Development of single nanometer-sized ultrafine oxygen bubbles to overcome the hypoxia-induced resistance to radiation therapy via the suppression of hypoxia-inducible factor‑1α

Iijima,Misaki; Gombodorj,Navchaa; Tachibana,Yoshiaki; Tachibana,Kohsuke; Yokobori,Takehiko; Honma,Kyoko; Nakano,Takashi; Asao,Takayuki; Kuwahara,Ryusuke; Aoyama,Kazuhiro; Yasuda,Hidehiro; Kelly,Matthew; Kuwano,Hiroyuki; Yamanouchi,Dai

doi:10.3892/ijo.2018.4248

Development of single nanometer-sized ultrafine oxygen bubbles to overcome the hypoxia-induced resistance to radiation therapy via the suppression of hypoxia-inducible factor‑1α

Authors:
- Misaki Iijima
- Navchaa Gombodorj
- Yoshiaki Tachibana
- Kohsuke Tachibana
- Takehiko Yokobori
- Kyoko Honma
- Takashi Nakano
- Takayuki Asao
- Ryusuke Kuwahara
- Kazuhiro Aoyama
- Hidehiro Yasuda
- Matthew Kelly
- Hiroyuki Kuwano
- Dai Yamanouchi
View Affiliations

Affiliations: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan, Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan, Sigma Technology Inc., Hitachinaka, Ibaraki 312-0053, Japan, Big Data Center for Integrative Analysis, Gunma University Initiative for Advance Research (GIAR), Maebashi, Gunma 371-8511, Japan, Research Center for Ultra-High Voltage Electron Microscopy, Osaka University, Ibaraki, Osaka 567-0047, Japan, Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA
Published online on: January 18, 2018 https://doi.org/10.3892/ijo.2018.4248
Pages: 679-686
Copyright: © Iijima 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

Radiation therapy can result in severe side-effects, including the development of radiation resistance. The aim of this study was to validate the use of oxygen nanobubble water to overcome resistance to radiation in cancer cell lines via the suppression of the hypoxia-inducible factor 1-α (HIF‑1α) subunit. Oxygen nanobubble water was created using a newly developed method to produce nanobubbles in the single-nanometer range with the ΣPM-5 device. The size and concentration of the oxygen nanobubbles in the water was examined using a cryo-transmission electron microscope. The nanobubble size was ranged from 2 to 3 nm, and the concentration of the nanobubbles was calculated at 2x1018 particles/ml. Cell viability and HIF-1α levels were evaluated in EBC‑1 lung cancer and MDA‑MB‑231 breast cancer cells treated with or without the nanobubble water and radiation under normoxic and hypoxic conditions in vitro. The cancer cells grown in oxygen nanobubble-containing media exhibited a clear suppression of hypoxia-induced HIF‑1α expression compared to the cells grown in media made with distilled water. Under hypoxic conditions, the EBC‑1 and MDA‑MB231 cells displayed resistance to radiation compared to the cells cultured under normoxic cells. The use of oxygen nanobubble medium significantly suppressed the hypoxia-induced resistance to radiation compared to the use of normal medium at 2, 6, 10 and 14 Gy doses. Importantly, the use of nanobubble media did not affect the viability and radiation sensitivity of the cancer cell lines, or the non‑cancerous cell line, BEAS‑2B, under normoxic conditions. This newly created single-nanometer range oxygen nanobubble water, without any additives, may thus prove to be a promising agent which may be used to overcome the hypoxia-induced resistance of cancer cells to radiation via the suppression of HIF-1α.

View Figures

View References

1	Nakagawa K, Watanabe SI, Kunitoh H and Asamura H; The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: The Lung Cancer Surgical Study Group of the Japan Clinical Oncology Group: Past activities, current status and future direction. Jpn J Clin Oncol. 47:194–199. 2017. View Article : Google Scholar : PubMed/NCBI
2	Arriagada R, Auperin A, Burdett S, Higgins JP, Johnson DH, Le Chevalier T, Le Pechoux C, Parmar MK, Pignon JP, Souhami RL, et al NSCLC Meta-analyses Collaborative Group: Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: Two meta-analyses of individual patient data. Lancet. 375:1267–1277. 2010. View Article : Google Scholar : PubMed/NCBI
3	Fiteni F, Westeel V and Bonnetain F: Surrogate endpoints for overall survival in lung cancer trials: A review. Expert Rev Anticancer Ther. 17:447–454. 2017. View Article : Google Scholar : PubMed/NCBI
4	Shafiq J, Hanna TP, Vinod SK, Delaney GP and Barton MB: A Population-based Model of Local Control and Survival Benefit of Radiotherapy for Lung Cancer. Clin Oncol (R Coll Radiol). 28:627–638. 2016. View Article : Google Scholar
5	Yang CF, Chan DY, Speicher PJ, Gulack BC, Wang X, Hartwig MG, Onaitis MW, Tong BC, D’Amico TA, Berry MF, et al: Role of adjuvant therapy in a population-based cohort of patients with early-stage small-cell lung cancer. J Clin Oncol. 34:1057–1064. 2016. View Article : Google Scholar : PubMed/NCBI
6	Giridhar P, Mallick S, Rath GK and Julka PK: Radiation induced lung injury: Prediction, assessment and management. Asian Pac J Cancer Prev. 16:2613–2617. 2015. View Article : Google Scholar : PubMed/NCBI
7	Bradley J and Movsas B: Radiation pneumonitis and esophagitis in thoracic irradiation. Cancer Treat Res. 128:43–64. 2006. View Article : Google Scholar
8	Marks LB, Yu X, Vujaskovic Z, Small W Jr, Folz R and Anscher MS: Radiation-induced lung injury. Semin Radiat Oncol. 13:333–345. 2003. View Article : Google Scholar : PubMed/NCBI
9	Bertout JA, Patel SA and Simon MC: The impact of O₂ availability on human cancer. Nat Rev Cancer. 8:967–975. 2008. View Article : Google Scholar : PubMed/NCBI
10	Kunz M and Ibrahim SM: Molecular responses to hypoxia in tumor cells. Mol Cancer. 2:232003. View Article : Google Scholar : PubMed/NCBI
11	Ke Q and Costa M: Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 70:1469–1480. 2006. View Article : Google Scholar : PubMed/NCBI
12	Semenza GL: Hypoxia-inducible factors: Mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 33:207–214. 2012. View Article : Google Scholar : PubMed/NCBI
13	Keith B, Johnson RS and Simon MC: HIF1α and HIF2α: Sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer. 12:9–22. 2011. View Article : Google Scholar : PubMed/NCBI
14	Wilson WR and Hay MP: Targeting hypoxia in cancer therapy. Nat Rev Cancer. 11:393–410. 2011. View Article : Google Scholar : PubMed/NCBI
15	Harrison LB, Chadha M, Hill RJ, Hu K and Shasha D: Impact of tumor hypoxia and anemia on radiation therapy outcomes. Oncologist. 7:492–508. 2002. View Article : Google Scholar : PubMed/NCBI
16	Brown JM and Wilson WR: Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 4:437–447. 2004. View Article : Google Scholar : PubMed/NCBI
17	Shannon AM, Bouchier-Hayes DJ, Condron CM and Toomey D: Tumour hypoxia, chemotherapeutic resistance and hypoxia-related therapies. Cancer Treat Rev. 29:297–307. 2003. View Article : Google Scholar : PubMed/NCBI
18	Shimoda LA and Semenza GL: HIF and the lung: Role of hypoxia-inducible factors in pulmonary development and disease. Am J Respir Crit Care Med. 183:152–156. 2011. View Article : Google Scholar : PubMed/NCBI
19	Goudar RK and Vlahovic G: Hypoxia, angiogenesis, and lung cancer. Curr Oncol Rep. 10:277–282. 2008. View Article : Google Scholar : PubMed/NCBI
20	Chen X, Wang P, Guo F, Wang X, Wang J, Xu J, Yuan D, Zhang J and Shao C: Autophagy enhanced the radioresistance of non-small cell lung cancer by regulating ROS level under hypoxia condition. Int J Radiat Biol. 93:764–770. 2017. View Article : Google Scholar : PubMed/NCBI
21	Ren W, Mi D, Yang K, Cao N, Tian J, Li Z and Ma B: The expression of hypoxia-inducible factor-1α and its clinical significance in lung cancer: A systematic review and meta-analysis. Swiss Med Wkly. 143:w138552013.
22	Yang SL, Ren QG, Wen L and Hu JL: Clinicopathological and prognostic significance of hypoxia-inducible factor-1 alpha in lung cancer: A systematic review with meta-analysis. J Huazhong Univ Sci Technolog Med Sci. 36:321–327. 2016. View Article : Google Scholar : PubMed/NCBI
23	Hung JJ, Yang MH, Hsu HS, Hsu WH, Liu JS and Wu KJ: Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. Thorax. 64:1082–1089. 2009. View Article : Google Scholar : PubMed/NCBI
24	Shibamoto Y, Sugie C, Ito M and Ogino H: The Japanese experiences with hypoxia-targeting pharmacoradiotherapy: From hypoxic cell sensitisers to radiation-activated prodrugs. Expert Opin Pharmacother. 5:2459–2467. 2004. View Article : Google Scholar : PubMed/NCBI
25	Owen J, McEwan C, Nesbitt H, Bovornchutichai P, Averre R, Borden M, McHale AP, Callan JF and Stride E: Reducing tumour hypoxia via oral administration of oxygen nanobubbles. PLoS One. 11:e01680882016. View Article : Google Scholar : PubMed/NCBI
26	Agarwal A, Ng WJ and Liu Y: Principle and applications of microbubble and nanobubble technology for water treatment. Chemosphere. 84:1175–1180. 2011. View Article : Google Scholar : PubMed/NCBI
27	Tachibana Y, Tachibana K, Harada K, Sasajima S, Tamahashi K, Honma K and Matsumoto Y: Method, a bubble generating nozzle, and an apparatus for generating micro-nano bubbles. Sigma Technology, Inc, JP, PCT/JP2013/066902. Filed. August 29–2013, issued July 23, 2014.
28	Takahashi M, Chiba K and Li P: Free-radical generation from collapsing microbubbles in the absence of a dynamic stimulus. J Phys Chem B. 111:1343–1347. 2007. View Article : Google Scholar : PubMed/NCBI
29	Kheir JN, Polizzotti BD, Thomson LM, O’Connell DW, Black KJ, Lee RW, Wilking JN, Graham AC, Bell DC and McGowan FX: Bulk manufacture of concentrated oxygen gas-filled microparticles for intravenous oxygen delivery. Adv Healthc Mater. 2:1131–1141. 2013. View Article : Google Scholar : PubMed/NCBI
30	Vaupel P, Thews O and Hoeckel M: Treatment resistance of solid tumors: Role of hypoxia and anemia. Med Oncol. 18:243–259. 2001. View Article : Google Scholar
31	Kim BM and Hong Y, Lee S, Liu P, Lim JH, Lee YH, Lee TH, Chang KT and Hong Y: Therapeutic implications for overcoming radiation resistance in cancer therapy. Int J Mol Sci. 16:26880–26913. 2015. View Article : Google Scholar : PubMed/NCBI
32	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI
33	Chan DA, Krieg AJ, Turcotte S and Giaccia AJ: HIF gene expression in cancer therapy. Methods Enzymol. 435:323–345. 2007. View Article : Google Scholar : PubMed/NCBI
34	Xia Y, Choi HK and Lee K: Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem. 49:24–40. 2012. View Article : Google Scholar : PubMed/NCBI
35	Semenza GL: Hypoxia-inducible factor 1 and cancer pathogenesis. IUBMB Life. 60:591–597. 2008. View Article : Google Scholar : PubMed/NCBI
36	Poprac P, Jomova K, Simunkova M, Kollar V, Rhodes CJ and Valko M: Targeting free radicals in oxidative stress-related human diseases. Trends Pharmacol Sci. 38:592–607. 2017. View Article : Google Scholar : PubMed/NCBI
37	Gào X and Schöttker B: Reduction-oxidation pathways involved in cancer development: A systematic review of literature reviews. Oncotarget. 8:51888–51906. 2017.PubMed/NCBI
38	Daly BD, Cerfolio RJ and Krasna MJ: Role of surgery following induction therapy for stage III non-small cell lung cancer. Surg Oncol Clin N Am. 20:721–732. 2011. View Article : Google Scholar : PubMed/NCBI
39	Xu YP, Li B, Xu XL and Mao WM: Is there a survival benefit in patients with stage IIIA (N2) non-small cell lung cancer receiving neoadjuvant chemotherapy and/or radiotherapy prior to surgical resection: A systematic review and meta-analysis. Medicine (Baltimore). 94:e8792015. View Article : Google Scholar
40	Baker S, Dahele M, Lagerwaard FJ and Senan S: A critical review of recent developments in radiotherapy for non-small cell lung cancer. Radiat Oncol. 11:1152016. View Article : Google Scholar : PubMed/NCBI
41	Campbell BA, Ball D and Mornex F: Multidisciplinary lung cancer meetings: Improving the practice of radiation oncology and facing future challenges. Respirology. 20:192–198. 2015. View Article : Google Scholar : PubMed/NCBI
42	Scagliotti GV, Novello S, Rapetti S and Papotti M: Current state-of-the-art therapy for advanced squamous cell lung cancer. Am Soc Clin Oncol Educ Book. 33:354–358. 2013. View Article : Google Scholar
43	Haasbeek CJ, Slotman BJ and Senan S: Radiotherapy for lung cancer: Clinical impact of recent technical advances. Lung Cancer. 64:1–8. 2009. View Article : Google Scholar
44	Cascales A, Martinetti F, Belemsagha D and Le Pechoux C: Challenges in the treatment of early non-small cell lung cancer: What is the standard, what are the challenges and what is the future for radiotherapy? Transl Lung Cancer Res. 3:195–204. 2014.
45	Huo M, Gorayski P, Pinkham MB and Lehman M: Advances in radiotherapy technology for non-small cell lung cancer: What every general practitioner should know. Aust Fam Physician. 45:805–809. 2016.PubMed/NCBI
46	Bhandari P, Wang X and Irudayaraj J: Oxygen nanobubble tracking by light scattering in single cells and tissues. ACS Nano. 11:2682–2688. 2017. View Article : Google Scholar : PubMed/NCBI
47	Bhandari PN, Cui Y, Elzey BD, Goergen CJ, Long CM and Irudayaraj J: Oxygen nanobubbles revert hypoxia by methylation programming. Sci Rep. 7:92682017. View Article : Google Scholar : PubMed/NCBI
48	Luo H, Wang L, Schulte BA, Yang A, Tang S and Wang GY: Resveratrol enhances ionizing radiation-induced premature senescence in lung cancer cells. Int J Oncol. 43:1999–2006. 2013. View Article : Google Scholar : PubMed/NCBI
49	Millet P, Granotier C, Etienne O and Boussin FD: Radiation-induced upregulation of telomerase activity escapes PI3-kinase inhibition in two malignant glioma cell lines. Int J Oncol. 43:375–382. 2013. View Article : Google Scholar : PubMed/NCBI
50	Lechtman E and Pignol JP: Interplay between the gold nanoparticle sub-cellular localization, size, and the photon energy for radiosensitization. Sci Rep. 7:132682017. View Article : Google Scholar : PubMed/NCBI