Abstract P1-07-25: SSA, a novel sulindac sulfide derivative, inhibits tumor cell growth and invasion in breast cancer

Abstract

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs), such as sulindac sulfide (SS), have been reported for striking chemopreventive activities in various types of human malignances, including breast cancer. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for chemoprevention in human cancer. We recently developed a novel amine derivative of SS named as SSA, which lacks inhibitory effect on COX-1 or -2, yet shows 10 times greater suppressive effect than SS on growth of a panel of breast cells. Moreover, SSA treatment at sub-cytotoxic concentration (4μM) for 36 hr can significantly inhibit both migration and invasion of highly aggressive breast tumor MDA-MB-231cells. To understand the molecular mechanism accounting for this activity, we examined 4 oncogenic miRNAs, including mir-17-92, mir-9, mir-10b, and mir-21 that were previously reported by our group to be associated with SS anti-invasive activity in breast and colorectal cancer. We found SSA could significantly down-regulate these miRNAs; whereas their forced expression was able to counteract the anti-invasive activity of SSA in MDA-MB-231 cells. There results imply that significance of SSA with non-COX inhibitory properties in suppression of tumor cell invasion could provide novel insights into development of safer and more effective strategies for prevention of breast cancer progression and metastasis. In addition, after inducing mobility of non-invasive breast MCF-7 cells by using TGF-β1, we treated these invading cells with SSA and found that their mobility was significantly decreased. These results support anti-invasive activity of SSA in human breast cancer cells and inhibition of TGF-β1 as well as oncogenic miRNAs may be responsible for the mechanistic basis by which SSA prevents breast tumor cell invasion. This study is supported by an American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC) and NIH/NCI R21 Grants (5R21CA160280 and 1R21CA182754) to Yaguang Xi. Citation Format: Bin Yi, Xiangling Feng, Hong Chang, Ruixia Ma, Xiaoguo Zhang, Gary A Piazza, Yaguang Xi. SSA, a novel sulindac sulfide derivative, inhibits tumor cell growth and invasion in breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-07-25.