Routing NSAIDs into the Golgi apparatus induces autophagy and apoptosis in cancer cells.

The Golgi apparatus (GA), a critical sub-cellular organelle, plays a pivotal role in numerous biological signaling pathways, including the post-translational modification of proteins and their secretion to various cellular destinations. Dysregulation of GA function is implicated in the development of several diseases, including cancer. As a result, detouring clinically approved drugs into the GA for an enhanced anti-cancer effect remained a major challenge. To address this, herein, we designed and synthesized NSAID-based conjugates incorporating a fluorophore (1,8-naphthalimide) and a Golgi-homing moiety (phenylsulfonamide). Screening these conjugates in cervical (HeLa) and colon (HCT-116) cancer cells identified a particularly promising candidate: the ibuprofen-1,8-naphthalimide-phenylsulfonamide conjugate (7a) which exhibited significant cytotoxicity against HCT-116 cells as well as in lung cancer (A549), colon carcinoma (Caco-2) and breast cancer (MCF7) cells. Interestingly, compound 7a self-assembled into nanoscale petal-like structures in water and efficiently homed into the GA as well as in the endoplasmic reticulum (ER) within 30 min to induce morphological damage to the GA. Compound 7a mediated GA damage increased the expression of Beclin and LC3-I/II proteins to induce autophagy which was further inhibited by chloroquine (CQ) and bafilomycin A1 (BFA) leading to remarkable HCT-116 cell death in combination with 7a. Moreover, compound 7a triggered apoptosis by downregulating anti-apoptotic Bcl-2 and Cas-3 as well as cleaving PARP proteins in HCT-116 cells, while demonstrating no toxicity towards non-cancerous human retinal pigment epithelial cells (RPE-1). Interestingly, compound 7a also reduced the size and growth of the HeLa 3D spheroids significantly after 72 h. This ibuprofen derivative (7a) holds promise as a valuable tool for illuminating the chemical biology of the GA in cancer cells and as a potential candidate for anti-cancer therapy.