Abstract A128: Protective effects of nexrutine, a phellodendron amurense extract, against breast cancer is associated with autophagy.

A128

Breast cancer is the most frequent cancer in women with over 40,000 deaths per year in the United States. The prognosis for a subset of these women with breast tumors that are either estrogen receptor (ER)-negative or ER- and overexpress ErbB2 (also known as HER2/Neu) is very poor because these tumor are aggressive and do not respond to standard treatments. This situation emphasizes the importance of developing new agents and protocols for preventing breast cancer. Numerous epidemiological studies suggest that plant-based diets are protective against many types of cancer. However, there is very little known about many of these botanicals for preventing breast cancer. Nexrutine is an herbal extract from the Chinese tree phellodendron amurense that has been used over hundreds of years in traditional Chinese medicine for treatment of inflammation, gastroenteritis, abdominal pain, and diarrhea. Numerous studies indicate a relationship between inflammation and cancer. In particular, many studies have reported that breast tumors have increased expression of cyclooxygenase (COX-2), the rate-limiting enzyme that controls the conversion of arachidonic acid into pro-inflammatory prostaglandins (PG). High levels of PGE2 in breast tumors are associated with increased proliferation, metastasis, resistance to apoptosis, and angiogenesis. Overexpression of COX-2 occurs more frequently in DCIS, which suggests that COX/PG is an important target for preventing the progression of DCIS to metastic breast cancer. However, considering the recent concerns of the cardiovascular risks associated with the COX-2 inhibitor drugs, there is an urgent need to develop nontoxic approaches to target the PGE pathway. Targeting PGE2 synthese and 15-hydroxy PG dehydrogenase (15-PGDH) provides an alternative strategy to block PGE2 without the risk the cardiovascular risks. SkBr3, MDA-MB 231, and BT474 cells were treated with nexrutine for 24, 48, and 72 h. Nexrutine produced a time and concentration decrease in cell survival, which was accompanied by a G0/G1 cell cycle arrest and decreased protein expression of cyclin D1. nexrutine reduced the production of PGE2 without altering PGI2. The reducing in PGE2 levels was associated with decreased protein expression of PGE2 synthase and increased 15-PGDH. Peroxisome proliferators-activated receptor (PPAR) γ is also increased in many cancers including breast. Recent studies have suggested that PPAR γ may function as a tumor promoter gene. Upregulation of PPAR γ has been demonstrated in ER- breast cancer tumors and may be a marker for reoccurrence of DCIS. We show that nexrutine decreased activation of PPAR γ. Nexrutine reduced protein levels of PPAR γ and activation of PPAR γ. Growth inhibitory effects of nexrutine were associated with increased PTEN and Beclin 1 protein expression, and type-2 cell death known as autophagy. Based upon these findings, we propose that the use of nexrutine could provide a novel approach for protection against breast cancer.

Citation Information: Cancer Prev Res 2008;1(7 Suppl):A128.