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“Curcumin modulates eukaryotic initiation factor 2 alpha and phosphorylated eukaryotic initiation factor 2 alpha in human lung carcinoma cell line A549” Curcumin, a phenolic compound from the rhizome of plant Curcuma Longa, has anti-inflammatory, antioxidant and anti-cancer activities (Pillai, 2004). The chemopreventive action could be due to the induction of apoptosis and thereby arrest the cell life cycle. The cellular and molecular changes that curcumin initiated and led to the induction of apoptosis in the human lung cancer cell lines-A549 and H1299 were investigated.

Results found A549 to be p53 proficient and H1299 p53 null mutant. Initially treatment of the cancer cells was done with 0-160 microM for 12-72 hours. The growth of both cell lines were inhibited in a concentration dependent way. In addition, the inhibition of the H1299 cell lines was also time-dependent. Apoptosis was found in both cell lines. After 12 hours exposure to 40microM curcumin, a decrease in the expression of p53, bcl-2 and bcl-X (L) was noted (Pillai, 2004). No change was observed in the Bak and Caspace genes upto a concentration of 60 microM but a decrease in expression was observed after that from 80-160 microM.

The induction of apoptosis in the cancer lung cells was independent of the p53. These results are similar to our study results. The differences are in the period of exposure and the concentration of the curcumin. Our study had an exposure of 96 hours to while the concentration of cucurmin was 240 microM to the lesser exposure here of 12 hours and concentration limited at 160microM. The A 549 cell death in our result was time and dose dependent while here it was found to be concentration dependent only. Another study shows surprisingly different results.

Curcumin acted differently in mitochondrial dependent induced apoptosis at a treatment concentration of 30microM in human lung cancer cells A549. The concentration of 5-10microM of curcumin did not induce apoptosis but induced G2/M phase arrest in the A549 cells (Song-Shei et al, 2008). The curcumin directly increased intracellular oxidative stress based on the cell permeable dye, 2? , 7? dichlorodihydro-fluorescein diacetate (DCFH-DA). It increased endoplasmic reticulum stress. The mitochondrial membrane potential was decreased in the A549cells.

The conclusion said that curcumin treatment causes cell death by activating pathways inducing G2/M-phase arrest and apoptosis. Interferon treated A549 cells showed an increase in protein expression levels and binding activity (Lee, 2005). The adding of curcumin suppressed the binding activity by inhibiting IFN-? -induced COX-2 expression in A549 cells. Interferon or IFN-? -induced activations of NF-? B and COX-2 were inhibited by the addition of curcumin in A549 cells (Lee, 2005). Our study did not include the study of the suppression of the binding activity. Curcumin has another action on the squamous cell lung carcinoma H520 cells.

In the presence of the chemotherapeutic agent Vinorelbine which causes cytotoxicity, addition of Curcumin enhanced the action of apoptosis (Sen, 2005). The protein expression of Bax and Bcl-xs increased while decreasing Bcl-2 and Bcl-X. Apotogenic cytochrome was released and the actions of caspace9 and caspace 3 were heightened. It was estimated that 38% apoptosis was caused by Vinorelbine while 23. 7% was caused by the curcumin (Sen, 2005). Pre-treatment with Curcumin caused the Vinorelbine to produce an apoptosis of 61. 3%. It was concluded that curcumin had the potential to act as an adjuvant chemotherapeutic agent.

Our study aims were different Curcumin produces apoptosis in many cancer cells. However the molecular action is still indefinite. Many pathways are postulated. In HL-60 cells in Human Leukemia, curcumin also causes endoplasmic stress apart from apoptosis. The evidence is provided by the survival molecules like the “phosphorylated protein kinase-like ER-resident kinase, phosphorylated eukaryotic initiation factor-2? , glucose-regulated protein-78, and the apoptotic molecules such as caspase-4 and (CHOP) CAAT/enhancer binding protein homologous protein” (Pae, 2007).

Curcumin-induced apoptosis was reduced significantly by using z-LEVD-FMK and small interfering RNA which inhibited the capsace-4 activity and the expression of CHOP. The action of curcumin caused a failure of the activation of apoptosis. Here the additional action of curcumin to cause endoplasmic stress was determined (Pae, 2007). The growth of rhabdomyosarcoma cells and the G1 phase of the cell cycle are inhibited by curcumin (Beevers, 2009). Apoptosis was induced and the motility caused by the type I insulin-like growth factor was inhibited by curcumin.

Rapid inhibition of phosphorylation of rapamycin and its effector molecules including binding eukaryotic initiation factor 4E (eIF4E) binding protein is done by curcumin. The phorphorylation of Akt in the cells is inhibited by curcumin at high concentrations. Blocking mTOR-mediated signaling pathways in the tumor cells may be the main action of curcumin in anti cancer activity. (Beevers, 2009). A study showed that the positive regulation of COX-2 expression is possible by Interferon alpha which is mediated by STAT-1 activation in A549 cells (Lee, 2006).

When curcumin was added to the Interferon alpha treated cells, the COX-2 expression and the STAT-1 activation were both inhibited. The IFN alpha or COX-2 inhibitors did not inhibit growth in A549 cells when alone. Significant growth inhibition occurred when curcumin was added. The addition of curcumin changed the sensitivity of the IFN alpha treated cells to cell growth inhibition (Lee, 2006). Lung diseases like fibrosis and cancer have been partially attributed to the chronic inhalation of quartz particles (Li, 2008). Quartz toxicity generates reactive oxidation species and

oxidative stress in rat lung epithelial cells. This study aimed at investigating whether curcumin could protect the lung epithelial cells from the cytotoxic, genotoxic and inflammatory effects associated with quartz. Curcumin was found to elicit many functions. The hydrogen peroxide-dependent hydroxyl–radical formation by quartz was reduced. It reduced the COX-2 expression (cyclooxygenase-2) mRNA expression. It stopped the release of macrophage inflammatory protein-2 (Li, 2008). It did not provide any protection to the rat lung epithelial cell from the oxidation by the quartz.

However it induced oxidative damage itself at lower concentrations which did not produce cytotoxicity or inflammation. It increased the mRNA expression of the stress response gene heme oxygenase-1. Curcumin produced oxidative damage to the rat lung epithelial cells when associated with quartz exposure. So its potential use in the prevention of lung diseases must be reconsidered (Li, 2008). The endoplasmic reticulum stress induces a family of stress proteins which allow the survival and growth of the tumor cells. Prolonged stress will lead to cell death by overcoming the

protective mechanisms. A new therapeutic method may be assumed by down regulating the protective proteins (Bakshi, 2008). This study demonstrated “that curcumin triggers ER stress and the activation of specific cell death pathways that feature caspase cleavage and activation, p23 cleavage, and downregulation of the anti-apoptotic Mcl-1 protein” (Bakshi, 2008). Another study studied the response of the lung epithelial cells A549 to curcumin. The N acetyl transferase activity was investigated in the A549 cells and the cytosols. This activity was suppressed in a dose dependent manner.

The results showed that curcumin inhibited and decreased the gene expression in the lung A549 cells (Chen, 2003). It also acts on the cells to reduce the AF-DNA adduct formation. References: Bakshi, J. et al. (2008). “Coupling endoplasmic reticulum stress to the cell death program in mouse melanoma cells: effect of curcumin”. Apoptosis, Vol. 13, No. 7 Pgs 904-914 Pubmed. Beevers, C. S. et al. (2009). “Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells” Cancer Research 69, 3, 1000-1008, February 1, 2009.

Published Online First January 27, 2009 doi: 10. 1158/0008-5472. CAN-08-2367 Wiley-Liss Inc. American Association for Cancer Research. Chen, Y. S. (2003). “Curcumin inhibited the arylamines N-acetyl transferase activity, gene expression and DNA adduct formation. ”Toxicology in vitro Vol. 17, No. 3, pgs 323-323 Pubmed. Lee, J. (2005. ). “Curcumin inhibits interferon-? induced NF-? B and COX-2 in human A549 non-small cell lung cancer cells”. Biochemical & Biophysical Research Communications, Aug2005, Vol. 334 Issue 2, p313-318 Springer Lee, J. et al (2006).

“Interferon-alpha resistance can be reversed by inhibition of IFN-alpha-induced COX-2 expression potentially via STAT1 activation in A549 cells”. Oncol Rep. 2006 Jun; 15(6):1541-9 Pubmed Li, H. (2008). “Curcumin protects against cytotoxic and inflammatory effects of quartz particles but causes oxidative DNA damage in a rat lung epithelial cell line”. Toxicological Applic. Pharmacology. Vol 227, No. 1, Pgs 114-124, Pubmed Pae, H. et al. (2007). “Curcumin induces pro-apoptotic endoplasmic reticulum stress in human leukemia HL-60 cells”.

Communications, Feb2007, Vol. 353 Issue 4, p1040-1045 Pillai, R. G. et al. (2004). “Induction of apoptosis in human lung cancer cells by curcumin”. Cancer letters, 2004, Vol. 208, No. 2, Pg. 163-170, Sen, S. et al, (2005). “Curcumin enhances Vinorelbine mediated apoptosis in NSCLC cells by the mitochondrial pathway”. Communications, Jun2005, Vol. 331 Issue 4, p1245-1252. Song-Shei et al. (2008). “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. ” Cancer Letters, Vol. 272, issue 1, Pgs 77-70. Springer.

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