Radiosensitization of non-small cell lung cancer by kaempferol

Kuo,Wei-Ting; Tsai,Yuan-Chung; Wu,His-Chin; Ho,Yung-Jen; Chen,Yueh-Sheng; Yao,Chen-Han; Yao,Chun-Hsu

doi:10.3892/or.2015.4204

Radiosensitization of non-small cell lung cancer by kaempferol

Authors:
- Wei-Ting Kuo
- Yuan-Chung Tsai
- His-Chin Wu
- Yung-Jen Ho
- Yueh-Sheng Chen
- Chen-Han Yao
- Chun-Hsu Yao
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Affiliations: Institute of Biomedical Engineering, National Taiwan University, Taipei 10051, Taiwan, R.O.C., Graduate Institute of Clinical Medical Science, China Medical University, Taichung 40402, Taiwan, R.O.C., School of Medicine, China Medical University, Taichung 40402, Taiwan, R.O.C., Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung 40402, Taiwan, R.O.C., Viator Catholic High School, Taichung 40402, Taiwan, R.O.C.
Published online on: August 19, 2015 https://doi.org/10.3892/or.2015.4204
Pages: 2351-2356

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Abstract

The aim of the present study was to determine whether kaempferol has a radiosensitization potential for lung cancer in vitro and in vivo. The in vitro radio-sensitization activity of kaempferol was elucidated in A-549 lung cancer cells by using an MTT (3-(4 5-dimethylthiazol-2-yl)-25-diphenyltetrazolium bromide) assay, cell cycle analysis and clonogenic assay. The in vivo activity was evaluated in the BALB/c nude mouse xenograft model of A-549 cells by hematoxylin and eosin staining and immunohistochemistry, and the tumor volume was recorded. Protein levels of the apoptotic pathway were detected by western blot analysis. Treatment with kaempferol inhibited the growth of A-549 cells through activation of apoptotic pathway. However, the same doses did not affect HFL1 normal lung cell growth. Kaempferol induced G2/M cell cycle arrest and the enhancement of radiation-induced death and clonogenic survival inhibition. The in vivo data showed that kaempferol increased tumor cell apoptosis and killing of radiation. In conclusion, the findings demonstrated that kaempferol increased tumor cell killing by radiation in vitro and in vivo through inhibition of the AKT/PI3K and ERK pathways and activation of the mitochondria apoptosis pathway. The results of the present study provided solid evidence that kaempferol is a safe and potential radiosensitizer.

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1	Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 127:2893–2917. 2010. View Article : Google Scholar
2	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
3	Herbst RS, Heymach JV and Lippman SM: Lung cancer. N Engl J Med. 359:1367–1380. 2008. View Article : Google Scholar : PubMed/NCBI
4	Pisters KM, Evans WK, Azzoli CG, Kris MG, Smith CA, Desch CE, Somerfield MR, Brouwers MC, Darling G, Ellis PM, et al Cancer Care Ontario; American Society of Clinical Oncology: Cancer Care Ontario and American Society of Clinical Oncology adjuvant chemotherapy and adjuvant radiation therapy for stages I-IIIA resectable non small-cell lung cancer guideline. J Clin Oncol. 25:5506–5518. 2007. View Article : Google Scholar : PubMed/NCBI
5	Crinò L, Weder W, van Meerbeeck J and Felip E; ESMO Guidelines Working Group: Early stage and locally advanced (non-metastatic) non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 21(Suppl 5): v103–v115. 2010. View Article : Google Scholar : PubMed/NCBI
6	Furuse K, Fukuoka M, Kawahara M, Nishikawa H, Takada Y, Kudoh S, Katagami N and Ariyoshi Y: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. J Clin Oncol. 17:2692–2699. 1999.PubMed/NCBI
7	Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker S Jr, Olak J, Stover D, Strawn JR, Turrisi AT, et al American Society of Clinical Oncology: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: Update 2003. J Clin Oncol. 22:330–353. 2004. View Article : Google Scholar
8	Eberhardt W, Pöttgen C and Stuschke M: Chemoradiation paradigm for the treatment of lung cancer. Nat Clin Pract Oncol. 3:188–199. 2006. View Article : Google Scholar : PubMed/NCBI
9	Wardman P: Chemical radiosensitizers for use in radiotherapy. Clin Oncol (R Coll Radiol). 19:397–417. 2007. View Article : Google Scholar
10	Kim IA, Bae SS, Fernandes A, Wu J, Muschel RJ, McKenna WG, Birnbaum MJ and Bernhard EJ: Selective inhibition of Ras, phosphoinositide 3 kinase, and Akt isoforms increases the radiosensitivity of human carcinoma cell lines. Cancer Res. 65:7902–7910. 2005.PubMed/NCBI
11	Reardon DB, Contessa JN, Mikkelsen RB, Valerie K, Amir C, Dent P and Schmidt-Ullrich RK: Dominant negative EGFR-CD533 and inhibition of MAPK modify JNK1 activation and enhance radiation toxicity of human mammary carcinoma cells. Oncogene. 18:4756–4766. 1999. View Article : Google Scholar : PubMed/NCBI
12	Fokas E, Im JH, Hill S, Yameen S, Stratford M, Beech J, Hackl W, Maira SM, Bernhard EJ, McKenna WG, et al: Dual inhibition of the PI3K/mTOR pathway increases tumor radiosensitivity by normalizing tumor vasculature. Cancer Res. 72:239–248. 2012. View Article : Google Scholar
13	Wang T, Hu YC, Dong S, Fan M, Tamae D, Ozeki M, Gao Q, Gius D and Li JJ: Co-activation of ERK, NF-kappaB, and GADD45beta in response to ionizing radiation. J Biol Chem. 280:12593–12601. 2005. View Article : Google Scholar : PubMed/NCBI
14	Kuo WT, Ho YJ, Kuo SM, Lin FH, Tsai FJ, Chen YS, Dong GC and Yao CH: Induction of the mitochondria apoptosis pathway by phytohemagglutinin erythroagglutinating in human lung cancer cells. Ann Surg Oncol. 18:848–856. 2011. View Article : Google Scholar
15	Miean KH and Mohamed S: Flavonoid (myricetin, quercetin, kaempferol, luteolin, and apigenin) content of edible tropical plants. J Agric Food Chem. 49:3106–3112. 2001. View Article : Google Scholar : PubMed/NCBI
16	Agarwal OP and Nagaratnam A: Radioprotective property of flavonoids in mice. Toxicon. 19:201–204. 1981. View Article : Google Scholar : PubMed/NCBI
17	Park JS, Rho HS, Kim DH and Chang IS: Enzymatic preparation of kaempferol from green tea seed and its antioxidant activity. J Agric Food Chem. 54:2951–2956. 2006. View Article : Google Scholar : PubMed/NCBI
18	Li W, Du B, Wang T, Wang S and Zhang J: Kaempferol induces apoptosis in human HCT116 colon cancer cells via the Ataxia-Telangiectasia Mutated-p53 pathway with the involvement of p53 upregulated modulator of apoptosis. Chem Biol Interact. 177:121–127. 2009. View Article : Google Scholar
19	Luo H, Rankin GO, Liu L, Daddysman MK, Jiang BH and Chen YC: Kaempferol inhibits angiogenesis and VEGF expression through both HIF dependent and independent pathways in human ovarian cancer cells. Nutr Cancer. 61:554–563. 2009. View Article : Google Scholar : PubMed/NCBI
20	DuPont MS, Day AJ, Bennett RN, Mellon FA and Kroon PA: Absorption of kaempferol from endive, a source of kaempferol-3-glucuronide, in humans. Eur J Clin Nutr. 58:947–954. 2004. View Article : Google Scholar : PubMed/NCBI
21	Nöthlings U, Murphy SP, Wilkens LR, Henderson BE and Kolonel LN: Flavonols and pancreatic cancer risk: The multiethnic cohort study. Am J Epidemiol. 166:924–931. 2007. View Article : Google Scholar : PubMed/NCBI
22	Leung HW, Lin CJ, Hour MJ, Yang WH, Wang MY and Lee HZ: Kaempferol induces apoptosis in human lung non-small carcinoma cells accompanied by an induction of antioxidant enzymes. Food Chem Toxicol. 45:2005–2013. 2007. View Article : Google Scholar : PubMed/NCBI
23	Jeong JC, Kim MS, Kim TH and Kim YK: Kaempferol induces cell death through ERK and Akt-dependent down-regulation of XIAP and survivin in human glioma cells. Neurochem Res. 34:991–1001. 2009. View Article : Google Scholar
24	Ackland ML, van de Waarsenburg S and Jones R: Synergistic antiproliferative action of the flavonols quercetin and kaempferol in cultured human cancer cell lines. In Vivo. 19:69–76. 2005.PubMed/NCBI
25	Kowalski J, Samojedny A, Paul M, Pietsz G and Wilczok T: Effect of kaempferol on the production and gene expression of monocyte chemoattractant protein-1 in J774.2 macrophages. Pharmacol Rep. 57:107–112. 2005.PubMed/NCBI
26	Sotibrán AN, Ordaz-Téllez MG and Rodríguez-Arnaiz R: Flavonoids and oxidative stress in Drosophila melanogaster. Mutat Res. 726:60–65. 2011. View Article : Google Scholar : PubMed/NCBI
27	Moon SS, Rahman MA, Manir MM and Jamal Ahamed VS: Kaempferol glycosides and cardenolide glycosides, cytotoxic constituents from the seeds of Draba nemorosa (Brassicaceae). Arch Pharm Res. 33:1169–1173. 2010. View Article : Google Scholar : PubMed/NCBI
28	Xu X, Xie H, Hao J, Jiang Y and Wei X: Flavonoid glycosides from the seeds of Litchi chinensis. J Agric Food Chem. 59:1205–1209. 2011. View Article : Google Scholar : PubMed/NCBI
29	Cory S and Adams JM: The Bcl2 family: Regulators of the cellular life-or-death switch. Nat Rev Cancer. 2:647–656. 2002. View Article : Google Scholar : PubMed/NCBI
30	Fletcher JI, Meusburger S, Hawkins CJ, Riglar DT, Lee EF, Fairlie WD, Huang DC and Adams JM: Apoptosis is triggered when prosurvival Bcl-2 proteins cannot restrain Bax. Proc Natl Acad Sci USA. 105:18081–18087. 2008. View Article : Google Scholar : PubMed/NCBI
31	Nguyen TT, Tran E, Ong CK, Lee SK, Do PT, Huynh TT, Nguyen TH, Lee JJ, Tan Y, Ong CS, et al: Kaempferol-induced growth inhibition and apoptosis in A549 lung cancer cells is mediated by activation of MEK-MAPK. J Cell Physiol. 197:110–121. 2003. View Article : Google Scholar : PubMed/NCBI
32	Pawlik TM and Keyomarsi K: Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys. 59:928–942. 2004. View Article : Google Scholar : PubMed/NCBI
33	Franken NA, Rodermond HM, Stap J, Haveman J and van Bree C: Clonogenic assay of cells in vitro. Nat Protoc. 1:2315–2319. 2006. View Article : Google Scholar