Department of Radiation Science, Hirosaki University Graduate School of Health Sciences, Hirosaki, Aomori 036‑8564, Japan.
Oncol Rep. 2024 Aug;52(2). doi: 10.3892/or.2024.8768. Epub 2024 Jul 4.
Arsenic trioxide (ATO) is expected to be a chemical drug with antitumor activity against acute promyelocytic leukemia (APL), a type of acute myeloid leukemia. In Japan, its antitumor effects were confirmed in clinical trials for APL, and it has been approved in various countries around the world. However, there have been no reports on ATO's antitumor effects on radioresistant leukemia cells, which can be developed during radiotherapy and in combination with therapeutic radiation beams. The present study sought to clarify the antitumor effect of ATO on APL cells with radiation resistance and determine its efficacy when combined with ionizing radiation (IR). The radiation‑resistant HL60 (Res‑HL60) cell line was generated by subjecting the native cells to 4‑Gy irradiation every week for 4 weeks. The half‑maximal inhibitory concentration (IC) for cell proliferation by ATO on native cell was 0.87 µM (R=0.67), while the IC for cell proliferation by ATO on Res‑HL60 was 2.24 µM (R=0.91). IR exposure increased the sub‑G1 and G2/M phase ratios in both cell lines. The addition of ATO resulted in a higher population of G2/M after 24 h rather than 48 h. When the rate of change in the sub‑G1 phase was examined in greater detail, the sub‑G1 phase in both control cells without ATO significantly increased by exposure to IR at 24 h, but only under the condition of 2 Gy irradiation, it had continued to increase at 48 h. Res‑HL60 supplemented with ATO showed a higher rate of sub‑G1 change at 24 h; however, 2 Gy irradiation resulted in a decrease compared with the control. There was a significant increase in the ratio of the G2/M phase in cells after incubation with ATO for 24 h, and exposure to 2 Gy irradiation caused an even greater increase. To determine whether the inhibition of cell proliferation and cell cycle disruptions is related to reactive oxygen species (ROS) activity, intracellular ROS levels were measured with a flow cytometric assay. Although the ROS levels of Res‑HL60 were higher than those of native cells in the absence of irradiation, they did not change after 0.5 or 2 Gy irradiation. Furthermore, adding ATO to Res‑HL60 reduced intracellular ROS levels. These findings provide important information that radioresistant leukemia cells respond differently to the antitumor effect of ATO and the combined effect of IR.
三氧化二砷（ATO）有望成为一种具有抗肿瘤活性的化学药物，可用于治疗急性早幼粒细胞白血病（APL），这是一种急性髓系白血病。在日本，其在 APL 的临床试验中已证实具有抗肿瘤作用，并已在世界各国获得批准。然而，目前尚无关于 ATO 对放射抗性白血病细胞的抗肿瘤作用的报道，放射抗性白血病细胞可能在放射治疗期间产生，并与治疗性射线束联合产生。本研究旨在阐明 ATO 对具有放射抗性的 APL 细胞的抗肿瘤作用，并确定其与电离辐射（IR）联合使用的疗效。通过每周对原代细胞进行 4Gy 照射，4 周共照射 4 次，生成放射抗性 HL60（Res-HL60）细胞系。ATO 对原代细胞的细胞增殖的半最大抑制浓度（IC）为 0.87µM（R=0.67），而 ATO 对 Res-HL60 的细胞增殖的 IC 为 2.24µM（R=0.91）。IR 暴露增加了两种细胞系的亚 G1 和 G2/M 期比例。加用 ATO 后，24 小时后 G2/M 期细胞比例更高，而非 48 小时后。更详细地检查亚 G1 期变化率时，在没有 ATO 的对照细胞中，IR 在 24 小时时显著增加亚 G1 期，但仅在 2Gy 照射的条件下，亚 G1 期在 48 小时时继续增加。加用 ATO 的 Res-HL60 在 24 小时时显示出更高的亚 G1 变化率，但与对照相比，2Gy 照射时则降低。用 ATO 孵育 24 小时后，G2/M 期细胞的比例显著增加，2Gy 照射后则进一步增加。为了确定细胞增殖抑制和细胞周期紊乱是否与活性氧（ROS）活性有关，我们使用流式细胞术测定了细胞内 ROS 水平。尽管在没有照射的情况下，Res-HL60 的 ROS 水平高于原代细胞，但在 0.5 或 2Gy 照射后没有变化。此外，在 Res-HL60 中加入 ATO 可降低细胞内 ROS 水平。这些发现提供了重要信息，表明放射抗性白血病细胞对 ATO 的抗肿瘤作用和 IR 的联合作用的反应不同。
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