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.
Highlights
Osteosarcoma (OSA) is the most frequent primary malignant bone tumor in children and adolescents [1,2]
To determine whether miR-29b is involved in regulating the radiosensitization effects of zoledronic acid (ZOL), we examined miR-29b expression levels in several OSA cell lines (KHOS, U2OS, HOS, MG63) and in 10 pairs of OSA tissues and matched adjacent histologically normal tissues by qRT-PCR
We found that miR-29b levels were significantly lower in the OSA cell lines and tumor tissues than in non-malignant tissues (Figure 1a,b)
Summary
Osteosarcoma (OSA) is the most frequent primary malignant bone tumor in children and adolescents [1,2]. Cancers 2020, 12, 698 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 has a high potential to kill radiochemo-resistant cancer stem cells (CSCs) compared to low LET radiation [15,16,17,18,19]. 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]
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