Abstract
Mesenchymal stem cells (MSCs) are an integral part of the bone marrow niche and aid in the protection, regeneration and proliferation of hematopoietic stem cells after exposure to myelotoxic taxane anti-cancer agents, but the influence of taxane compounds on MSCs themselves remains incompletely understood. Here, we show that bone marrow-derived MSCs are highly sensitive even to low concentrations of the prototypical taxane compound paclitaxel. While MSCs remained metabolically viable, they were strongly impaired regarding both their proliferation and their functional capabilities after exposure to paclitaxel. Paclitaxel treatment resulted in reduced cell migration, delays in cellular adhesion and significant dose-dependent inhibition of the stem cells’ characteristic multi-lineage differentiation potential. Cellular morphology and expression of the defining surface markers remained largely unaltered. Paclitaxel only marginally increased apoptosis in MSCs, but strongly induced premature senescence in these stem cells, thereby explaining the preservation of the metabolic activity of functionally inactivated MSCs. The reported sensitivity of MSC function to paclitaxel treatment may help to explain the severe bone marrow toxicities commonly caused by taxane-based anti-cancer treatments.
Highlights
The taxanes form a class of cytotoxic diterpene compounds that are widely used for the treatment of solid malignancies
Treatment with increasing concentrations of paclitaxel did not influence the morphology of the investigated Mesenchymal stem cells (MSCs) and fibroblast specimens, and no signs of increased apoptosis could be detected by light microscopy at 24 or 48 hours after paclitaxel treatment (Fig. 1c)
Systematic analyses regarding the influence of the chemotherapeutic treatments on the functional characteristics of MSCs are needed to investigate the stem cells’ potential use for regeneration of chemotherapy-induced tissue damage
Summary
The taxanes form a class of cytotoxic diterpene compounds that are widely used for the treatment of solid malignancies. The taxanes have shown beneficial effects in various clinical trials, and the compounds paclitaxel, docetaxel and cabazitaxel have been introduced into therapeutic regimens for ovarian, breast, bladder, prostate, esophageal and lung cancers as well as melanoma and Kaposi’s sarcoma[2,3,4,5,6]. Taxanes promote their cytotoxic effects by associating with GDP-bound tubulin proteins, thereby stabilizing polymerized microtobules and preventing the dynamic function of the cytoskeleton[7,8]; this in turn results in mitotic arrest, inhibition of cellular division and apoptotic cell death[9]. The influence of taxanes on MSCs themselves is widely unknown
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