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Molecules 2018, 23(11), 2895; https://doi.org/10.3390/molecules23112895

Novel Rhodanine Derivative, 5-[4-(4-Fluorophenoxy) phenyl]methylene-3-{4-[3-(4-methylpiperazin-1-yl) propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride, Induces Apoptosis via Mitochondria Dysfunction and Endoplasmic Reticulum Stress in Human Colon Cancer Cells

1
Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea
2
Department of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, Seoul 130-701, Korea
3
Department of Oriental Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 130-701, Korea
4
Department of Urology, College of Medicine, Dong-A University, Pusan 602-715, Korea
5
Life/Health Division, Korea Institute of Science and Technology, 5Wolsong-gil, Seongbuk-gu, Seoul 136-791, Korea
6
Integrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do 420-743, Korea
These authors contributed equally to this study.
*
Authors to whom correspondence should be addressed.
Received: 19 October 2018 / Revised: 3 November 2018 / Accepted: 4 November 2018 / Published: 6 November 2018
(This article belongs to the Section Medicinal Chemistry)
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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. View Full-Text
Keywords: rhodanine derivative; apoptosis; colon cancer; ER stress; calcium; mitochondria rhodanine derivative; apoptosis; colon cancer; ER stress; calcium; mitochondria
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Jung, H.-U.; Lee, J.-H.; Chung, K.-S.; Hong, J.Y.; Choi, J.-H.; Kim, S.-D.; Roh, E.J.; Shin, K.J.; Lee, K.-T. Novel Rhodanine Derivative, 5-[4-(4-Fluorophenoxy) phenyl]methylene-3-{4-[3-(4-methylpiperazin-1-yl) propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride, Induces Apoptosis via Mitochondria Dysfunction and Endoplasmic Reticulum Stress in Human Colon Cancer Cells. Molecules 2018, 23, 2895.

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