Exisulind (Sulindac Sulfone): A Comprehensive Monograph on a Selective Apoptotic Anti-neoplastic Drug—From Preclinical Promise to Clinical Setbacks and Potential Repurposing

Executive Summary

Exisulind, known chemically as sulindac sulfone, is the primary oxidative metabolite of the non-steroidal anti-inflammatory drug (NSAID) sulindac.[1] It was developed as the lead compound in a novel class of agents termed Selective Apoptotic Anti-neoplastic Drugs (SAANDs), distinguished by an anticancer mechanism deliberately separated from the cyclooxygenase (COX) inhibition characteristic of its parent compound.[2] The core mechanism of Exisulind involves the inhibition of cyclic guanosine monophosphate phosphodiesterases (cGMP-PDEs), particularly isoforms PDE2 and PDE5.[5] This inhibition leads to a sustained elevation of intracellular cGMP, which in turn activates protein kinase G (PKG). Activated PKG promotes programmed cell death (apoptosis) through downstream pathways, including the degradation of oncogenic β-catenin and activation of the c-Jun NH2-terminal kinase (JNK) pathway.[5]

The drug underwent an extensive clinical development program investigating its potential as both a chemopreventive and therapeutic agent across several cancers. The most promising signals of efficacy were observed in familial adenomatous polyposis (FAP) and prostate cancer. In FAP, clinical trials demonstrated that Exisulind could significantly reduce the formation of precancerous colorectal polyps.[3] In patients with biochemically recurrent prostate cancer, it significantly slowed the rate of rise in prostate-specific antigen (PSA) levels.[9] In contrast, multiple combination trials in non-small cell lung cancer (NSCLC) failed to show any benefit over standard chemotherapy, despite strong preclinical evidence of synergy.[10]