Browse > Article
http://dx.doi.org/10.7314/APJCP.2015.16.14.5883

Treatment with a Small Synthetic Compound, KMU-193, induces Apoptosis in A549 Human Lung Carcinoma Cells through p53 Up-Regulation  

Choi, Eun Young (Department of Internal Medicine, Yeungnam University College of Medicine)
Shin, Kyeong-Cheol (Department of Internal Medicine, Yeungnam University College of Medicine)
Lee, Jinho (Department of Chemistry, Keimyung University)
Kwon, Taeg Kyu (Department of Immunology, School of Medicine, Keimyung University)
Kim, Shin (Department of Immunology, School of Medicine, Keimyung University)
Park, Jong-Wook (Department of Immunology, School of Medicine, Keimyung University)
Publication Information
Asian Pacific Journal of Cancer Prevention / v.16, no.14, 2015 , pp. 5883-5887 More about this Journal
Abstract
Despite recent advances in therapeutic strategies for lung cancer, mortality still is increasing. In the present study, we investigated the anti-cancer effects of KMU-193, 2-(4-Ethoxy-phenyl)-N-{5-[2-fluoro-4-(4-methylpiperazine-1-carbonyl)-phenylamino]-1H-indazol-3-yl}-acetamide in a human non-small cell lung cancer cell line A549. KMU-193 strongly inhibited the proliferation of A549 cells, but it did not have anti-proliferative effect in other types of cancer cell lines. KMU-193 further induced apoptosis in association with activation of caspase-3 and cleavage of PLC-${\gamma}1$. However, KMU-193 had no apoptotic effect in untransformed cells such as TMCK-1 and BEAS-2B. Interestingly, pretreatment with z-VAD-fmk, a pan-caspase inhibitor, strongly abrogated KMU-193-induced apoptosis. KMU-193 treatment enhanced the expression levels of p53 and PUMA. Importantly, p53 siRNA transfection attenuated KMU-193-induced apoptosis. Collectively, these results for the first time demonstrate that KMU-193 has strong apoptotic effects on A549 cells and these are largely mediated through caspase-3- and p53-dependent pathways.
Keywords
KMU-193; lung cancer; Apoptosis; caspase; p53;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
1 Ahmad N, Feyes DK, Nieminen AL, et al (1997). Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst, 89, 1881-6.   DOI
2 Amaral JD, Xavier JM, Steer CJ, et al (2010). The role of p53 in apoptosis. Discov Med, 9, 145-52.
3 Bae SS, Perry DK, Oh YS, et al (2000). Proteolytic cleavage of phospholipase C-gamma1 during apoptosis in Molt-4 cells. FASEB J, 14, 1083-92.
4 Binder D, Hegenbarth K (2013). Emerging options for the management of non-small cell lung cancer. Clin Med Insights Oncol, 7, 221-34.
5 Donnerstag B, Ohlenschlager G, Cinatl J, et al (1996). Reduced glutathione and S-acetylglutathione as selective apoptosisinducing agents in cancer therapy. Cancer Lett, 110, 63-70.   DOI
6 Emoto Y, Manome Y, Meinhardt G, et al (1995). Proteolytic activation of protein kinase C delta by an ICE-like protease in apoptotic cells. EMBO J, 14, 6148-56.
7 Feng Z (2010). p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartment. Cold Spring Harb Perspect Biol, 2, 1057.   DOI
8 Fossella F, Pereira JR, von Pawel J, et al (2003). Randomized, multinational, phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for advanced non-small-cell lung cancer: the TAX 326 study group. J Clin Oncol, 21, 3016-24.   DOI
9 Fridman JS, Lowe SW (2003). Control of apoptosis by p53. Oncogene, 22, 9030-40.   DOI
10 Hong H, Park YK, Park JW, et al (2012). BAI, a 3-aminoindazole derivative, inhibits interleukin-1beta-induced expression of cyclooxygenase-2 in A549 human airway cells. Int J Mol Med, 29, 454-60.
11 Jemal A, Center MM, DeSantis C, et al (2010). Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev, 19, 1893-907.   DOI
12 Kim S, Lee J, Jang BC, et al (2013). BAI, a novel cyclindependent kinase inhibitor induces apoptosis in A549 cells through activation of caspases and inactivation of Akt. J Cell Biochem, 114, 282-93.   DOI
13 Lee J, Choi H, Kim KH, et al (2008). Synthesis and biological evaluation of 3,5-diaminoindazoles as cyclin-dependent kinase inhibitors. Bioorg Med Chem Lett, 18, 2292-5.   DOI
14 Li Q, Ren FQ, Yang CL, et al (2015). Anti-proliferation effects of isorhamnetin on lung cancer cells in vitro and in vivo. Asian Pac J Cancer Prev, 16, 3035-42.   DOI
15 Liu CJ, Zhang XL, Luo DY, et al (2015). Exogenous p53 upregulated modulator of apoptosis (PUMA) decreases growth of lung cancer A549 cells. Asian Pac J Cancer Prev, 16, 741-6.   DOI
16 Logue SE, Martin SJ (2008). Caspase activation cascades in apoptosis. Biochem Soc Trans, 36, 1-9.   DOI   ScienceOn
17 Nakano K, Vousden KH (2001). PUMA, a novel proapoptotic gene, is induced by p53. Mol Cell, 7, 683-94.   DOI
18 Saika K, Machii R (2012). Cancer mortality attributable to tobacco by region based on the WHO Global Report. Jpn J Clin Oncol, 42, 771-2.   DOI
19 Oh JH, Park EJ, Park JW, et al (2010). A novel cyclin-dependent kinase inhibitor down-regulates tumor necrosis factor-alpha (TNF-alpha)-induced expression of cell adhesion molecules by inhibition of NF-kappaB activation in human pulmonary epithelial cells. Int Immunopharmacol, 10, 572-9.   DOI
20 Rufini A, Tucci P, Celardo I, et al (2013). Senescence and aging: the critical roles of p53. Oncogene, 32, 5129-43.   DOI
21 Scagliotti GV, De Marinis F, Rinaldi M, et al (2002). Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol, 20, 4285-91.   DOI
22 Schiller JH, Harrington D, Belani CP, et al (2002). Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med, 346, 92-8.   DOI
23 Shin HC, Song DW, Baek WK, et al (2009). Anticancer activity and differentially expressed genes in head and neck cancer cells treated with a novel cyclin-dependent kinase inhibitor. Chemotherapy, 55, 353-62.   DOI
24 Siegel R, DeSantis C, Virgo K, et al (2012). Cancer treatment and survivorship statistics, 2012. CA Cancer J Clin, 62, 220-41.   DOI
25 Sledge GW, Jr. (2005). What is targeted therapy? J Clin Oncol, 23, 1614-5.   DOI
26 Wu DM, Zhang P, Xu GC, et al (2015). Pemetrexed induces G1 phase arrest and apoptosis through inhi`biting Akt activation in human non small lung cancer cell line A549. Asian Pac J Cancer Prev, 16, 1507-13.   DOI
27 Xu Y, Zhang Y, Ma S (2011). EGFR inhibitors with concurrent thoracic radiation therapy for locally advanced non-small cell lung cancer. Lung Cancer, 73, 249-55.   DOI