The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered “undruggable,” and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail’s interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.
The aim of the present study was to determine the effects of Licochalcone D (LD) on the apoptosis and migration and invasion in human melanoma A375 cells. Cell proliferation was determined by sulforhodamine B assay. Apoptosis was assessed by Hoechst 33258 and Annexin V-FITC/PI staining and JC-1 assay. Total intracellular reactive oxygen species (ROS) was examined by DCFH-DA. Wound healing and Transwell assays were used to detect migration and invasion of the cells. The activities of matrix metalloproteinase (MMP-2 and MMP-9) were assessed via gelatin zymography. Tumor growth in vivo was evaluated in C57BL/6 mice. RT-PCR, qPCR, ELISA and western blot analysis were utilized to measure the mRNA and protein levels. Our results showed that LD inhibited the proliferation of A375 and SK-MEL-5 cells in a concentration-dependent manner. After treatment with LD, A375 cells displayed obvious apoptotic characteristics, and the number of apoptotic cells was significantly increased. Pro-apoptotic protein Bax, caspase-9 and caspase-3 were upregulated, while anti-apoptotic protein Bcl-2 was downregulated in the LD-treated cells. Meanwhile, LD induced the loss of mitochondrial membrane potential (ΔΨm) and increased the level of ROS. ROS production was inhibited by the co-treatment of LD and free radical scavenger N-acetyl-cysteine (NAC). Furthermore, LD also blocked A375 cell migration and invasion in vitro which was associated with the downregulation of MMP-9 and MMP-2. Finally, intragastric administration of LD suppressed tumor growth in the mouse xenograft model of murine melanoma B16F0 cells. These results suggest that LD may be a potential drug for human melanoma treatment by inhibiting proliferation, inducing apoptosis via the mitochondrial pathway and blocking cell migration and invasion.
The first-line chemotherapy drug adriamycin (ADM) is widely used for the treatment of breast cancer, but the acquired drug resistance and the normal tissue toxicity remain clinical challenges. Alteronol has been reported to exert wide-ranging anti-tumor activity. In this study, we firstly examined the synergistic anti-tumor effects and the underlying mechanisms of alteronol combined with ADM in breast cancer. We have found that the combination of alteronol and ADM significantly suppressed the expression levels of the cell cycle-related proteins (CDC2 and Cyclin B1) and induced cell cycle arrest at the G2/M phase, leading to cell proliferation inhibition in breast cancer 4T1 cells. Moreover, co-treatment of alteronol and ADM (i) remarkably activated p38 and JNK kinases, (ii) elevated ROS levels, (iii) triggered mitochondrial dysfunction, (iv) released cytochrome c into the cytoplasm, (v) upregulated apoptosis-related proteins, e.g., cleaved PARP, Bax, and cleaved caspase-3/9, and (vi) downregulated the expression of Bcl-2, followed by apoptosis. Furthermore, our in vivo studies showed that the low-dose combination of alteronol (2 mg/kg) and ADM (1 mg/kg) significantly inhibited tumor growth in tumor bearing mice, and the anti-tumor effect of the combination was the same as that of high-dose ADM (8 mg/kg). In addition, the low-dose combination group showed lower toxicities to major organs than the high-dose ADM group. Taken together, these data demonstrate that the low-dose combination of alteronol and ADM could notably improve the anti-tumor activity and have lower toxicities to major organs than those in high-dose ADM group.
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