ANTICANCER ACTIVITY OF PHENOLIC ANTIOXIDANTS AGAINST BREAST CANCER CELLS AND A SPONTANEOUS MAMMARY TUMOUR

The present study was focused on known specific phenolic antioxidants to investigate their chemotherapeutic potential. Although tamoxifen showed greater potency in breast cancer patients endometrial cancer emerges after prolonged treatment. Because no predictive biomarker for response is currently available to guide the choice of cytotoxic chemotherapy for breast cancer, the choice of drugs is usually empiric. One important goal of this investigation was to initiate research to determine the cellular target(s) for phenolic antioxidants and to characterize their molecular mechanism of action to rationally design new, more efficient modulators based on their chemical structure. Phytochemicals constitute a wide family of natural components with a considerable range of bioactive properties with potential clinical applications as anticancer drugs.

The four phenolics namely ferulic acid, caffeic acid, gallic acid and curcumin showed selective antiproliferaive effect against estrogen – positive human breast cancer MCF-7 cells. The values do show relevant differences between cytotoxic effects of various phenolics among themselves as well as when compared with the chemotherapeutic drug cisplatin. It appeared that breast cancer cells were slightly more sensitive to caffeic acid. Minimal inhibition was observed when MCF-7 cells were exposed to cisplatin. The vehicle dimethylsulphoxide as such had no effect on the proliferation of MCF-7 breast cancer cells.

In a next attempt to enhance the antiproliferative effect of the phenolic compounds, combination studies were carried out. Caffeic acid when co-administered with cisplain was more effective than the remaining combinations. Colony formation assays indicate that caffeic acid is a better in vitro growth inhibitor of MCF-7 cells. Interestingly its growth inhibitory effect with cisplatin was greater when a comparison was made with the rest of the combinations with respect to the plating efficiency.

There is no doubt that the phenolic acids appear promising while analysing the results obtained in the present investigation and as such they will be more effective in the form of esters as the case with caffeic acid ester, nonetheless curcumin follows similar growth inhibitory pattern as a single agent as well as in combination. Besides following observations justifies further studies on this widely consumed dietary supplement.

The phytochemical curcumin present in turmeric arrested many cell types in G2/M phase of the cell cycle after treatment. It is one of the potent agents to inhibit nuclear transcription factor NF-kappa B pathway. NF-kB has the ability to suppress apoptosis (programmed cell death) and to induce expression of proto-oncogene such as c-myc and cyclin D1, which directly stimulate cellular proliferation, suggesting that NF-kB may participate in many aspects of oncogenesis. Indeed, constitutive NF-kB activity has been observed in a number of human cancers, including breast cancer and inhibition of NF-kB abrogates tumor cell proliferation. All these augments go well for curcumin suggesting it an ideal candidate in the treatment of human cancer.

Cyclodextrins are the cyclic oligosaccharides having the ability to form inclusion complex with wide variety of compounds. Cyclodextrins can entrap poorly soluble drug molecules of appropriate size and polarity in their hydrophobic cavity to form reversible non-covalent inclusion complexes. This can improve aqueous solubility, stability and bioavailability of the drug molecule.

Angiogenesis, a process by which new blood vessels sprout from existing ones is a prerequisite for out growth and metastasis of tumor. Growth of solid tumors depends on the induction of angiogenesis to provide adequate oxygen and nutrients to proliferating cells. Thus angiogenesis constitutes a very promising therapeutic target.  A chick embryo chorioallantoic membrane (CAM) model was used to demonstrate that the administration of physiological relevant doses of curcumin and its beta cyclodextrin complex cause significant decrease in induction of angiogenesis. Because angiostatic therapy would require a prolonged maintenance of therapeutic levels in vivo , the continuous delivery of CMN would be more effective. In this way its inclusion complex might be a helpful additional therapeutic tool for breast cancer patients.

For tumor growth inhibitory studies curcumin was administered by oral gavages (100 mg/kg) for 10 days for the duration of the experiment. It inhibited the growth of mammary tumor markedly in the beginning of the treatment whereas its cyclodextrin complex showed significantly greater activity within the 5-week period of observations. These results provide a basis for the ability of the inclusion complex for in depth studies.

In summary, our results show that caffeic acid and its combination with cisplatin results in greater antiproliferative activity in breast cancer cells in the assays conducted. Curcumin shows similar tendency towards cell growth inhibition. Importantly increased activity of curcumin inclusion complex was observed in spontaneous mammary tumor. Potentially, this effect was due to enhanced oral absorption and oral bioavailability and its antiangiogenic properties.

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Source: Indap M A, Radhika S, Motiwale L, Rao K. Indian J Pharm Sci 2006;68:470-4

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