Abstract
We previously reported that 5-[4-(4-fluorophenoxy) phenyl] methylene-3-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride (KSK05104) has potent, selective and metabolically stable IKKβ inhibitory activities. However, the apoptosis-inducing of KSK05104 and its underlying mechanism have not yet been elucidated in human colon cancer cells. We show that KSK05104 triggered apoptosis, as indicated by externalization of Annexin V-targeted phosphatidylserine residues in HT-29 and HCT-116 cells. KSK05104 induced the activation of caspase-8, -9, and -3, and the cleavage of poly (ADP ribose) polymerase-1 (PARP-1). KSK05104-induced apoptosis was significantly suppressed by pretreatment with z-VAD-fmk (a broad caspase inhibitor). KSK05104 also induced release of cytochrome c (Cyt c), apoptosis inducing factor (AIF), and endonuclease G (Endo G) by damaging mitochondria, resulting in caspase-dependent and -independent apoptotic cell death. KSK05104 triggered endoplasmic reticulum (ER) stress and changed the intracellular calcium level ([Ca2+]i). Interestingly, treatment with KSK05104 activated not only ER stress marker proteins including inositol-requiring enzyme 1-alpha (IRE-1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), but also μ-calpain, and caspase-12 in a time-dependent manner. KSK05104-induced apoptosis substantially decreased in the presence of BAPTA/AM (an intracellular calcium chelator). Taken together, these results suggest that mitochondrial dysfunction and ER stress contribute to KSK05104-induced apoptosis in human colon cancer cells.
Highlights
The colon and rectum both belong to the digestive system of humans, and cancers affecting either of these organs are known as colorectal cancer (CRC)
One of the hallmarks of cancer is the escape of tumor cells from cell death, mainly from apoptosis
The present results demonstrate that KSK05104 is a potent cytotoxic agent in human colon adenocarcinoma HT-29 and HCT-116 cells, and its cytotoxic effect is associated with the induction of apoptosis
Summary
The colon and rectum both belong to the digestive system of humans, and cancers affecting either of these organs are known as colorectal cancer (CRC). Similar as Bax, Bak oligomerization requires BH3-only proteins to induce mitochondrial membrane potential (∆Ψm ) [8], and after a loss in membrane permeability, apoptotic proteins including Cyt c, apoptosis inducing factor (AIF), endonuclease G (Endo G), and second mitochondria-derived activator of caspase/direct inhibitor of apoptosis protein (IAP)-binding protein with low pI (Smac/DIABLO) are released from the mitochondrial inter-membrane space into the cytosol. Rhodanine derivatives exhibited various biological characteristics such as anti-convulsant, anti-bacterial, anti-viral, and anti-diabetic activities [19] One of their anti-viral functions involves inhibiting hepatitis C virus (HCV) protease [20]. Inactivation of NF-κB in colon cancer cells by IKK inhibitors was demonstrated to blunt the ability of the cells to grow by the function antiapoptotic function of NF-κB.
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