Mechanistic studies on the anticancer activity of formulated citrus peel extract (Gold lotion)

Shiming Li1, Michiko Suzawa2, Chi-Chen Lin3

1. Department of Food Science, Rutgers University, New Brunswick, NJ 08901, USA

2. Miyauchi Citrus ResearchCenter, Shigoka-Machi, Takasaki, gunma, Japan

3. Institute of Biomedical Sciences, College of Life Science, National Chung Hsing University, Taichung, 402, Taiwan

Gold lotion (GL), a formulated product made from the peels of six citrus fruits (navel oranges, Citrus hassaku, Citrus limon, Citrus natsudaidai, Citrus miyauchi and Satsuma), was initially developed as a cosmetic in Japan to protect skin exposure to UV light. Chemical analysis of GL has found that it contains abundant flavonoids including polymethoxylated flavonoids (PMFs). Evidence showed that GL has antitumor effects. However, molecular mechanisms of antitumor actions of GL and the potential bioactive compounds responsible for its antitumor activity remain unknown. In our recent study, we observed that GL and its bioactive compound namely 3,5,6,7,8,3’,4’-heptamethoxyflavone (HMF) could be new chemotherapeutic agent for the treatment of A549 non-small cell lung cancer (NSCLC) and MIA CaPa pancreatic cancer by the following observations: (1) induction of G2/M phase arrest, 2) promoted abnormal microtubule dynamics, 3) studies conducted with isolated tubulin and docking models further suggest that 3,5,6,7,8,3’, 4’-heptamethoxyflavone (HMF) binds to the taxol site, (4) induced mitochondrial dependent apoptosis. Additionally, GL induce autophagy via activation of the JNK signaling pathway in A549 and MIA CaPa cells. Pretreatment of the cells with autophagy inhibitor 3-methyladenine (3-MA) significantly potentiated GL-induced apoptosis, suggesting that GL-induced autophagy mitigated cell apoptosis. Further investigation revealed that oral GL treatment inhibition of A549 lung cancer cell growth was reproducible in a nude mouse model. Taken together, these data suggested that GL induces mitotic arrest, apoptosis and autophagy in cancer cells and provides the framework for further development as a novel chemotherapeutic agent for the cancer treatment.