Kozhukharova Irina, Zemelko Victoria, Kovaleva Zoya, Alekseenko Larisa, Lyublinskaya Olga, Nikolsky Nikolay
Department of Intracellular Signaling and Transport, Institute of Cytology Russian Academy of Sciences, Tikhoretskiy Prospect 4, Saint-Petersburg, 194064, Russia.
Int J Hematol. 2018 Mar;107(3):286-296. doi: 10.1007/s12185-017-2346-6. Epub 2017 Oct 11.
Doxorubicin (Dox) is an effective anticancer drug with known activity against a wide spectrum of malignancies, hematologic malignancies in particular. Despite extensive clinical use, the mechanisms of its side effects and negative action on normal cells remain under study. The aim of this study was to investigate the effect of Dox on cultured human mesenchymal stem cells (MSCs) derived from menstrual blood (eMSCs), bone marrow (BMSCs) and adipose tissue (AMSCs). Dox treatment in high doses decreased the survival of MSCs in a dose-dependent manner. Clinically relevant low doses of Dox induced premature senescence of eMSCs, BMSCs and AMSCs, but did not kill the cells. Dox caused cell cycle arrest and formation of γ-H2AX foci, and increased the number of SA-β-gal-positive cells. BMSCs entered premature senescence earlier than other MSCs. It has been reported that neural-like cells differentiated from MSCs of various origins are more sensitive to Dox than their parent cells. Dox-treated differentiated MSCs exhibited lower viability and earlier generation of γ-H2AX foci. Dox administration inhibited secretory activity in neural-like cells. These findings suggest that a clinically relevant Dox dose damages cultured MSCs, inducing their premature senescence. MSCs are more resistant to this damage than differentiated cells.
阿霉素（Dox）是一种有效的抗癌药物，对多种恶性肿瘤，尤其是血液系统恶性肿瘤具有已知活性。尽管在临床上广泛使用，但其副作用机制以及对正常细胞的负面影响仍在研究中。本研究的目的是调查阿霉素对源自月经血（eMSCs）、骨髓（BMSCs）和脂肪组织（AMSCs）的培养人骨髓间充质干细胞（MSCs）的影响。高剂量阿霉素处理以剂量依赖方式降低了间充质干细胞的存活率。临床相关的低剂量阿霉素诱导eMSCs、BMSCs和AMSCs过早衰老，但未杀死细胞。阿霉素导致细胞周期停滞和γ-H2AX焦点形成，并增加了SA-β-半乳糖苷酶阳性细胞的数量。BMSCs比其他间充质干细胞更早进入过早衰老状态。据报道，源自各种来源间充质干细胞的神经样细胞比其亲代细胞对阿霉素更敏感。经阿霉素处理的分化间充质干细胞表现出较低的活力和更早产生γ-H2AX焦点。阿霉素给药抑制了神经样细胞的分泌活性。这些发现表明，临床相关剂量的阿霉素会损害培养的间充质干细胞，诱导其过早衰老。间充质干细胞比分化细胞对这种损伤更具抵抗力。
