Novel thiosemicarbazides induced apoptosis in human MCF-7 breast cancer cells via JNK signaling

Abstract

In this study, novel thiosemicarbazides and 1,3,4-oxadiazoles were synthesized and evaluated for their anticancer effects on human MCF-7 breast cancer cell lines. Among the synthesized derivatives studied, compound 2-(3-(4-chlorophenyl)-3-hydroxybutanoyl)-N-phenylhydrazinecarbothioamide 4c showed the highest cytotoxicity against MCF-7 breast cancer cells as it reduced cell viability to approximately 15% compared to approximately 25% in normal breast epithelial cells. Therefore, we focused on 4c for further investigations. Our data showed that 4c induced apoptosis in MCF-7 cells which was further confirmed by TUNEL assay. Western blotting analysis showed that compound 4c up-regulated the pro-survival proteins Bax, Bad and ERK1/2, while it down-regulated anti-apoptotic proteins Bcl-2, Akt and STAT-3. Additionally, 4c induced phosphorylation of SAPK/JNK in MCF-7 cells. Pretreatment of MCF-7 cells with 10 mM of JNK inhibitor significantly reduced 4c-induced apoptosis. Molecular docking results suggested that compound 4c showed a binding pattern close to the pattern observed in the structure of the lead fragment bound to JNK1. Collectively, the data of current study suggested that the thiosemicarbazide 4c might trigger apoptosis in human MCF-7 cells by targeting JNK signaling.

Increased fucoxanthin in Chaetoceros calcitrans extract exacerbates apoptosis in liver cancer cells via multiple targeted cellular pathways

“…Also, JNK functions to directly phosphorylate Bcl-2 (B-cell CLL/Lymphoma-2) to enable co-localizing and collaborating with Bcl-2 to mediate prolonged cell survival [39]. Increased expressions of JNK and Bcl-2 in cancer cells were not desirable, and as such cancer cell proliferation could be inhibited if this pathway was modulated [40,41]. Accordingly, both extracts significantly downregulated JNK expression with FxRF exhibiting a significantly higher downregulating effect than CME treatment (p < 0.05).

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Cytokeratin 19 (KRT19) has a Role in the Reprogramming of Cancer Stem Cell-Like Cells to Less Aggressive and More Drug-Sensitive Cells

“…We next aimed to explore the underlying mechanism by which KRT19 regulates cancer reprogramming. Although KRT19 regulates EGR1/PTEN/AKT, β-catenin/NUMB/NOTCH, and HER2/ERK/SP1 cascades [ 29 , 46 , 47 ], we focused on the AKT, GSK3β, ERK, Src, and JNK signaling pathway in this study, as these signaling pathways are crucially involved in cancer progression [ 52 , 53 , 54 , 55 , 56 ]. The WB analysis demonstrated that the phosphorylation of p-GSK3β (Tyr216) and p-Src levels were increased significantly upon the knockdown or overexpression of KRT19 in MDA-MB231 or KU-CSLC cells, while the expression of p-AKT, p-GSK3β (Ser9), p-ERK, and p-JNK was unchanged ( Figure 6 C,D), which is suggested that KRT19 could regulate the cancer stem cell reprogramming by partially modulating the phosphorylation of GSK3β (Tyr216) and Src in breast cancer or cancer stem cells.…”

Synthesis, antibacterial and antiproliferative potential of some new 1-pyridinecarbonyl-4-substituted thiosemicarbazide derivatives

“…Additionally, thiosemicarbazides are one of the most promising biologically active compounds which can be used in cancer treatment (Arora et al , 2014 ; Mohsen et al , 1981 ). These derivatives have been effectively used against a number of carcinoma cell lines (Perković et al , 2012 ; Bhata et al , 2008 ; Malki et al , 2014 ; Zhang et al , 2011 ). It has been found that thiosemicarbazide derivatives demonstrated cytotoxic and antiproliferative activity against HeLa, HepG2, MDA-MB-231 and HT-29 cell lines (Mavrova et al , 2014 ).…”