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衰老细胞清除剂无法预防化疗对骨量的不良影响。

The adverse effects of chemotherapy on bone mass are not prevented by senolytics.

作者信息

Ali Md Mohsin, Simmons Pilar, Warren Aaron, Gatrell Landon B, Resende-Coelho Ana, McElroy Taylor, Allen Antiño R, Almeida Maria

机构信息

Division of Endocrinology and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.

Division of Radiation Health, University of Arkansas for Medical Sciences, Little Rock, AR, USA.

出版信息

Sci Rep. 2025 May 19;15(1):17279. doi: 10.1038/s41598-025-01717-5.

Abstract

Cancer survivors experience many short- and long-term side effects caused by chemotherapy, including low bone mineral density and deterioration of bone microarchitecture. Administration of chemotherapy drugs to disease free mice causes rapid bone loss. However, whether the bone effects persist throughout life and the mechanisms responsible remain unclear. One plausible cause of chemotherapy-induced bone loss is cellular senescence. Here, female mice were administered doxorubicin, cyclophosphamide and docetaxel, a chemotherapy regimen commonly used in breast cancer patients, in combination with two types of drugs that kill senescent cells (senolytics), namely dasatinib + quercetin or piperlongumine. Mice receiving chemotherapy experienced a rapid decrease in trabecular bone mass, which was detectable two weeks after initiation of treatment and was associated with increased expression of senescence markers. None of the senolytics prevented the effects of chemotherapy on bone mass. In separate experiments, we examined the skeletal effects of chemotherapy six and twelve months after the cessation of treatment. The deleterious effects of chemotherapy on bone mass remained up to 12 months after cessation of treatment, while no markers of senescence could be detected in bone. Together, these results suggest that the deleterious effects of this chemotherapy regimen on bone health are not due to the accumulation of senescent cells.

摘要

癌症幸存者会经历化疗引起的许多短期和长期副作用,包括低骨矿物质密度和骨微结构恶化。给无病小鼠施用化疗药物会导致快速的骨质流失。然而,骨骼影响是否会持续一生以及其背后的机制仍不清楚。化疗诱导骨质流失的一个可能原因是细胞衰老。在这里,给雌性小鼠施用多柔比星、环磷酰胺和多西他赛(一种乳腺癌患者常用的化疗方案),并联合使用两种杀死衰老细胞的药物(衰老细胞溶解剂),即达沙替尼+槲皮素或胡椒碱。接受化疗的小鼠小梁骨量迅速减少,在治疗开始两周后即可检测到,并且与衰老标志物表达增加有关。没有一种衰老细胞溶解剂能阻止化疗对骨量的影响。在单独的实验中,我们在治疗停止6个月和12个月后检查了化疗对骨骼的影响。化疗对骨量的有害影响在停止治疗后长达12个月仍存在,而在骨骼中未检测到衰老标志物。总之,这些结果表明,这种化疗方案对骨骼健康的有害影响并非由于衰老细胞的积累。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/604e/12089391/5c8c266d7e07/41598_2025_1717_Fig1_HTML.jpg

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