Sertaconazole nitrate targets IDO1 and regulates the MAPK signaling pathway to induce autophagy and apoptosis in CRC cells.

Colorectal cancer (CRC) has become the third most frequently occurring malignant tumor worldwide. It is vital to identify novel, effective targeted treatments while considering side effects and drug resistance in the clinic. Recently, the tryptophan-metabolizing enzyme indole-2, 3-dioxygenase 1 (IDO1) has been widely reported to be overexpressed in CRC, indicating that blocking IDO1 with small-molecule inhibitors may be a promising approach to CRC treatment. In this study, the antifungal drug sertaconazole nitrate (STZ) was repurposed and showed antitumor activity, and therefore, its anticancer effect was further investigated in CRC cells. The SwissTargetPrediction analysis indicated that STZ binding to IDO1 was significantly and highly probable, and STZ was found to downregulate IDO1 in CRC cells in a dose-dependent manner. STZ exhibited considerable antiproliferative activity and induced apoptosis and autophagy in HCT116 and RKO cells. Moreover, based on an RNA-seq analysis, STZ was shown to regulate signal transducer and activator of transcription 3 (STAT3) and the mitogen-activated protein kinase (MAPK) signaling pathways. We discovered that STZ suppressed tumor growth in an HCT116 nude mouse xenograft tumor model without causing evident cytotoxicity. In conclusion, our results reveal that STZ induces antitumor effects in CRC by inhibiting IDO1-modulated autophagy and apoptosis, providing a clue for repurposing STZ as a novel and potentially effective candidate medication for the future treatment of CRC.

Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications.

Ferroptosis is a novel type of regulated cell death which is driven by iron-dependent lipid peroxidation and subsequent plasma membrane ruptures. Since ferroptosis was coined fairly in 2012, the research in the field of ferroptosis has grown at an exponential rate. Several small-molecule drugs have been shown to trigger ferroptosis and decrease tumor growth in the last decade. Sorafenib can induce ferroptosis in human hepatocellular carcinoma cell lines (Huh7, Hep3B and HepG2), and sulfasalazine as a ferroptosis inducer can inhibit the proliferation of a series of cancer cell lines (including HT-1080 fibrosarcoma cells, Calu-1 non-small cell lung cancer cells, etc.) by specifically inhibit cystine transport which mediated by system Xc-. The purpose of this review is discussing the current crosstalk between ferroptosis and tumor-related signaling pathways, as well as comprehensively summarizing the small-molecule compounds that may regulate cancer cells death by inducing ferroptosis which will shed new light on the development of ferroptosis-related anticancer drugs in the future.