Carbon-Ion Beam Irradiation Alone or in Combination with Zoledronic acid Effectively Kills Osteosarcoma Cells

Abstract

Osteosarcoma (OSA) is the most common malignant bone tumor in children and adolescents. The overall five-year survival rate for all bone cancers is below 70%; however, when the cancer has spread beyond the bone, it is about 15-30%. Herein, we evaluated the effects of carbon-ion beam irradiation alone or in combination with zoledronic acid (ZOL) on OSA cells. Carbon-ion beam irradiation in combination with ZOL significantly inhibited OSA cell proliferation by arresting cell cycle progression and initiating KHOS and U2OS cell apoptosis, compared to treatments with carbon-ion beam irradiation, X-ray irradiation, and ZOL alone. Moreover, we observed that this combination greatly inhibited OSA cell motility and invasion, accompanied by the suppression of the Pi3K/Akt and MAPK signaling pathways, which are related to cell proliferation and survival, compared to individual treatments with carbon-ion beam or X-ray irradiation, or ZOL. Furthermore, ZOL treatment upregulated microRNA (miR)-29b expression; the combination with a miR-29b mimic further decreased OSA cell viability via activation of the caspase 3 pathway. Thus, ZOL-mediated enhancement of carbon-ion beam radiosensitivity may occur via miR-29b upregulation; co-treatment with the miR-29b mimic further decreased OSA cell survival. These findings suggest that the carbon-ion beam irradiation in combination with ZOL has high potential to increase OSA cell death.Cancers 2020, 12, 698 2 of 15 increasing amount of evidence has demonstrated that high linear energy transfer (LET) carbon-ion radiation therapy is suitable for targeting many kinds of radioresistant tumors such as those associated with bone and soft tissue malignancies including OSA [9][10][11][12][13][14] because it primarily does not elicit cell cycle-and oxygen-dependent cell-killing effects; it also has a high potential to kill radiochemo-resistant cancer stem cells (CSCs) compared to low LET radiation [15][16][17][18][19]. However, although carbon ion beam radiotherapy treatment has yielded promising results, the prognosis of OSA still remains unsatisfactory; developing novel combinational therapeutic strategies to further improve overall survival is required.Bisphosphonates comprise the most important class of osteoclast-mediated bone resorption inhibitors and are used extensively for treating skeletal diseases such as postmenopausal osteoporosis and tumor-induced osteolysis [20,21]. Zoledronic acid (ZOL), a third-generation nitrogen-containing bisphosphonate, is an inhibitor of osteoclast-mediated bone resorption that has demonstrated efficacy in treating bone metastases in cancer patients with breast, prostate, lung, and other solid tumors [22][23][24]. ZOL significantly enhances radiation-induced apoptosis and decreases cell viability, suggesting that it may exhibit radiosensitizing effects [25][26][27][28][29][30][31][32][33]. We have previously reported that ZOL enhanced γ-ray radiation-induced DNA damage and suppressed OSA cell migration and invasion [34,35]. Recently, we also found that it signi...

Radiotherapy in the Management of Pediatric and Adult Osteosarcomas: A Multi-Institutional Cohort Analysis

“…Another way to enhance the efficacy of RT for osteosarcoma is the use of high linear energy transfer carbon-ion RT (CIRT) that causes more double-strand breaks in DNA than photon or proton therapy, with great dose conformity [22][23][24]. It has been shown as a promising method of overcoming radioresistance of osteosarcoma cells [25]. Researchers from the Gunma University Heavy Ion Medical Center (Japan) presented a series of patients treated with CIRT for unresectable bone and soft tissue tumors, which included seven patients with osteosarcoma [7].…”

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