MHY2251, a New SIRT1 Inhibitor, Induces Apoptosis via JNK/p53 Pathway in HCT116 Human Colorectal Cancer Cells

Abstract

Despite the recent advances in diagnostic and surgical techniques, colorectal cancer (CRC) remains the third most frequently diagnosed cancer and second most common cause of cancer-related mortality worldwide (Li, 2018). CRC is mainly treated by surgical removal, radiotherapy, chemotherapy, or a combination of surgery and chemotherapy (Yang et al., 2017). Despite various treatment strategies, many patients with CRC continue to experience relapse-hence, improved chemotherapeutic agents that can effectively induce apoptosis in CRC cells are urgently needed.Apoptosis involves two types of signaling pathways. The extrinsic pathway is initiated by the binding of specific receptors on the cell surface, called death receptors, with an extracellular ligand. This involves the binding of Fas receptors, known as differentiation clusters, to Fas ligands, and tumor necrosis factor (TNF) receptors to TNF (Ashkenazi, 2008;Fulda, 2015). These binding events induce the activation of caspase 8 in the intracellular domain of the receptor (O'Brien and Kirby, 2008;Wong, 2011). Activated caspase 8 can affect mitochondria or further activate caspase 3 (Ashkenazi, 2008). The intrinsic pathway is initiated by the loss of mitochondrial membrane potential, resulting in the release of internalized cytochrome c into the cytoplasm (Saelens et al., 2004). The released cytochrome c activates caspase 3 by forming a complex called the apoptosome with apoptosis protease activator 1 and caspase 9 (Elmore, 2007). A family of proteins called B-cell lymphoma

Thymoquinone induces G2/M cell cycle phase arrest and apoptosis through inhibition of JNK phosphorylation and induction of p53 and p21 expression in HT-1080 fibrosarcoma cells

“…In agreement with earlier ndings (33,42), we documented that SP600125 induced increased rate of apoptosis, coupled with reduced cell viability and increased rate of cells in G2/M phase. While our results were in accord with most studies which concluded that activation of JNK pathway was pro-apoptotic and was counteracted by SP600125 (33,35), they were in apparent disagreement with an earlier study which reported that inhibition of the JNK pathway by SP600125 enhanced TQ-induced apoptosis and increased overall caspase-3 activity in colon cancer DLD-1 cells (22). While not addressed by the authors, this apparent synergy between SP600125 (and thus JNK pathway) and TQ phosphorylation appears to be both cell-type and stimulus speci c.…”

“…Several studies reported on the contribution of JNK cascade to apoptosis, highlighted by the ndings that JNK induced cell cycle arrest and apoptosis in osteosarcoma (33), multiple myeloma (34), colorectal cancer (35), and HT-1080 brosarcoma (36) cells. We demonstrated that induction of apoptosis by TQ was linked with inhibition of the phosphorylation and blockade of JNK1/2 pathway, which was con rmed by the anti-apoptotic capacity of the JNK1/2 inhibitor, SP600125.…”

Domperidone Exerts Antitumor Activity in Triple-Negative Breast Cancer Cells by Modulating Reactive Oxygen Species and JAK/STAT3 Signaling

“…1A , 1B ). The proliferation of cancer cells could be blocked either by initiating the apoptotic pathway, or inactivating the survival pathway ( Wong, 2011 ), and the induction of apoptosis could be a promising strategy for antineoplastic therapy ( Kang et al ., 2023 ). Therefore, we investigated whether domperidone induced apoptosis in TNBC BT-549 and CAL-51 cells, given that we observed its cytotoxic effects on these cells.…”