Abstract
Schiff base compounds and their metal complexes have become important synthetic organic drugs due to their extensive biological activities, which include anticancer, antibacterial and antiviral effects. In this study, we investigated the cytotoxic and apoptotic effects of VALD-3, a Schiff base ligand synthesized from o-vanillin derivatives, on human breast cancer cells and the possible underlying mechanisms. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test was used to observe the proliferation of human breast cancer MCF-7 and MDA-MB-231 cells induced by VALD-3. Flow cytometry analysis showed that VALD-3 triggered cell cycle arrest and induced apoptosis of breast cancer cells. Western blot analysis revealed that VALD-3 upregulated pro-apoptotic proteins (Bad and Bax), downregulated anti-apoptotic proteins (Bcl-2, Bcl-xl, survivin and XIAP) and increased the expression of cleaved caspase-3, cleaved caspase-8, Cyto-c and cleaved PARP. VALD-3 also regulated the Wnt/β-catenin signaling pathway in breast cancer cells, inhibiting the activation of downstream molecules. By xenografting human breast cancer cells into nude mice, we found that VALD-3 significantly suppressed tumor cell growth while showing low toxicity against major organs. In addition, survival analysis showed that VALD-3 can significantly prolong the survival time of mice (P = 0.036). This study is the first to show that VALD-3 induces apoptosis and cell cycle arrest in human breast cancer cells by suppressing Wnt/β-catenin signaling, indicating that it could be a potential drug for the treatment of breast cancer.
Highlights
Schiff base compounds and their metal complexes have become important synthetic organic drugs due to their extensive biological activities, which include anticancer, antibacterial and antiviral effects
Primary antibodies against Bax and Bad were obtained from Abcam (MA, USA), and against Bcl-2, cytochrome c, BCL-XL, caspase[3], caspase[8], PARP, X-linked inhibitor of apoptosis protein (XIAP), CyclinD1, CyclinB1, CDK-1 and β-actin were obtained from Proteintech Group Inc. (Chicago, IL, USA)
The results showed that VALD-3 markedly inhibited MCF-7 and MDA-MB-231 proliferation after 48 h (Fig. 1A)
Summary
Schiff base compounds and their metal complexes have become important synthetic organic drugs due to their extensive biological activities, which include anticancer, antibacterial and antiviral effects. By xenografting human breast cancer cells into nude mice, we found that VALD-3 significantly suppressed tumor cell growth while showing low toxicity against major organs. This study is the first to show that VALD-3 induces apoptosis and cell cycle arrest in human breast cancer cells by suppressing Wnt/β-catenin signaling, indicating that it could be a potential drug for the treatment of breast cancer. Numerous studies have reported that Schiff base compounds can effectively eliminate stem cell-enriched cancer cells (HMLER-shEcad) and bulk cancer cells (HMLER)[10], induce apoptosis to inhibit gastric tumor g rowth[11], and significantly inhibit the growth of various human carcinoma cell lines derived from lung (A-549), breast (MDAMB-231) and colon (LS174T)[12,13,14]
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