Phytochemical-rich potato extracts and potential for risk reduction in tamoxifen treatment of breast cancer : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Nutritional Science at Massey University, Palmerston North, New Zealand
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Date
2013
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Massey University
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Abstract
Existing data suggest an inverse correlation between breast cancer risk and
vegetable consumption, and the anticancer effects of vegetables are attributed
to the diversity and abundance of phytochemicals. Standard endocrine
therapies for breast cancer are associated with significant side effects and not
always effective. Undoubtedly, there is a need for improved treatment of breast
cancer. In the quest for better breast cancer treatments with fewer side effects,
food and nutrition represent a logical strategy to explore. Potato (Solanum
tuberosum L.) was chosen for the present project as the target vegetable for
investigation. Pigmented potato has recently attracted research attention
because of its potential health benefits. Two potato extracts were prepared
from a white and purple variety (‘Urenika’) and referred to as WPE and PPE
respectively. Tamoxifen and estradiol exhibited paradoxical effects: each of
them was inhibitory at high doses but stimulatory at low to moderate doses, on
proliferation of two breast cancer cell lines, MCF-7 and T-47D. In contrast, both
PPE and WPE inhibited cell proliferation in a dose-dependent manner without
paradoxical effects. The potato extracts also blocked estradiol- or tamoxifeninduced
cell proliferation of these two cell lines. These findings imply that both
potato extracts may have a role to play in prevention of breast cancer, or
complementing tamoxifen to achieve desirable treatment efficacy. Since both
PPE and WPE were equivalent in efficacy, one (PPE) was selected for further
study, given the intention of developing a nutraceutical or therapeutic product
of New Zealand proprietary value. Phytochemical compositions of the potato
extracts were identified and quantified using ultra high performance liquid
chromatography-mass spectrometry, many of which were reported for the first
time in variety ‘Urenika’. Several compounds were found at doses which have
been reported individually to exert bioactive effects against cancer. It is possible
the antiproliferative effects of potato extracts resulted from more than one of
these bioactive compounds working together. Dose-dependent apoptotic effects
of PPE were observed in T-47D culture, and a combined effect seems to exist
between PPE and tamoxifen in modulating the S and G2/M phase. In summary,
the key contributions and significance of current thesis are: (1) demonstration
of the “risk” zone for tamoxifen (10-8 to 10-6 M) and estradiol (10-10 to 10-8 M)
concentrations which may stimulate breast cancer cell growth. Note that these
concentrations of tamoxifen or estradiol are physiologically achievable.
Furthermore, one key novel finding is regarding the estradiol dependency of
tamoxifen action. Specifically, at low to moderate doses (10-9 to 10-8 M) of
tamoxifen, there is a threshold of estradiol (> 10-8 M) which allows a significant
inhibitory action to occur. The stimulatory action of tamoxifen and complex
interaction between tamoxifen and estradiol observed in vitro may partially
explain the failure of tamoxifen treatment in some patients. Owing to the vast
differences between cell culture experiments and the human body, a more
systematic in vivo investigation of clinical effects of tamoxifen over a range of
different doses under various estradiol concentrations is warranted; (2)
pioneering data on the efficacy of ‘Urenika’ extract against breast cancer in
vitro; (3) a metastatic breast cancer animal model which successfully generated
metastasis to distant sites (lymph nodes, lungs, livers and spleens), mimicking
advanced stage of breast cancer in humans. This model could be used in future
testing of the effect of PPE and the combined treatments (PPE with tamoxifen)
on establishment and metastasis; and (4) a ‘refined’ non-invasive feeding
methodology, which is more ethical than oral gavages, for tamoxifen
administration in mice was developed and results obtained were comparable to
the method of intraperitoneal injection. Using this model and the non-invasive
feeding method, a dose-dependent stimulatory effect of tamoxifen on growth of
4T1 tumours was observed in mice. The current thesis has derived a new
hypothesis which may be worth clinical investigation: tamoxifen may induce
excessive leukocytosis which contributes to tumour invasiveness and growth.
This thesis also represents a significant contribution to the potential use of
potato extracts in reducing the risk of tamoxifen in stimulating cancer growth.
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Keywords
Breast cancer treatment, Tamoxifen, Potato, Solanum tuberosum, Phytochemicals