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
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 an...
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MDPI AG
2018-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/23/11/2895 |
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| author | Hye-Uk Jung Jeong-Hun Lee Kyung-Sook Chung Joo Young Hong Jung-Hye Choi Soo-Dong Kim Eun Joo Roh Kye Jung Shin Kyung-Tae Lee |
| author_facet | Hye-Uk Jung Jeong-Hun Lee Kyung-Sook Chung Joo Young Hong Jung-Hye Choi Soo-Dong Kim Eun Joo Roh Kye Jung Shin Kyung-Tae Lee |
| author_sort | Hye-Uk Jung |
| collection | DOAJ |
| description | 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 <i>c</i> (Cyt <i>c</i>), 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 ([Ca<sup>2+</sup>]<sub>i</sub>). 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. |
| first_indexed | 2024-12-11T22:06:37Z |
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| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-11T22:06:37Z |
| publishDate | 2018-11-01 |
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| spelling | doaj.art-2086aa4e110f4f22b5dd83c682362df22022-12-22T00:48:56ZengMDPI AGMolecules1420-30492018-11-012311289510.3390/molecules23112895molecules23112895Novel 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 CellsHye-Uk Jung0Jeong-Hun Lee1Kyung-Sook Chung2Joo Young Hong3Jung-Hye Choi4Soo-Dong Kim5Eun Joo Roh6Kye Jung Shin7Kyung-Tae Lee8Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, KoreaDepartment of Life and Nanopharmaceutical Science, Graduate School, Kyung Hee University, Seoul 130-701, KoreaDepartment of Urology, College of Medicine, Dong-A University, Pusan 602-715, KoreaLife/Health Division, Korea Institute of Science and Technology, 5Wolsong-gil, Seongbuk-gu, Seoul 136-791, KoreaIntegrated Research Institute of Pharmaceutical Sciences, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon, Gyeonggi-do 420-743, KoreaDepartment of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 130-701, KoreaWe 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 <i>c</i> (Cyt <i>c</i>), 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 ([Ca<sup>2+</sup>]<sub>i</sub>). 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.https://www.mdpi.com/1420-3049/23/11/2895rhodanine derivativeapoptosiscolon cancerER stresscalciummitochondria |
| spellingShingle | Hye-Uk Jung Jeong-Hun Lee Kyung-Sook Chung Joo Young Hong Jung-Hye Choi Soo-Dong Kim Eun Joo Roh Kye Jung Shin Kyung-Tae Lee 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 rhodanine derivative apoptosis colon cancer ER stress calcium mitochondria |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | rhodanine derivative apoptosis colon cancer ER stress calcium mitochondria |
| url | https://www.mdpi.com/1420-3049/23/11/2895 |
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