growth: a comparative study *in vivo* and

*BRCA1/2* mutation on short-term and long-term breast cancer survival: a systematic

sulfonylurea N-(4-methylphenylsulfonyl)-N-(4-chlorophenyl)urea (LY181984) at an

cancer, cellular time-keeping, growth, aging and neurodegenerative diseases. Free

sulfonylurea N-4-methylphenylsulfonyl-N'-4-chlorophenylurea LY181984 specific

sulfonylurea-inhibited NADH oxidase of cultured HeLa cells shed into media.

sera altered by capsaicin is widely distributed among cancer patients. Arch

gallate of the cell surface NADH oxidase and growth of transformed cells in

inhibition of cancer cell proliferation and of a cancer-specific cell surface oxidase

inhibit the cancer-specific ENOX2 of the HeLa cell surface with no effect on the

comply with six capsule per day taken one every four hours became problematic. Preliminary human studies on patients (compassionate intervention) with severe head and neck carcinomas who were treated with a commercial preparation of the dietary supplement Capsibiol-T containing the mixture of decaffeinated green tea and modified chili peppers (*Capsicum* sp.), generated results that indicated a positive role for herbal mixtures of green tea and *Capsicum* for clinical use to eliminate cancer cells from the body (Fernandez et al., 2003).

#### **5. References**


comply with six capsule per day taken one every four hours became problematic. Preliminary human studies on patients (compassionate intervention) with severe head and neck carcinomas who were treated with a commercial preparation of the dietary supplement Capsibiol-T containing the mixture of decaffeinated green tea and modified chili peppers (*Capsicum* sp.), generated results that indicated a positive role for herbal mixtures of green tea and *Capsicum* for clinical use to eliminate cancer cells from the body (Fernandez et al.,

Altekruse SF, Kosary CL, Krapcho M, Neyman N, Aminou R, Waldron W, Ruhl J, Howlader

Cho N, Chueh PJ, Kim C, Caldwell S, Morré DM, Morré DJ: Monoclonal antibody to a

Chueh PJ, Kim C, Cho N, Morré DM, Morré DJ: Molecular cloning and characterization of a

oxidase (tNOX) of the HeLa cell surface. Biochemistry 41:3732-3741, 2002. Chueh, PJ, Wu, LY, Morré DM, Morré DJ: tNOX is both necessary and sufficient as a cellular

Cooper RD, Morré DJ, Morré DM: Medicinal benefits of green tea: Part II. Review of

Davies SL, Bozzo J: Spotlight on tNOX: A tumor-selective target for cancer therapies. Drug

De Luca T, Morré DM, Morré DJ: Reciprocal relationship between cytosolic NADH and

Fernandez, RF, Ganzon D: Use of green tea *Capsicum* supplement (Capsibiol-T) as adjuvant cancer treatment. Phillipine Soc Ontolaryngol Head Neck Surg 18:171-177, 2003 Fujiki H: Two stages of cancer prevention with green tea. J Cancer Res Clin Oncol 125:589-

Goncalves A, Bertucci F: Clinical application of proteomics in breast cancer: State of the art

Hostetler B, Kim C: Patent GB2441860. Detecting neoplasia specific tNOX isoforms, 2011. Hostetler B, Weston N, Kim C, Morré DM, Morré DJ: Cancer site-specific isoforms of ENOX2 (tNOX), a cancer-specific cell surface oxidse. Clin Proteomics 5:46-51, 2009 Isbrucker RA, Bausch J, Edwards JA, Wolz E: Safety studies on epigallocatechin gallate (EGCg) preparations. Part 1: Genotoxicity, Food Chem Toxicol 44:626-635, 2006a. Isbrucker RA, Edwards JA, Wolz E, Davidovich A, Bausch J: Safety studies on

of cancer patients. Cancer Immunol Immunother 51:121-129, 2002.

2007, National Cancer Institute. Bethesda, MD, 2010.

epigallocatechin-3-gallate. BioFactors 20:249-263, 2004.

and perspectives. Med Princ Pract 204:4-18, 2011.

toxicity studies. Food Chem Toxicol 44: 636-650, 2006b.

News Prospect 19:223-225, 2006.

Biochem 110:1504-1511, 2010.

597, 1999.

anticancer properties. J Altern Comp Med 11:639-652, 2005.

N, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Cronin K, Chen HS, Feuer EJ, Stinchcomb DG, Edwards BK (eds).: SEER Cancer Statistics Review, 1975-

cancer-specific and drug-responsive hydroquinone (NADH) oxidase from the sera

tumor-associated, growth-related, and time-keeping hydroquinone (NADH)

target for the anticancer actions of capsaicin and the green tea catechin (-)-

ENOX2 inhibition triggers sphingolipid-induced apoptosis in HeLa cells. J Cell

epigallocatechin gallate (EGCg) preparations. Part 2: Dermal, acute and short-term

epigallocatechin gallate (EGCg) preparations. Part 3. Teratogenicity and

Isbrucker RA, Edwards JA, Wolz E, Davidovich A, Bausch J: Safety studies on

reproductive toxicity studies in rats. Food Chem Toxicol 44:651-661, 2006c.

2003).

**5. References** 


**16** 

*USA* 

**Creating a Sustainable Cancer Workforce:** 

Maureen Y. Lichtveld, Lovell Jones, Alison Smith, Armin Weinberg,

Roy Weiner and Farah A. Arosemena

*Life Beyond Cancer Foundation* 

*Tulane University, MD Anderson Cancer Center, C-Change,* 

**Focus on Disparities and Cultural Competence** 

While the role of culture in addressing health care disparities in general and, cancer health disparities specifically is increasingly recognized, a systemic approach aimed at bolstering the cultural competence of our nation's health care workforce is absent. Among the health outcomes, the impact of this gap is most pronounced in cancer. Ample scientific evidence exists affirming that eliminating cancer health disparities requires a multi-sectorial approach. The lack of cultural competence among frontline providers - physicians, nurses, pharmacists, health educators – is only compounded by the cancer workforce crisis, a national threat to assuring quality cancer care to a growing vulnerable and increasingly culturally diverse global population. Traditional solutions to the health care workforce crisis in general and that of the cancer workforce specifically have largely failed because of a silorather than a systems approach, focusing on one specific segment of the workforce or one specific aspect of cancer care. Furthermore, much of those efforts were limited to addressing the quantitative aspect of the problem – increase the number of cancer care professionals, ignoring the equally important qualitative component- assuring a health care workforce, *competent* in providing cancer care across the cancer spectrum to culturally diverse

The cancer workforce is faced with various obstacles as cancer prevalence and mortality rates swell worldwide and cancer patients and survivors are directly affected by the shortage in a workforce to provide care. Compounding the shortfall in health prevention and clinical care, the disproportionate impact of cancer on minorities and disadvantaged populations has been apparent for decades with few innovative cancer care delivery models implemented. A growing body of evidence indicates that in addition to race, and geo-socioeconomic parameters, culture is a strong influencing factor on cancer outcomes.(Grouse 2005; Chin, Walters et al. 2007; Fisher, Burnet et al. 2007) Converting the role culture plays in eliminating cancer health disparities from a barrier to an asset, requires cultural competence from those providing care across the entire cancer care continuum – from

**1. Introduction** 

populations. (C-Change 2008; Lichtveld 2009)

prevention to survivorship. (Lichtveld 2009)

