Aspirin inhibits camptothecin-induced p21(CIP1) levels and potentiates apoptosis in human breast cancer cells

作者：Alfonso Lloyd F; Srivenugopal Kalkunte S; Arumugam Thiruma V; Abbruscato Thomas J; Weidanz Jon A; Bhat G Jayarama^*

来源：International Journal of Oncology, 2009, 34(3): 597-608.

DOI：10.3892/ijo_00000185

• aspirin
• chemoprevention
• chemotherapy
• breast cancer
• apoptosis
• gene expression

The ability of aspirin to trigger apoptosis in cancer cells is well known and is consistent with the clinical and epidemiological evidence on its chemopreventive effects in curtailing epithelial cancers, including breast cancer. We hypothesized that the anticancer effects of aspirin may involve acetylation of the tumor suppressor protein p53, a known regulator of apoptosis. In the present study, we determined if aspirin at the physiologically achievable concentration of 100 mu M acetylates p53 and modulates the expression of p21(CIP1), a protein involved in cell cycle arrest, and Bax, a pro-apoptotic protein. Using MDA-MB-231 human breast cancer cells, we demonstrate that aspirin at 100 mu M concentration markedly acetylated the p53 protein, which was primarily localized to the nucleus. Aspirin induced p21(CIP1) protein levels in a transient fashion in contrast to the sustained induction of Bax. The induction of p21(CIP1) protein levels began at 3 h and was maximal at 6-8 h; however, it decreased to control levels by 30 h. In contrast, the anticancer drug, camptothecin (CPT) induced a steady accumulation of p21(CIP1) protein. Remarkably, when cells were co-treated with aspirin and CPT, p21(CIP1) levels were drastically downregulated, and this phenomenon was observed in many cancer cell lines. Incubation of recombinant p21 with cytoplasmic extracts from aspirin-treated cells caused its degradation suggesting the involvement of proteases in the disappearance of p21(CIP1). Consistent with this data, aspirin decreased the survival of CPT-treated cells and greatly increased the extent of apoptosis. Our observation that aspirin has the ability to inhibit p21(CIP1) alter its initial induction has important implications in chemotherapy, and suggests its potential use to increase the efficacy of anticancer agents.

• 出版日期2009-3