Sulindac (Sulindac sulfoxide) is a sulfinylindene derivative prodrug with potential antineoplastic activity. Converted in vivo to an active metabolite, sulindac, a nonsteroidal anti-inflammatory drug (NSAID), blocks cyclic guanosine monophosphate-phosphodiesterase (cGMP-PDE), an enzyme that inhibits the normal apoptosis signal pathway; this inhibition permits the apoptotic signal pathway to proceed unopposed, resulting in apoptotic cell death.

In intestinal tissues of Min/+ mice, Sulindac does not alter the levels of PGE2 and LTB4 but reduces the number of tumors. Within a mouse model of familial adenomatous polyposis, Sulindac decreases small intestine COX-2 and prostaglandin E (2), thereby inhibiting tumor formation.

In colorectal cancer (CRC) cell lines, Sulindac and its metabolites sulindac sulfide and sulindac sulfone inhibit the NF-κB pathway, reducing IKKbeta kinase activity mediated by Sulindac. In HT-29 cells, Sulindac significantly reduces cell growth. Sulindac inhibits cell proliferation across various epithelial and fibroblast tumor cell lines. In CRC cell lines DLD1 and SW480, Sulindac suppresses beta-catenin/TCF-mediated gene transcription and decreases levels of non-phosphorylated beta-catenin.