Abstract
Compelling efficacy on intervention of tumorigenesis by nonsteroidal anti-inflammatory drugs (NSAIDs) has been documented intensively. However, the toxicities related to cyclooxygenase (COX) inhibition resulting in suppression of physiologically important prostaglandins limit their clinical use for human cancer chemoprevention. A novel derivative of the NSAID sulindac sulfide (SS), referred as sulindac sulfide amide (SSA), was recently developed, which lacks COX inhibitory activity, yet shows greater suppressive effect than SS on growth of various cancer cells. In this study, we focus on the inhibitory activity of SSA on breast tumor cell motility, which has not been studied previously. Our results show that SSA treatment at non-cytotoxic concentrations can specifically reduce breast tumor cell motility without influencing tumor cell growth, and the mechanism of action involves the suppression of TGFβ signaling by directly blocking Smad2/3 phosphorylation. Moreover, miR-21, a well-documented oncogenic miRNA for promoting tumor cell metastasis, was also found to be involved in inhibitory activity of SSA in breast tumor cell motility through the modulation of TGFβ pathway. In conclusion, we demonstrate that a non-COX inhibitory derivative of sulindac can inhibit breast tumor metastasis by a mechanism involving the TGFβ/miR-21 signaling axis.
Highlights
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat a variety of inflammatory conditions and pain associated with arthritis
sulindac sulfide amide (SSA) is an amide derivative of sulindac sulfide (SS) lacking COX inhibitory properties but with potent tumor cell growth inhibitory activity compared with SS [18]
Using a protocol as reported previously [19], we determined the effect of non-cytotoxic concentrations of SSA on tumor cell invasion, and we found that SSA treatment at 4 μM for 36 h significantly inhibited the invasion of highly metastatic breast cancer cell lines, MDA-MB-231, BT-20, and SKBR-3 (Figure 2)
Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat a variety of inflammatory conditions and pain associated with arthritis. Previous studies have reported promising cancer chemopreventive activity from regular use of aspirin and other NSAIDs for a variety of malignancies including breast cancer, colon cancer, and other solid tumors [1,2,3,4]. The long-term use of NSAIDs for cancer chemoprevention is not recommended because of gastrointestinal, renal, or cardiovascular toxicities associated with the depletion of physiologically important prostaglandins resulting from COX-2 inhibition [10, 11]. Different studies have reported that distinct mechanisms from COX inhibition could be fully or partially responsible for the cancer chemoprevention activity of NSAIDs [12,13,14,15]
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