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AXIN1 mutations are observed in 8–10% of hepatocellular carcinomas (HCCs) and originally were considered to support tumor growth by aberrantly enhancing β-catenin signaling. This view has however been challenged by reports showing neither a clear nuclear β-catenin accumulation nor clearly enhanced expression of β-catenin target genes. Here, using nine HCC lines, we show that AXIN1 mutation or siRNA mediated knockdown contributes to enhanced β-catenin signaling in all AXIN1-mutant and non-mutant lines, also confirmed by reduced signaling in AXIN1-repaired SNU449 cells. Both AXIN1 and AXIN2 work synergistically to control β-catenin signaling. While in the AXIN1-mutant lines, AXIN2 is solely responsible for keeping signaling in check, in the non-mutant lines both AXIN proteins contribute to β-catenin regulation to varying levels. The AXIN proteins have gained substantial interest in cancer research for a second reason. Their activity in the β-catenin destruction complex can be increased by tankyrase inhibitors, which thus may serve as a therapeutic option to reduce the growth of β-catenin-dependent cancers. At concentrations that inhibit tankyrase activity, some lines (e.g. HepG2, SNU398) were clearly affected in colony formation, but in most cases apparently independent from effects on β-catenin signaling. Overall, our analyses show that AXIN1 inactivation leads to enhanced β-catenin signaling in HCC cell lines, questioning the strong statements that have been made in this regard. Enhancing AXIN activity by tankyrase monotherapy provides however no effective treatment to affect their growth exclusively through reducing β-catenin signaling. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the world's fourth most deadly cancer. CRC, as a genetic susceptible disease, faces significant challenges in optimizing prognosis through optimal drug treatment modalities. In recent decades, the development of innovative small-molecule drugs is expected to provide targeted interventions that accurately address the different molecular characteristics of CRC. Although the clinical application of single-target drugs is limited by the heterogeneity and high metastasis of CRC, novel small-molecule drug treatment strategies such as dual/multiple-target drugs, drug repurposing, and combination therapies can help overcome these challenges and provide new insights for improving CRC treatment. In this review, we focus on the current status of a range of small molecule drugs that are being considered for CRC therapy, including single-target drugs, dual/multiple-target drugs, drug repurposing and combination strategies, which will pave the way for targeting CRC vulnerabilities with small-molecule drugs in future personalized treatment. [Display omitted] • The current status of CRC small-molecule drugs. • CRC related progress in recent years. • Signaling pathway and protein target of CRC therapeutic. [ABSTRACT FROM AUTHOR]

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. • Antifungal drug sertraconazole nitrate (STZ) was repurposed to antitumor activity. • STZ inhibited CRC cells proliferation and induced apoptosis and autophagy. • STZ blocking IDO1 might be a promising approach to CRC treatment. • STZ was shown to regulate STAT3 and MAPK signaling pathways. [ABSTRACT FROM AUTHOR]