Effect of low- and high-linear energy transfer radiation on in vitro and orthotopic in vivo models of osteosarcoma by activation of caspase-3 and -9

Kim,Eun  Ho; Kim,Mi-Sook; Lee,Kyung-Hee; Sai,Sei; Jeong,Youn  Kyoung; Koh,Jae-Soo; Kong,Chang-Bae

doi:10.3892/ijo.2017.4102

Effect of low- and high-linear energy transfer radiation on in vitro and orthotopic in vivo models of osteosarcoma by activation of caspase-3 and -9

Authors:
- Eun Ho Kim
- Mi-Sook Kim
- Kyung-Hee Lee
- Sei Sai
- Youn Kyoung Jeong
- Jae-Soo Koh
- Chang-Bae Kong
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Affiliations: Division of Heavy Ion Clinical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea, Department of Radiation Oncology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea, Department of Orthopaedic Surgery, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea, Department of Basic Medical Sciences for Radiation Damages, National Institute of Radiological Sciences, Chiba, Japan, Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea, Department of Pathology, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Republic of Korea
Published online on: August 25, 2017 https://doi.org/10.3892/ijo.2017.4102
Pages: 1124-1134
Copyright: © Kim et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Osteosarcoma (OS) is a malignant tumor of the bone derived from primitive transformed cells of the mesenchymal origin. Local low-linear energy transfer (LET) radiotherapy has limited benefits on OS owing to its radioresistance. Thus, this study aimed to investigate the effects of high-LET radiation on human OS. Therefore, the human OS cell lines, U2O2 and KHOS/NP, were examined in vitro, or an orthotopic mouse xenograft model was studied in vivo after treatment with low-LET (gamma-ray) and high-LET (neutron) radiation. Notably, OS cells were significantly more sensitive to high-LET radiation in vitro and in the orthotopic xenograft tumor model. Specifically, neutron radiation treatment increased the relative percentage of apoptotic sub-G1 phase cells via caspase-3/9 activation; increased intracellular reactive oxygen species, autophagy, and DNA damage; and decreased invasion and migration. Similarly, the mean size of gamma-irradiated (8 Gy) orthotopic KHOS/NP OS was 195 mm3 at 6 weeks after gamma-irradiation (8 Gy), but it was only 150 mm3 in mice treated with high-LET neutron radiotherapy. Significantly, our results provide a rationale for the use of high-LET radiotherapy to treat patients with OS.

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1	Unni KK and Dahlin DC: Osteosarcoma: Pathology and classification. Semin Roentgenol. 24:143–152. 1989. View Article : Google Scholar : PubMed/NCBI
2	Ciernik IF, Niemierko A, Harmon DC, Kobayashi W, Chen YL, Yock TI, Ebb DH, Choy E, Raskin KA, Liebsch N, et al: Proton-based radiotherapy for unresectable or incompletely resected osteosarcoma. Cancer. 117:4522–4530. 2011. View Article : Google Scholar : PubMed/NCBI
3	Ta HT, Dass CR, Choong PF and Dunstan DE: Osteosarcoma treatment: State of the art. Cancer Metastasis Rev. 28:247–263. 2009. View Article : Google Scholar : PubMed/NCBI
4	Schwarz R, Bruland O, Cassoni A, Schomberg P and Bielack S: The role of radiotherapy in oseosarcoma. Cancer Treat Res. 152:147–164. 2009. View Article : Google Scholar
5	Beck JC, Wara WM, Bovill EG Jr and Phillips TL: The role of radiation therapy in the treatment of osteosarcoma. Radiology. 120:163–165. 1976. View Article : Google Scholar : PubMed/NCBI
6	DeLaney TF, Park L, Goldberg SI, Hug EB, Liebsch NJ, Munzenrider JE and Suit HD: Radiotherapy for local control of osteosarcoma. Int J Radiat Oncol Biol Phys. 61:492–498. 2005. View Article : Google Scholar : PubMed/NCBI
7	Imai R, Kamada T, Tsuji H, Tsujii H, Tsuburai Y and Tatezaki S; Working Group for Bone and Soft Tissue Sarcomas: Cervical spine osteosarcoma treated with carbon-ion radiotherapy. Lancet Oncol. 7:1034–1035. 2006. View Article : Google Scholar : PubMed/NCBI
8	Mankin HJ, Hornicek FJ, Rosenberg AE, Harmon DC and Gebhardt MC: Survival data for 648 patients with osteosarcoma treated at one institution. Clin Orthop Relat Res. 429:286–291. 2004. View Article : Google Scholar
9	Lisle JW, Choi JY, Horton JA, Allen MJ and Damron TA: Metastatic osteosarcoma gene expression differs in vitro and in vivo. Clin Orthop Relat Res. 466:2071–2080. 2008. View Article : Google Scholar : PubMed/NCBI
10	Skarsgard LD: Radiobiology with heavy charged particles: A historical review. Phys Med. 14(Suppl 1): 1–19. 1998.
11	Okayasu R: Repair of DNA damage induced by accelerated heavy ions - a mini review. Int J Cancer. 130:991–1000. 2012. View Article : Google Scholar
12	Kamada T, Tsujii H, Blakely EA, Debus J, De Neve W, Durante M, Jäkel O, Mayer R, Orecchia R, Pötter R, et al: Carbon ion radiotherapy in Japan: An assessment of 20 years of clinical experience. Lancet Oncol. 16:e93–e100. 2015. View Article : Google Scholar : PubMed/NCBI
13	Kanai T, Endo M, Minohara S, Miyahara N, Koyama-ito H, Tomura H, Matsufuji N, Futami Y, Fukumura A, Hiraoka T, et al: Biophysical characteristics of HIMAC clinical irradiation system for heavy-ion radiation therapy. Int J Radiat Oncol Biol Phys. 44:201–210. 1999. View Article : Google Scholar : PubMed/NCBI
14	Zhang W, Tanaka M, Sugimoto Y, Takigawa T and Ozaki T: Carbon-ion radiotherapy of spinal osteosarcoma with long-term follow. Eur Spine J. 25(Suppl 1): 113–117. 2016. View Article : Google Scholar
15	Matsunobu A, Imai R, Kamada T, Imaizumi T, Tsuji H, Tsujii H, Shioyama Y, Honda H and Tatezaki S; Working Group for Bone and Soft Tissue Sarcomas: Impact of carbon ion radiotherapy for unresectable osteosarcoma of the trunk. Cancer. 118:4555–4563. 2012. View Article : Google Scholar : PubMed/NCBI
16	Futamura G, Kawabata S, Siba H, Kuroiwa T, Suzuki M, Kondo N, Ono K, Sakurai Y, Tanaka M, Todo T, et al: A case of radiation-induced osteosarcoma treated effectively by boron neutron capture therapy. Radiat Oncol. 9:2372014. View Article : Google Scholar : PubMed/NCBI
17	Lee DH, Seo SH and Ji YH: Characteristics of radiation generated by BNCT irradiator of Hanaro nucleasr reactor. J Korean Soc Ther Radiol Oncol. 24:s1582006.
18	Eom KY, Wu HG, Park HJ, Huh SN, Ye SJ, Lee DH and Park SW: Evaluation of biological characteristics of neutron beam generated from MC50 cyclotron. J Korean Soc Ther Radiol Oncol. 24:280–284. 2006.
19	Luu HH, Kang Q, Park JK, Si W, Luo Q, Jiang W, Yin H, Montag AG, Simon MA, Peabody TD, et al: An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis. Clin Exp Metastasis. 22:319–329. 2005. View Article : Google Scholar : PubMed/NCBI
20	Song WS, Jeon DG, Cho WH, Kong CB, Cho SH and Lee SY and Lee SY: Spontaneous necrosis and additional tumor necrosis induced by preoperative chemotherapy for osteosarcoma: A case-control study. J Orthop Sci. 20:174–179. 2015. View Article : Google Scholar
21	Kong CB, Byun BH, Lim I, Choi CW, Lim SM, Song WS, Cho WH, Jeon DG, Koh JS, Yoo JY, et al: ¹⁸F-FDG PET SUVmax as an indicator of histopathologic response after neoadjuvant chemotherapy in extremity osteosarcoma. Eur J Nucl Med Mol Imaging. 40:728–736. 2013. View Article : Google Scholar : PubMed/NCBI
22	McIlwain DR, Berger T and Mak TW: Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol. 5:a0086562013. View Article : Google Scholar : PubMed/NCBI
23	Los M, Mozoluk M, Ferrari D, Stepczynska A, Stroh C, Renz A, Herceg Z, Wang ZQ and Schulze-Osthoff K: Activation and caspase-mediated inhibition of PARP: A molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. Mol Biol Cell. 13:978–988. 2002. View Article : Google Scholar : PubMed/NCBI
24	Goodhead DT, Thacker J and Cox R: Weiss Lecture. Effects of radiations of different qualities on cells: Molecular mechanisms of damage and repair. Int J Radiat Biol. 63:543–556. 1993. View Article : Google Scholar : PubMed/NCBI
25	Goodhead DT: Energy deposition stochastics and track structure: What about the target? Radiat Prot Dosimetry. 122:3–15. 2006. View Article : Google Scholar
26	Anderson RM, Marsden SJ, Wright EG, Kadhim MA, Goodhead DT and Griffin CS: Complex chromosome aberrations in peripheral blood lymphocytes as a potential biomarker of exposure to high-LET alpha-particles. Int J Radiat Biol. 76:31–42. 2000. View Article : Google Scholar : PubMed/NCBI
27	Brenner DJ and Ward JF: Constraints on energy deposition and target size of multiply damaged sites associated with DNA double-strand breaks. Int J Radiat Biol. 61:737–748. 1992. View Article : Google Scholar : PubMed/NCBI
28	Tanaka K, Gajendiran N, Endo S, Komatsu K, Hoshi M and Kamada N: Neutron energy-dependent initial DNA damage and chromosomal exchange. J Radiat Res (Tokyo). 40(Suppl): S36–S44. 1999. View Article : Google Scholar