Abstract 602: Chemopreventive efficacy of sustained release curcumin microparticles depends on tumorigenesis stage during initial treatment
Authors: Grill Alex , Shahani Komal , Kalscheuer Steve , Koniar Brenda , Panyam Jayanth 
Published: August 2012

Abstract
Our lab has developed novel curcumin loaded PLGA microparticles for effectively maintaining curcumin blood and tissue levels for at least 45 days. Efficacy of this system was tested in Balb-neuT mice, a transgenic model of HER2 driven breast cancer. This model mimics human tumorigenesis and follows a well predicted timeline: hyperplasia begins at 3 weeks of age followed by carcinoma in situ at 8 weeks, palpable tumors appearing at 17 weeks, and all mammary glands developing tumors by 33 weeks of age. Our previous studies showed that starting curcumin microparticle treatment at 4 weeks of age resulted in significant chemopreventive efficacy. The goal of the current work was to examine the chemopreventive efficacy of curcumin microparticle treatment as a function of tumorigenesis stage at which the treatment was started. Mice were injected subcutaneously with curcumin loaded or empty microparticles at 2, 4, 7 or 12 weeks of age and then once a month thereafter until all mammary pads developed palpable tumors. Mice that started receiving curcumin microparticle treatment at 2 weeks of age showed similar delays in tumor multiplicity compared to mice initially treated at 4 weeks. Times to first tumor (14 vs 15.5 weeks) and 100% tumor multiplicity (18.5 vs 21 weeks) were significantly delayed compared to blank microparticle controls. Additionally, tumor growth was slower in curcumin treated animals. At 8 weeks of age, mammary tissue showed significantly decreased abnormal mammary tissue (3 vs 7%) and decreased CD-31 staining (16 vs 20 counts/field) compared to age-matched controls. Mammary vasculature was also visually smaller and less developed. Based on these results, decreased angiogenesis appears to be an important chemopreventive mechanism for curcumin before the onset of hyperplasia. In mice receiving curcumin microparticle treatment initially at 4 weeks of age showed a difference in age to 100% tumor multiplicity (19 vs 21 weeks) compared to mice that received control microparticles. At 12 weeks, histology studies showed that curcumin treatment resulted in a significant (p&lt;0.05) decrease in Ki-67 expression and overall percent area of abnormal mammary tissue (lobular hyperplasia, carcinoma in situ and invasive carcinoma). Western blotting showed decreased HER2 protein levels in curcumin-treated mice. Decreased cellular proliferation is a key chemopreventive mechanism of action in this case. No difference in tumor multiplicity was seen when the treatments were started at 7 or 12 weeks of age. In summary, sustained release curcumin microparticles show promise as a chemopreventive against HER-2 positive breast cancer. These results indicate that curcumin treatment should be started before the appearance of carcinoma in situ. Future studies will further examine the different mechanisms of action of curcumin in HER2 driven breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 602. doi:1538-7445.AM2012-602