Epidemiological, clinical and preclinical studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs) possess striking cancer chemopreventive activities. However, toxicities related to cyclooxygenase (COX) inhibition and the suppression of physiologically important prostaglandins limit the regular use of NSAIDs by humans for cancer chemoprevention. Previous studies have demonstrated that the antineoplastic activities of NSAIDs can be attributed to a COX-independent mechanism that induces apoptosis. Thus, there is strong evidence to support the development of new drugs that have the potential to be safer and more efficacious for cancer chemoprevention. Recent preliminary observations have prompted us to hypothesize that specific microRNAs (miRNAs) can mediate the cancer chemopreventive activity of the NSAID sulindac sulfide (SS). MiRNAs are small, non-coding RNA molecules that play important roles in controlling cell growth, differentiation, apoptosis, and tumorigenesis through the translational repression of their cognate target genes. Our pilot results showed that SS treatment of human breast cancer cells up-regulated 58 and down-regulated 59 miRNAs when a 2-fold cutoff was used. One miRNA, termed miR-200b, exhibited a pronounced induction in response to treatment with SS and a more active, non-COX-inhibitory SS derivative, sulindac sulfide amide (SSA), which we recently found to inhibit mammary tumorigenesis in the DMBA rat model. MiR-200b can reduce the expression of the cGMP-specific phosphodiesterase PDE5, which has been previously reported to be overexpressed in tumor cells and closely associated with the apoptosis-inducing activity of SS. These results suggest that miR-200b is involved in a key molecular event that mediates the cancer chemopreventive activity of sulindac. Moreover, we found that miRNAs could mediate the suppression of breast cancer cell invasion by SS through a mechanism involving NF-:B transcriptional regulation.
The specific aims to address this hypothesis are as follows: 1) determine if miR-200b mediates the sensitivity of breast tumor cells to SS and SSA by suppressing PDE5 and 2) determine if the inhibitory effects of SS and SSA on tumor cell invasion are mediated by miRNA and NF-:B inhibition. The proposed studies are anticipated to provide valuable insights into how specific miRNAs mediate the breast cancer chemopreventive activity of sulindac, and these studies will explore new activities involving the suppression of tumor cell invasion.

Public Health Relevance

The antineoplastic properties of NSAIDs are well recognized, but side effects associated with cyclooxygenase inhibition and the depletion of physiologically important prostaglandins limit their use for cancer chemoprevention. Previous studies have shown that the basis for the anticancer properties of NSAIDs involve a cyclooxygenase-independent mechanism, which suggests that the development of safer and more efficacious drugs for preventing cancer may be feasible. Preliminary evidence suggests that microRNAs play a key role in orchestrating COX-independent apoptosis and suppression of tumor cell invasion in human breast tumor cells by the NSAID sulindac, and the proposed studies are expected to provide valuable insights that will accelerate the discovery of new drugs for cancer chemoprevention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Chemo/Dietary Prevention Study Section (CDP)
Program Officer
Perloff, Marjorie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of South Alabama
Schools of Medicine
United States
Zip Code
Yi, Bin; Chang, Hong; Ma, Ruixia et al. (2016) Inhibition of breast cancer cell motility with a non-cyclooxygenase inhibitory derivative of sulindac by suppressing TGFβ/miR-21 signaling. Oncotarget 7:7979-92
Wang, Junyi; Ma, Ruixia; Ma, Wei et al. (2016) LncDisease: a sequence based bioinformatics tool for predicting lncRNA-disease associations. Nucleic Acids Res 44:e90
Ma, Ruixia; Yi, Bin; Piazza, Gary A et al. (2015) Mechanistic Role of MicroRNA in Cancer Chemoprevention by Nonsteroidal Anti-inflammatory Drugs. Curr Pharmacol Rep 1:154-160
Feng, Xiangling; Wang, Zhengming; Fillmore, Rebecca et al. (2014) MiR-200, a new star miRNA in human cancer. Cancer Lett 344:166-73
Tinsley, Heather N; Grizzle, William E; Abadi, Ashraf et al. (2013) New NSAID targets and derivatives for colorectal cancer chemoprevention. Recent Results Cancer Res 191:105-20
Wang, Bin; Xi, Yaguang (2013) Challenges for MicroRNA Microarray Data Analysis. Microarrays (Basel) 2:
Wang, Zheng-ming; Du, Wen-jun; Piazza, Gary A et al. (2013) MicroRNAs are involved in the self-renewal and differentiation of cancer stem cells. Acta Pharmacol Sin 34:1374-80
Shen, Guomin; Li, Xiaobo; Jia, Yong-feng et al. (2013) Hypoxia-regulated microRNAs in human cancer. Acta Pharmacol Sin 34:336-41
Li, Nan; Xi, Yaguang; Tinsley, Heather N et al. (2013) Sulindac selectively inhibits colon tumor cell growth by activating the cGMP/PKG pathway to suppress Wnt/β-catenin signaling. Mol Cancer Ther 12:1848-59
Yi, Bin; Piazza, Gary A; Su, Xiulan et al. (2013) MicroRNA and cancer chemoprevention. Cancer Prev Res (Phila) 6:401-9

Showing the most recent 10 out of 14 publications