Critical roles of intracellular thiols and calcium in parthenolide-induced apoptosis in human colorectal cancer cells.
Parthenolide is one of the main components responsible for the anti-inflammatory property of Feverfew. Recently, parthenolide has shown to induce apoptosis in cancer cells. Here we further studied the mechanism of parthenolide-induced apoptosis by focusing on the role of intracellular thiols and calcium in a human colorectal cancer cell, COLO 205. Parthenolide rapidly depleted intracellular thiols, including both free glutathione (GSH) and protein thiols. Concomitantly, there were dose- and time-dependent increases in intracellular reactive oxygen species (ROS) and calcium levels. Increased expression of GRP78 protein, a marker for endoplasmic reticulum stress was also detected. All these changes preceded parthenolide-induced apoptotic cell death. More importantly, pretreatment with N-acetylcysteine, a precursor of GSH synthesis, protected the cells from parthenolide-induced thiol depletion, ROS production, cytosolic calcium increase and completely blocked parthenolide-induced apoptosis. On the contrary, pretreatment of buthionine sulfoximine, an inhibitor of GSH synthesis sensitized the cell to apoptosis. These data clearly demonstrate that the intracellular thiols and calcium equilibrium play a critical role in parthenolide-induced apoptotic cell death.
Zhang
Siyuan
S
Department of Community, Occupational and Family Medicine, Faculty of Medicine (MD3), National University of Singapore, 16 Medical Drive, Singapore 117597.
Ong
Choon-Nam
CN
Shen
Han-Ming
HM
D000111:Acetylcysteine / Q000494:pharmacology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes / Q000494:pharmacology*; D013438:Sulfhydryl Compounds / Q000502:physiology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D013438:Sulfhydryl Compounds; C002669:parthenolide; D019328:Buthionine Sulfoximine; D002118:Calcium; D000111:Acetylcysteine