Chen Wei-Ting, Tsai Yuan-Hsin, Tan Peggy, Hsu Fei-Ting, Wang Hui-Min David, Lin Wei-Chin, Lin Feng-Huei, Wu Ching-Te
Department of Psychosomatics, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan, R.O.C.
Ph.D. Program in Tissue Engineering and Regenerative Medicine, National Chung Hsing University, Taichung, Taiwan, R.O.C.
Anticancer Res. 2023 Mar;43(3):1193-1199. doi: 10.21873/anticanres.16265.
BACKGROUND/AIM: Osteosarcoma (OS) is a common primary malignancy of bone in adolescents. Its highly metastatic characteristics can lead to treatment failure and poor prognosis. Although standard treatments, including surgery, radiotherapy, and chemotherapy, have progressed in the past decade, treatment options to overcome metastatic progression remain sparse. Fluoxetine, an anti-depressant, has been widely used in patients with cancer for their mental issues and was reported to possess antitumor potential. However, the effect of fluoxetine on OS remains unclear.
In this study, we used cell viability, invasion/migration transwell, wound-healing and aortic ring assays to identify the effects of fluoxetine on metastasis and progression in OS.
Fluoxetine induced cytotoxicity in OS cells by activating both extrinsic/intrinsic apoptosis signaling pathways. Proliferation and anti-apoptosis-related factors such as cyclin D1 and X-linked inhibitor of apoptosis were suppressed by fluoxetine. Additionally, fluoxetine suppressed the invasive/migratory abilities of OS and inhibited the development of angiogenesis by reducing the phosphorylation of signal transducer and activator of transcription 3 (STAT3). Metastasis-associated factors, vascular endothelial growth factors, matrix metallopeptidase 2 and -9, were all reduced in OS cells by fluoxetine treatment.
Fluoxetine not only induces cytotoxicity and apoptosis of OS cells, but also suppresses metastasis and angiogenesis by targeting STAT3.
背景/目的：骨肉瘤（OS）是青少年常见的原发性骨恶性肿瘤。其高度转移的特性可导致治疗失败和预后不良。尽管包括手术、放疗和化疗在内的标准治疗在过去十年中取得了进展，但克服转移进展的治疗选择仍然有限。氟西汀是一种抗抑郁药，已广泛用于癌症患者的精神问题治疗，并有报道称其具有抗肿瘤潜力。然而，氟西汀对骨肉瘤的作用仍不清楚。
在本研究中，我们使用细胞活力、侵袭/迁移Transwell、伤口愈合和主动脉环实验来确定氟西汀对骨肉瘤转移和进展的影响。
氟西汀通过激活外源性/内源性凋亡信号通路诱导骨肉瘤细胞的细胞毒性。氟西汀抑制了增殖和抗凋亡相关因子，如细胞周期蛋白D1和X连锁凋亡抑制蛋白。此外，氟西汀抑制了骨肉瘤的侵袭/迁移能力，并通过降低信号转导和转录激活因子3（STAT3）的磷酸化来抑制血管生成的发展。氟西汀处理后，骨肉瘤细胞中与转移相关的因子、血管内皮生长因子、基质金属蛋白酶2和-9均减少。
氟西汀不仅诱导骨肉瘤细胞的细胞毒性和凋亡，还通过靶向STAT3抑制转移和血管生成。
