Iodine‑125 interstitial brachytherapy reduces tumor growth via Warburg effect inhibition in non‑small cell lung cancer A549 xenografts

Zhang,Jun; Zhu,Yangjun; Dong,Mengjie; Yang,Jun; Weng,Wanwen; Teng,Lisong

doi:10.3892/ol.2018.9346

Iodine‑125 interstitial brachytherapy reduces tumor growth via Warburg effect inhibition in non‑small cell lung cancer A549 xenografts

Authors:
- Jun Zhang
- Yangjun Zhu
- Mengjie Dong
- Jun Yang
- Wanwen Weng
- Lisong Teng
View Affiliations

Affiliations: Department of Nuclear Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Department of Ultrasonography, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Department of Surgical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Published online on: August 21, 2018 https://doi.org/10.3892/ol.2018.9346
Pages: 5969-5977
Copyright: © Zhang 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

Iodine‑125 interstitial brachytherapy (125I‑IBT) is an alternative and effective treatment option for unresectable non‑small cell lung cancer (NSCLC), and the Warburg effect is a determinant of tumor growth. The present study aimed to explore the influence of 125I‑IBT on tumor growth and the Warburg effect, and the potential mechanisms underlying NSCLC progression. Mice with A549 cell xenografts were evenly divided into a control group without 125I‑IBT, and three treatment groups receiving 125I‑IBT with 20, 40 and 60 Gy. Tumor volume (TV), maximum standardized uptake value (SUVmax) determined by 18F‑fluorodeoxyglucose (18F‑FDG) micro‑positron emission tomography/computed tomography and mean optical density (MOD) of mammalian target of rapamycin (mTOR), c‑Myc, hypoxia inducible factor‑1α (HIF‑1α) and glucose transporter 1 (GLUT1) staining were compared among groups. Tumor inhibition rate (TIR), 18F‑FDG uptake attenuation rate (FUAR) and expression suppression rate (ESR) were also calculated on day 14 and 28. The results demonstrated that the mean TV in the 60 and 40 Gy groups was smaller compared with the control TVs since days 14 and 16, respectively. The mean SUVmax value of the 60 Gy group at day 14, and all treatment group SUVmax values at day 28 were lower compared with the controls. In addition, the MOD of mTOR and GLUT1 was lower in the 60 Gy group, compared with the other groups, and c‑Myc and HIF‑1α values were lower in the 40 and 60 Gy groups, compared with the control and 20 Gy group (P<0.05). SUVmax positively correlated to TV (day 14, r=0.711; day 28, r=0.586) and the MOD of c‑Myc and GLUT1 (r=0.621 and 0.546, respectively; P<0.01). Furthermore, dose dependent increases were observed for TIR, FUAR and ESR. In conclusion, 125I‑IBT reduced tumor growth by inhibiting the Warburg effect, which may have resulted from downregulation of mTOR, c‑Myc, HIF‑1α and GLUT1 expression, particularly c‑Myc and GLUT1, in NSCLC A549 xenografts

View Figures

View References

1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R and Jemal A: Cancer treatment and survivorship statistics, 2016. CA Cancer J Clin. 66:271–289. 2016. View Article : Google Scholar : PubMed/NCBI
3	Huo X, Wang H, Yang J, Li X, Yan W, Huo B, Zheng G, Chai S, Wang J, Guan Z and Yu Z: Effectiveness and safety of CT-guided (125)I seed brachytherapy for postoperative locoregional recurrence in patients with non-small cell lung cancer. Brachytherapy. 15:370–380. 2016. View Article : Google Scholar : PubMed/NCBI
4	Li W, Guan J, Yang L, Zheng X, Yu Y and Jiang J: Iodine-125 brachytherapy improved overall survival of patients with inoperable stage III/IV non-small cell lung cancer versus the conventional radiotherapy. Med Oncol. 32:3952015. View Article : Google Scholar : PubMed/NCBI
5	Yu X, Li J, Zhong X and He J: Combination of Iodine-125 brachytherapy and chemotherapy for locally recurrent stage III non-small cell lung cancer after concurrent chemoradiotherapy. BMC Cancer. 15:6562015. View Article : Google Scholar : PubMed/NCBI
6	Li W, Dan G, Jiang J, Zheng Y, Zheng X and Deng D: Repeated iodine-125 seed implantations combined with external beam radiotherapy for the treatment of locally recurrent or metastatic stage III/IV non-small cell lung cancer: A retrospective study. Radiat Oncol. 11:1192016. View Article : Google Scholar : PubMed/NCBI
7	Chen HH, Jia RF, Yu L, Zhao MJ, Shao CL and Cheng WY: Bystander effects induced by continuous low-dose-rate 125I seeds potentiate the killing action of irradiation on human lung cancer cells in vitro. Int J Radiat Oncol Biol Phys. 72:1560–1566. 2008. View Article : Google Scholar : PubMed/NCBI
8	Qu A, Wang H, Li J, Wang J, Liu J, Hou Y, Huang L and Zhao Y: Biological effects of (125)i seeds radiation on A549 lung cancer cells: G2/M arrest and enhanced cell death. Cancer Invest. 32:209–217. 2014. View Article : Google Scholar : PubMed/NCBI
9	Wang Z, Zhao Z, Lu J, Chen Z, Mao A, Teng G and Liu F: A comparison of the biological effects of 125I seeds continuous low-dose-rate radiation and 60Co high-dose-rate gamma radiation on non-small cell lung cancer cells. PLoS One. 10:e1337282015.
10	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
11	Ganapathy V, Thangaraju M and Prasad PD: Nutrient transporters in cancer: Relevance to Warburg hypothesis and beyond. Pharmacol Ther. 121:29–40. 2009. View Article : Google Scholar : PubMed/NCBI
12	Liu J, Dong M, Sun X, Li W, Xing L and Yu J: Prognostic value of 18F-FDG PET/CT in surgical non-small cell lung cancer: A meta-analysis. PLoS One. 11:e1461952016.
13	Madsen PH, Holdgaard PC, Christensen JB and Høilund-Carlsen PF: Clinical utility of F-18 FDG PET-CT in the initial evaluation of lung cancer. Eur J Nucl Med Mol Imaging. 43:2084–2097. 2016. View Article : Google Scholar : PubMed/NCBI
14	Ruilong Z, Daohai X, Li G, Xiaohong W, Chunjie W and Lei T: Diagnostic value of 18F-FDG-PET/CT for the evaluation of solitary pulmonary nodules: A systematic review and meta-analysis. Nucl Med Commun. 38:67–75. 2017. View Article : Google Scholar : PubMed/NCBI
15	Sheikhbahaei S, Mena E, Yanamadala A, Reddy S, Solnes LB, Wachsmann J and Subramaniam RM: The value of FDG PET/CT in treatment response assessment, follow-up, and surveillance of lung cancer. AJR Am J Roentgenol. 208:420–433. 2017. View Article : Google Scholar : PubMed/NCBI
16	Cremonesi M, Gilardi L, Ferrari ME, Piperno G, Travaini LL, Timmerman R, Botta F, Baroni G, Grana CM, Ronchi S, et al: Role of interim ¹⁸F-FDG-PET/CT for the early prediction of clinical outcomes of non-small cell lung cancer (NSCLC) during radiotherapy or chemo-radiotherapy. A systematic review. Eur J Nucl Med Mol Imaging. 44:1915–1927. 2017. View Article : Google Scholar : PubMed/NCBI
17	Allen KT, Chin-Sinex H, DeLuca T, Pomerening JR, Sherer J, Watkins JR, Foley J, Jesseph JM and Mendonca MS: Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells. Free Radic Biol Med. 89:263–273. 2015. View Article : Google Scholar : PubMed/NCBI
18	Lv XB, Liu L, Cheng C, Yu B, Xiong L, Hu K, Tang J, Zeng L and Sang Y: SUN2 exerts tumor suppressor functions by suppressing the Warburg effect in lung cancer. Sci Rep. 5:179402015. View Article : Google Scholar : PubMed/NCBI
19	Liu T and Yin H: PDK1 promotes tumor cell proliferation and migration by enhancing the Warburg effect in non-small cell lung cancer. Oncol Rep. 37:193–200. 2017. View Article : Google Scholar : PubMed/NCBI
20	Ma JX, Jin ZD, Si PR, Liu Y, Lu Z, Wu HY, Pan X, Wang LW, Gong YF, Gao J and Zhao-shen L: Continuous and low-energy 125I seed irradiation changes DNA methyltransferases expression patterns and inhibits pancreatic cancer tumor growth. J Exp Clin Cancer Res. 30:352011. View Article : Google Scholar : PubMed/NCBI
21	Jian L, Zhongmin W, Kemin C, Yunfeng Z and Gang H: MicroPET-CT evaluation of interstitial brachytherapy in pancreatic carcinoma xenografts. Acta Radiol. 54:800–804. 2013. View Article : Google Scholar : PubMed/NCBI
22	Subocz E, Hałka J and Dziuk M: The role of FDG-PET in Hodgkin lymphoma. Contemp Oncol (Pozn). 21:104–114. 2017.PubMed/NCBI
23	Cremonesi M, Garibaldi C, Timmerman R, Ferrari M, Ronchi S, Grana CM, Travaini L, Gilardi L, Starzynska A, Ciardo D, et al: Interim ¹⁸F-FDG-PET/CT during chemo-radiotherapy in the management of oesophageal cancer patients. A systematic review. Radiother Oncol. 125:200–212. 2017. View Article : Google Scholar : PubMed/NCBI
24	Upadhyay M, Samal J, Kandpal M, Singh OV and Vivekanandan P: The Warburg effect: Insights from the past decade. Pharmacol Ther. 137:318–330. 2013. View Article : Google Scholar : PubMed/NCBI
25	Thorens B and Mueckler M: Glucose transporters in the 21st Century. Am J Physiol Endocrinol Metab. 298:E141–E145. 2010. View Article : Google Scholar : PubMed/NCBI
26	Lu H, Forbes RA and Verma A: Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem. 277:23111–23115. 2002. View Article : Google Scholar : PubMed/NCBI
27	Chen X, Qian Y and Wu S: The Warburg effect: Evolving interpretations of an established concept. Free Radic Biol Med. 79:253–263. 2015. View Article : Google Scholar : PubMed/NCBI
28	Dang CV: Links between metabolism and cancer. Genes Dev. 26:877–890. 2012. View Article : Google Scholar : PubMed/NCBI
29	Hsieh AL, Walton ZE, Altman BJ, Stine ZE and Dang CV: MYC and metabolism on the path to cancer. Semin Cell Dev Biol. 43:11–21. 2015. View Article : Google Scholar : PubMed/NCBI
30	Makinoshima H, Takita M, Saruwatari K, Umemura S, Obata Y, Ishii G, Matsumoto S, Sugiyama E, Ochiai A, Abe R, et al: Signaling through the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) axis is responsible for aerobic glycolysis mediated by glucose transporter in epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma. J Biol Chem. 290:17495–17504. 2015. View Article : Google Scholar : PubMed/NCBI
31	Toschi A, Lee E, Thompson S, Gadir N, Yellen P, Drain CM, Ohh M and Foster DA: Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. Cancer Lett. 299:72–79. 2010. View Article : Google Scholar : PubMed/NCBI
32	Dang CV: MYC on the path to cancer. Cell. 149:22–35. 2012. View Article : Google Scholar : PubMed/NCBI
33	Dang CV, Kim JW, Gao P and Yustein J: The interplay between MYC and HIF in cancer. Nat Rev Cancer. 8:51–56. 2008. View Article : Google Scholar : PubMed/NCBI
34	Liu J, Wang H, Qu A, Li J, Zhao Y and Wang J: Combined effects of C225 and 125-iodine seed radiation on colorectal cancer cells. Radiat Oncol. 8:2192013. View Article : Google Scholar : PubMed/NCBI
35	Tian Y, Xie Q, Tian Y, Liu Y, Huang Z, Fan C, Hou B, Sun D, Yao K and Chen T: Radioactive ¹²⁵I seed inhibits the cell growth, migration, and invasion of nasopharyngeal carcinoma by triggering DNA damage and inactivating VEGF-A/ERK signaling. PLoS One. 8:e740382013. View Article : Google Scholar : PubMed/NCBI
36	Cron GO, Beghein N, Crokart N, Chavée E, Bernard S, Vynckier S, Scalliet P and Gallez B: Changes in the tumor microenvironment during low-dose-rate permanent seed implantation iodine-125 brachytherapy. Int J Radiat Oncol Biol Phys. 63:1245–1251. 2005. View Article : Google Scholar : PubMed/NCBI
37	Hu L, Wang H, Huang L, Zhao Y and Wang J: The protective roles of ROS-mediated mitophagy on ¹²⁵I seeds radiation induced cell death in HCT116 cells. Oxid Med Cell Longev. 2016:94604622016. View Article : Google Scholar : PubMed/NCBI
38	Brown RS, Leung JY, Kison PV, Zasadny KR, Flint A and Wahl RL: Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer. J Nucl Med. 40:556–565. 1999.PubMed/NCBI
39	van Baardwijk A, Dooms C, van Suylen RJ, Verbeken E, Hochstenbag M, Dehing-Oberije C, Rupa D, Pastorekova S, Stroobants S, Buell U, et al: The maximum uptake of (18)F-deoxyglucose on positron emission tomography scan correlates with survival, hypoxia inducible factor-1alpha and GLUT-1 in non-small cell lung cancer. Eur J Cancer. 43:1392–1398. 2007. View Article : Google Scholar : PubMed/NCBI
40	Suzawa N, Ito M, Qiao S, Uchida K, Takao M, Yamada T, Takeda K and Murashima S: Assessment of factors influencing FDG uptake in non-small cell lung cancer on PET/CT by investigating histological differences in expression of glucose transporters 1 and 3 and tumour size. Lung Cancer. 72:191–198. 2011. View Article : Google Scholar : PubMed/NCBI
41	Chung JK, Lee YJ, Kim SK, Jeong JM, Lee DS and Lee MC: Comparison of [18F]fluorodeoxyglucose uptake with glucose transporter-1 expression and proliferation rate in human glioma and non-small-cell lung cancer. Nucl Med Commun. 25:11–17. 2004. View Article : Google Scholar : PubMed/NCBI
42	de Geus-Oei LF, van Krieken JH, Aliredjo RP, Krabbe PF, Frielink C, Verhagen AF, Boerman OC and Oyen WJ: Biological correlates of FDG uptake in non-small cell lung cancer. Lung Cancer. 55:79–87. 2007. View Article : Google Scholar : PubMed/NCBI
43	Dang CV: Rethinking the Warburg effect with Myc micromanaging glutamine metabolism. Cancer Res. 70:859–862. 2010. View Article : Google Scholar : PubMed/NCBI
44	Morrish F, Isern N, Sadilek M, Jeffrey M and Hockenbery DM: c-Myc activates multiple metabolic networks to generate substrates for cell-cycle entry. Oncogene. 28:2485–2491. 2009. View Article : Google Scholar : PubMed/NCBI
45	Collier JJ, Doan TT, Daniels MC, Schurr JR, Kolls JK and Scott DK: c-Myc is required for the glucose-mediated induction of metabolic enzyme genes. J Biol Chem. 278:6588–6595. 2003. View Article : Google Scholar : PubMed/NCBI
46	Broecker-Preuss M, Becher-Boveleth N, Bockisch A, Dührsen U and Müller S: Regulation of glucose uptake in lymphoma cell lines by c-MYC- and PI3K-dependent signaling pathways and impact of glycolytic pathways on cell viability. J Transl Med. 15:1582017. View Article : Google Scholar : PubMed/NCBI