DNA damage and endoplasmic reticulum stress mediated curcumin-induced cell cycle arrest and apoptosis in human lung carcinoma A-549 cells through the activation caspases cascade- and mitochondrial-dependent pathway.
Curcumin, a major component of the Curcuma species, is known to have antioxidant, anti-inflammatory properties and induce apoptosis of cancer cells, however, the precise molecular mechanisms of apoptosis in vitro are unclear. In this study, we showed that curcumin, a plant product containing the phenolic phytochemical, caused DNA damage and endoplasmic reticulum (ER) stress and mitochondrial-dependent-induced apoptosis through the activation of caspase-3 at a treatment concentration of 30 microM in human lung cancer A-549 cells. In contrast, treatment with 5-10 microM of curcumin did not induce significant apoptosis, but rather induced G2/M-phase arrest in A-549 cells. Flow cytometric analysis indicated that curcumin directly increased intracellular oxidative stress based on the cell permeable dye, 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) acting as an indicator of reactive oxygen species (ROS) generation. GADD153 and GRP78 were increased by curcumin which was indicative of ER stress. Curcumin increased Ca(2+) levels and the mitochondrial membrane potential (DeltaPsi(m)), was decreased in A-549 cells. Overall, our results demonstrated that curcumin treatment causes cell death by activating pathways inducing G2/M-phase arrest and apoptosis.
Lin
Song-Shei
SS
Department of Radiological Technology, Central Taiwan University of Science and Technology, No. 11, Buzih Lane, Buzih District, Taichung 40605, Taiwan.
Huang
Hsuan-Pang
HP
Yang
Jai-Sing
JS
Wu
Jeng-Yuan
JY
Hsia
Te-Chun
TC
Hsai
Te-Chun
TC
Lin
Chin-Chung
CC
Lin
Cheng-Wen
CW
Kuo
Chao-Lin
CL
Gibson Wood
W
W
Chung
Jing-Gung
JG
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D020169:Caspases / Q000187:drug effects / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000627:therapeutic use*; D004249:DNA Damage; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism
D000970:Antineoplastic Agents; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D017382:Reactive Oxygen Species; D004533:Egtazic Acid; D020169:Caspases; D003474:Curcumin; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium