Mechanism of apoptosis induced by a newly synthesized derivative of macrosphelides with a thiazole side chain
| Autor: | Toshiro Sugiyama, Yoko Yoshihisa, Yuji Matsuya, Syed Faisal Zaidi, Hideo Nemoto, Takashi Kondo, Kanwal Ahmed, Tadamichi Shimizu |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
MAP Kinase Kinase 4
Blotting Western Apoptosis Toxicology Dermal fibroblast Superoxide dismutase chemistry.chemical_compound Heterocyclic Compounds Humans Thiazole Protein Kinase Inhibitors chemistry.chemical_classification Caspase 8 Reactive oxygen species biology U937 cell Caspase 3 Chemistry Kinase Cytochromes c U937 Cells General Medicine Acetylcysteine Cell biology Thiazoles Biochemistry biology.protein DNA fragmentation Calcium Reactive Oxygen Species human activities Cell Division BH3 Interacting Domain Death Agonist Protein |
| Zdroj: | Chemico-Biological Interactions. 177:218-226 |
| ISSN: | 0009-2797 |
| DOI: | 10.1016/j.cbi.2008.10.030 |
| Popis: | The apoptosis-inducing ability of hybrid compounds composed of macrosphelide and thiazole-containing side chain of epothilones was investigated. Among the tested series of hybrid compounds the one containing thiazole side chain at C15 (MSt-2) showed the maximum potency to induce apoptosis, while another containing thiazole side chain at C3 (MSt-6) was less potent. MSt-2 was found to induce apoptosis in human lymphoma (U937) cells in a dose- and time-dependent manner as confirmed by DNA fragmentation analysis. MSt-2 treated cells showed rapid reactive oxygen species (ROS) formation and c-Jun N-terminal kinase (JNK) activation. Furthermore, significant activation of extrinsic pathway as evident by Fas expression and caspase-8 activation was also observed. MSt-2-mediated decreased expression of Bid is an important event for cross talk between intrinsic and extrinsic signaling. N-acetyl-l-cysteine pre-treatment rescued cells from MSt-2-induced ROS formation, mitochondrial membrane potential (Delta psi(m)) loss, Fas expression, caspase-8 and -3 activation and DNA fragmentation. Moreover, antioxidant enzymes catalase and/or superoxide dismutase conjugated with polyethylene glycol also inhibit MSt-2-induced ROS formation, apoptosis and Delta psi(m) loss suggesting thereby pro-oxidant effects of MSt-2. Furthermore, JNK and pan-caspase inhibitors also protect cells from MSt-2-induced apoptosis. In addition to this, MSt-2 was found to be more potent in human colon carcinoma (HCT116) and human gastric cancer (AGS) cells while it has no effect on human normal dermal fibroblast. The important structure-activity relationship observed in the current study which makes MSt-2 more potent than MSt-6 is the position of thiazole side chain and stereochemistry of position 3 in chemical structure. In short the results of our study demonstrate that MSt-2-induced rapid ROS generation and mitochondrial dysfunction in cells trigger events responsible for mitochondria-dependent apoptosis pathway. |
| Databáze: | OpenAIRE |
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