**10. Summary**

aberrant crypt foci (ACF) indicates that oral dosing of curcumin (4g per day for 30 days) significantly reduces colorectal ACF, a biomarker of colon carcinogenesis. [416] The reported anti-carcinogenic effect of curcumin is not associated with increased levels of curcumin in local tissue but increased levels of conjugate concentrations in suggesting that curcumin may mediate its effects by cuccumin conjugates delivered systemically. The same study showed that the presence of curcumin conjugates in plasma and tissue prior to treatment (believed to be originated from the normal diet of the studied population) were accompanied by a steady increase of curcumin conjugates following the month-long daily dosing [416]. A study examining the pharmacokinetics of curcumin at the concentrations of 10g and 12g in twelve healthy volunteers indicates comparable results. Accordingly, a single dose of orally admin‐ istered curcumin resulted in the detection of conjugates, glucuronides and sulfates in plasma in all subjects while free curcumin was evident in only one subject [414]. Even though curcumin conjugates and other breakdown products have not been assessed for their anticarcinogenic properties [416], these findings shed some light on the potential of curcumin as a treatment of all cancers, including those of colorectal origin. This may offer a likely explanation of how continuous exposure to small quantities of curcumin via normal diets protects Asian women

376 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

A phase I dose escalation trial of combined effects of docetaxel and curcumin in patients with advanced and metastatic breast cancer was published very recently. This study involved 14 patients and demonstrated the feasibility, safety and tolerability of a combination of curcumin with a standard dose of docetaxel which warrants further investigation and progression to a Phase II clinical trial [417]. Similarly, the curcumin inhibiting effects of chemotherapy induced

The properties of CSC's are connected with major signaling pathways. The signaling pathways active in mammary stem cells are shown to be Wnt/β catenin, Hh and Notch [60],[51],[185],

A recent study by Karkarala *et al.* has demonstrated the potent inhibitory effect of curcumin and piperine on Wnt/β-catenin signaling in primary human breast epithelial cells [419]. In this study, inhibition of Wnt signaling pathway was shown to affect breast stem cell renewal by inhibiting the mammosphere formation. According to the authors, curcumin and piperine (separately and in combination) inhibited breast stem cell self-renewal; however toxicity to differentiated cells was not reported. The plasma concentration of curcumin in people taking high oral doses has been shown to be very low due to many reasons such as metabolism of the

The lack of bioavailability of curcumin was known as a potential disadvantage for years and various strategies have been investigated to overcome the problem. One such strategy has been the use of piperine in combination of curcumin. Accordingly, concomitant administration of piperine and curcumin tends to increase the bioavailability (up to 2000%) compared to

compound in the intestine and the liver, as reviewed by Burgos-Moron *et al.* [420].

apoptosis in models of human breast cancer have been identified [418].

*9.2.3. Curcumins' ability to destroy cancer stem cells*

from breast cancer.

[206],[269].

Considering the existence of CSC's in breast cancer, and the inability of current therapeutic approaches to destroy such, we propose targeting CSC's as a tool to investigate the effect of natural dietary compounds. Specifically, we suggest isolates of soy and turmeric, and their effects on breast cancer tumors and metastasis reoccurrence in breast cancer. Similar to other developmental agents aimed at cancer signaling pathways, the optimal dosing, dosing regimens and adverse effects will have to be refined. However, these prospects are notably different than conventional therapeutics in several ways and such should be contemplated upon exploring such molecules. For example, consider the complex cross-talk of both interand intra-cell signaling pathways and how feedback mechanism effects may eliminate inhibitors via the actions of a single pathway. Figure 2 summarizes targeted areas of interrup‐ tion via the major pathways involved in stem cell renewal as well as those pathways that may be responsible for downstream signaling to these major pathways. Additionally, if CSC's are primary targets, then metastasis incidence and/or cancer free survival may be a more appro‐ priate efficacy endpoint in clinical trials than tumor volume. Perhaps then it would be more strategic in breast cancer to design preclinical trials based on incorporating combination regimens at the early stages of drug development while targeting multiple pathways and focusing on appropriate endpoints; all to avoid missing potentially important therapeutic benefits. While plant based derivatives, such as those considered in this chapter hold promise in breast cancer treatment and management, their development should be pursued systemat‐ ically, guided by sound scientific principles.

**Figure 2.** (Tobin, GA, 2012) An Overview of the Major Signaling Networks Involved in Breast Cancer and CSC Self-re‐ newal, including Notch, NFκB, Wnt and Hh. Symbols and acronyms have been discussed previously, with the exception of P = phosphorylation, BAD = Bcl-2-associated death promoter, and SHH = Sonic Hh. Also, NUMB references the Pro‐ tein numb homolog that in humans is encoded by the NUMB gene.
