Phloretin induces apoptosis of non-small cell lung carcinoma A549 cells via JNK1/2 and p38 MAPK pathways

Min,Jie; Li,Xu; Huang,Kenan; Tang,Hua; Ding,Xinyu; Qi,Chen; Qin,Xiong; Xu,Zhifei

doi:10.3892/or.2015.4325

Phloretin induces apoptosis of non-small cell lung carcinoma A549 cells via JNK1/2 and p38 MAPK pathways

Authors:
- Jie Min
- Xu Li
- Kenan Huang
- Hua Tang
- Xinyu Ding
- Chen Qi
- Xiong Qin
- Zhifei Xu
View Affiliations

Affiliations: Department of Thoracic and Cardiovascular Surgery, Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China, Department of Thoracic and Cardiovascular Surgery, First People's Hospital of Shanghai, Shanghai Jiaotong University, Shanghai, P.R. China
Published online on: October 2, 2015 https://doi.org/10.3892/or.2015.4325
Pages: 2871-2879
Copyright: © Min et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Phloretin (Ph) existing in apples, pears and various vegetables is known to have antitumor activities in several cancer cell lines. However, little is known about its effect on human lung cancer cells. The aim of the present study was to see whether Ph could induce apoptosis of non-small cell lung cancer (NSCLC) cells, and explore the possible underlying mechanism of action. We found that Ph markedly induced cell apoptosis of NSCLC cell line A549, and inhibited the migration of A549 cells in a dose-dependent manner. The expression level of BAX, cleaved caspase-3 and -9, and degraded form of PARP was increased and Bcl-2 was decreased after Ph treatment. In addition, the phosphorylation of P38 MAPK, ERK1/2 and JNK1/2 was increased in a dose‑dependent manner in parallel with Ph treatment. Inhibition of P38 MAPK and JNK1/2 by specific inhibitors significantly abolished the Ph-induced activation of the caspase-3 and -9. In vivo tumor-suppression assay further indicated that Ph (20 mg/kg) displayed a more significant inhibitory effect on A549 xenografts in tumor growth. All these findings indicate that Ph is able to inhibit NSCLC A549 cell growth by inducing apoptosis through P38 MAPK and JNK1/2 pathways, and therefore may prove to be an adjuvant to the treatment of NSCLC.

View Figures

View References

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	Shankar S, Ganapathy S, Hingorani SR and Srivastava RK: EGCG inhibits growth, invasion, angiogenesis and metastasis of pancreatic cancer. Front Biosci. 13:440–452. 2008. View Article : Google Scholar
3	Boyer J and Liu RH: Apple phytochemicals and their health benefits. Nutr J. 3:52004. View Article : Google Scholar : PubMed/NCBI
4	Fordham JB, Naqvi AR and Nares S: Leukocyte production of inflammatory mediators is inhibited by the antioxidants phloretin, silymarin, hesperetin, and resveratrol. Mediators Inflamm. 2014:9387122014. View Article : Google Scholar : PubMed/NCBI
5	Zhu SP, Liu G, Wu XT, Chen FX, Liu JQ, Zhou ZH, Zhang JF and Fei SJ: The effect of phloretin on human γδ T cells killing colon cancer SW-1116 cells. Int Immunopharmacol. 15:6–14. 2013. View Article : Google Scholar
6	Devi MA and Das NP: In vitro effects of natural plant polyphenols on the proliferation of normal and abnormal human lymphocytes and their secretions of interleukin-2. Cancer. 69:191–196. 1993.
7	Nelson JA and Falk RE: The efficacy of phloridzin and phloretin on tumor cell growth. Anticancer Res. 13:2287–2292. 1993.PubMed/NCBI
8	Yang KC, Tsai CY, Wang YJ, Wei PL, Lee CH, Chen JH, Wu CH and Ho YS: Apple polyphenol phloretin potentiates the anticancer actions of paclitaxel through induction of apoptosis in human hep G2 cells. Mol Carcinog. 48:420–431. 2009. View Article : Google Scholar
9	Zare Jahromi M, Ranjbarian P and Shiravi S: Cytotoxicity evaluation of Iranian propolis and calcium hydroxide on dental pulp fibroblasts. J Dent Res Dent Clin Dent Prospects. 8:130–133. 2014.PubMed/NCBI
10	Shen J, Song G, An M, Li X, Wu N, Ruan K, Hu J and Hu R: The use of hollow mesoporous silica nanospheres to encapsulate bortezomib and improve efficacy for non-small cell lung cancer therapy. Biomaterials. 35:316–326. 2014. View Article : Google Scholar
11	Zuo Y, Yang J, He J, Zhao Y and He Y: An uncoordinated-5 homolog B receptor monoclonal antibody regulates A375 melanoma cell migration. Monoclon Antib Immunodiagn Immunother. 33:280–286. 2014. View Article : Google Scholar : PubMed/NCBI
12	Wu CH, Ho YS, Tsai CY, Wang YJ, Tseng H, Wei PL, Lee CH, Liu RS and Lin SY: In vitro and in vivo study of phloretin-induced apoptosis in human liver cancer cells involving inhibition of type II glucose transporter. Int J Cancer. 124:2210–2219. 2009. View Article : Google Scholar : PubMed/NCBI
13	Shao X, Bai N, He K, Ho CT, Yang CS and Sang S: Apple polyphenols, phloretin and phloridzin: New trapping agents of reactive dicarbonyl species. Chem Res Toxicol. 21:2042–2050. 2008. View Article : Google Scholar : PubMed/NCBI
14	Diefenbach J and Bürkle A: Introduction to poly(ADP-ribose) metabolism. Cell Mol Life Sci. 62:721–730. 2005. View Article : Google Scholar : PubMed/NCBI
15	Björklund M and Koivunen E: Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta 2005. 1755:37–69. 2005.
16	Dong ZH, Wang DC, Liu TT, Li FH, Liu RL, Wei JW and Zhou CL: The roles of MAPKs in rabbit nucleus pulposus cell apoptosis induced by high osmolality. Eur Rev Med Pharmacol Sci. 18:2835–2845. 2014.PubMed/NCBI
17	Han R, Liang H, Qin ZH and Liu CY: Crotoxin induces apoptosis and autophagy in human lung carcinoma cells in vitro via activation of the P38 MAPK signaling pathway. Acta Pharmacol Sin. 35:1323–1332. 2014. View Article : Google Scholar : PubMed/NCBI
18	Palanivel K, Kanimozhi V and Kadalmani B: Verrucarin A alters cell-cycle regulatory proteins and induces apoptosis through reactive oxygen species-dependent P38 MAPK activation in the human breast cancer cell line MCF-7. Tumour Biol. 35:10159–10167. 2014. View Article : Google Scholar : PubMed/NCBI
19	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
20	Jemal A, Center MM, DeSantis C and Ward EM: Global patterns of cancer incidence and mortality rates and trends. Cancer Epidemiol Biomarkers Prev. 19:1893–1907. 2010. View Article : Google Scholar : PubMed/NCBI
21	Woodle ES and Kulkarni S: Programmed cell death. Transplantation. 66:681–691. 1998. View Article : Google Scholar : PubMed/NCBI
22	Bobba A, Amadoro G, La Piana G, Calissano P and Atlante A: Glycolytic enzyme upregulation and numbness of mitochondrial activity characterize the early phase of apoptosis in cerebellar granule cells. Apoptosis. 20:10–28. 2015. View Article : Google Scholar
23	Schwingel TE, Klein CP, Nicoletti NF, Dora CL, Hadrich G, Bica CG, Lopes TG, da Silva VD and Morrone FB: Effects of the compounds resveratrol, rutin, quercetin, and quercetin nanoemulsion on oxaliplatin-induced hepatotoxicity and neurotoxicity in mice. Naunyn Schmiedebergs Arch Pharmacol. 387:837–848. 2014. View Article : Google Scholar : PubMed/NCBI
24	Hong JY, Park SH, Min HY, Park HJ and Lee SK: Anti-proliferative effects of evodiamine in human lung cancer cells. J Cancer Prev. 19:7–13. 2014. View Article : Google Scholar : PubMed/NCBI
25	Zhao B and Hu M: Gallic acid reduces cell viability, proliferation, invasion and angiogenesis in human cervical cancer cells. Oncol Lett. 6:1749–1755. 2013.
26	Wang L, Li ZW, Zhang W, Xu R, Gao F, Liu YF and Li YJ: Synthesis, crystal structure, and biological evaluation of a series of phloretin derivatives. Molecules. 19:16447–16457. 2014. View Article : Google Scholar : PubMed/NCBI
27	Chang WT, Huang WC and Liou CJ: Evaluation of the anti-inflammatory effects of phloretin and phlorizin in lipopolysaccharide-stimulated mouse macrophages. Food Chem. 134:972–979. 2012. View Article : Google Scholar : PubMed/NCBI
28	Kim MS, Kwon JY, Kang NJ, Lee KW and Lee HJ: Phloretin induces apoptosis in H-Ras MCF10A human breast tumor cells through the activation of p53 via JNK and p38 mitogen-activated protein kinase signaling. Ann N Y Acad Sci. 1171:479–483. 2009. View Article : Google Scholar : PubMed/NCBI
29	Gross A, Jockel J, Wei MC and Korsmeyer SJ: Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. EMBO J. 17:3878–3885. 1998. View Article : Google Scholar : PubMed/NCBI
30	Park WH and Kim SH: MAPK inhibitors augment gallic acid-induced A549 lung cancer cell death through the enhancement of glutathione depletion. Oncol Rep. 30:513–519. 2013.PubMed/NCBI
31	Hsiao YC, Kuo WH, Chen PN, Chang HR, Lin TH, Yang WE, Hsieh YS and Chu SC: Flavanone and 2′-OH flavanone inhibit metastasis of lung cancer cells via down-regulation of proteinase activities and MAPK pathway. Chem Biol Interact. 167:193–06. 2007. View Article : Google Scholar : PubMed/NCBI