Mesenchymal stem cells exhibit resistance to topoisomerase inhibition

Nicolay, Nils H.; Rühle, Alexander; Perez, Ramon Lopez; Trinh, Thuy; Sisombath, Sonevisay; Weber, Klaus; Schmezer, Peter; Ho, Anthony D.; Debus, Jürgen; Saffrich, Rainer; Huber, Peter E.

doi:10.1016/j.canlet.2016.02.007

Cited by 23 publications

(21 citation statements)

References 58 publications

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“…In mice, etoposide has been reported to reduce peripheral monocytes, yet the etoposide impact in the bone marrow of murine models is unclear [24]. Human mesenchymal stem cells were found to be relatively resistant to etoposide, and their differentiation was preserved in vitro [25] which is similar to what the present study found in mice in vivo. In humans, etoposide is most frequently administered with other chemotherapeutic agents and hence, little is known about the specific effect of etoposide on cells in the bone marrow or bone.…”

Section: Discussionsupporting

confidence: 79%

The skeletal impact of the chemotherapeutic agent etoposide

et al. 2017

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Summary Effects of the chemotherapeutic agent etoposide on the skeleton were determined in mice. Numbers of bone marrow cells were reduced and myeloid cells were increased. Bone volume was significantly decreased with signs of inhibition of bone formation. Etoposide after pre-treatment with zoledronic acid still reduced bone but overall bone volume was higher than with etoposide alone. Introduction Chemotherapeutics target rapidly dividing tumor cells yet also impact hematopoietic and immune cells in an off target manner. A wide array of therapies have negative side effects on the skeleton rendering patients osteopenic and prone to fracture. This study focused on the pro-apoptotic chemotherapeutic agent etoposide and its short- and long-term treatment effects in the bone marrow and skeleton. Methods Six- to 16-week-old mice were treated with etoposide (20–25 mg/kg) or vehicle control in short-term (daily for 5–9 days) or long-term (3×/week for 17 days or 6 weeks) regimens. Bone marrow cell populations and their phagocytic/efferocytic functions were analyzed by flow cytometry. Blood cell populations were assessed by CBC analysis. Bone volume and area compartments and osteoclast numbers were measured by microCT, histomorphometry, and TRAP staining. Biomarkers of bone formation (P1NP) and resorption (TRAcP5b) were assayed from serum. Gene expression in bone marrow was assessed using qPCR. Results Flow cytometric analysis of the bone marrow revealed short-term etoposide reduced overall cell numbers and B220+ cells, with increased marrow apoptotic (AnnexinV+PI−) cells, mesenchymal stem-like cells, and CD68+, CD45+, and CD11b+ monocyte/myeloid cells (as a percent of the total marrow). After 6 weeks, the CD68+, Gr1+, CD11b+, and CD45+ cell populations were still relatively increased in etoposide-treated bone marrow. Skeletal phenotyping revealed etoposide decreased bone volume, trabecular thickness, and cortical bone volume. Gene expression in the marrow for the leptin receptor and CXCL12 were reduced with short-term etoposide, and an increased ratio of RANKL/OPG mRNA was observed. In whole bone, Runx2 and osteocalcin gene expressions were reduced, and in serum, P1NP was significantly reduced with etoposide. Treatment with the antiresorptive agent zoledronic acid prior to etoposide increased bone volume and improved the etoposide-induced decrease in skeletal parameters. Conclusions These data suggest that etoposide induces apoptosis in the bone marrow and significantly reduces parameters of bone formation with rapid reduction in bone volume. Pre-treatment with an antiresorptive agent results in a preservation of bone mass. Preventive approaches to preserving the skeleton should be considered in human clinical studies.

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Section: Discussionsupporting

confidence: 79%

The skeletal impact of the chemotherapeutic agent etoposide

et al. 2017

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“…Published data about the inhibitors' effects on MSCs reveal heterogeneous results. It was demonstrated that MSCs exhibited a relative resistance to both type I and type II topoisomerase inhibitors regarding their viability and proliferation . However, another publication suggested that MSC recovery after drug withdrawal was delayed and incomplete .…”

Section: Effects Of Chemotherapeutic Anti‐cancer Agents On Mscsmentioning

confidence: 99%

“…However, another publication suggested that MSC recovery after drug withdrawal was delayed and incomplete . MSCs have been shown to efficiently repair DNA double‐strand breaks caused by type I and II inhibitors, but the impact of an efficient DNA repair on the apoptosis induction of MSCs has been controversial . While several publications demonstrated an evasion of apoptosis, increased apoptosis of bmMSCs has been reported after treatment with etoposide .…”

Section: Effects Of Chemotherapeutic Anti‐cancer Agents On Mscsmentioning

confidence: 99%

The current understanding of mesenchymal stem cells as potential attenuators of chemotherapy‐induced toxicity

Rühle

Huber

Saffrich

et al. 2018

Intl Journal of Cancer

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Chemotherapeutic agents are part of the standard treatment algorithms for many malignancies; however, their application and dosage are limited by their toxic effects to normal tissues. Chemotherapy-induced toxicities can be long-lasting and may be incompletely reversible; therefore, causative therapies for chemotherapy-dependent side effects are needed, especially considering the increasing survival rates of treated cancer patients. Mesenchymal stem cells (MSCs) have been shown to exhibit regenerative abilities for various forms of tissue damage. Preclinical data suggest that MSCs may also help to alleviate tissue lesions caused by chemotherapeutic agents, mainly by establishing a protective microenvironment for functional cells. Due to the systemic administration of most anticancer agents, the effects of these drugs on the MSCs themselves are of crucial importance to use stem cell-based approaches for the treatment of chemotherapy-induced tissue toxicities. Here, we present a concise review of the published data regarding the influence of various classes of chemotherapeutic agents on the survival, stem cell characteristics and physiological functions of MSCs. Molecular mechanisms underlying the effects are outlined, and resulting challenges of MSC-based treatments for chemotherapy-induced tissue injuries are discussed.

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“…[34][35][36][37] Recently, nutlin family compositions have been introduced as key to MDM2-TP53 intervention in cancer treatment. These cells have formerly displayed resistance to numerous anticancer treatments such as ionizing radiation, Cisplatin, and topoisomerase inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…These cells have formerly displayed resistance to numerous anticancer treatments such as ionizing radiation, Cisplatin, and topoisomerase inhibition. [34][35][36][37] Recently, nutlin family compositions have been introduced as key to MDM2-TP53 intervention in cancer treatment. nutlin-3 was the first compound in this family that was shown to have efficacy in vivo and in vitro 22,38,39 ; nevertheless, the effect of nutlin-3 has not been yet fully confirmed on human bone marrow stem cells, especially MSCs.…”

Section: Discussionmentioning

confidence: 99%

Resistance of human primary mesenchymal stem cells to cytotoxic effects of nutlin‐3 in vitro

Bajelan

Zaki‐Dizaji

Rahmani

et al. 2019

J of Cellular Biochemistry

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Background The small‐molecule nutlin‐3 was found to be an effective therapeutic compound and p53 activator, and acts as a murine double minute 2 antagonist, although these findings need to be clinically confirmed. The essential components of the bone marrow include mesenchymal stem cells (MSCs), which play a key role in protecting, regenerating, and proliferating hematopoietic stem cells (HSCs). This feature is vital for HSC after exposure to myelotoxic anticancer agents; nevertheless, the effects of nutlin‐3 on MSCs remain to be disclosed. The present research study was conducted to examine the antiproliferative and proapoptotic effectiveness of nutlin‐3 in bone marrow MSCs (BMSCs). Materials and Methods Human‐derived BMSCs were cultured for different durations, that is, 24, 48, and 72 hours, and treated using various concentrations of nutlin‐3, including 5, 10, 25, 50, and 100 μΜ. To investigate the effect of nutlin‐3 on the apoptosis, cell vitality and proliferation in BMSCs, the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), thiazolyl blue tetrazolium bromide, propidium iodide (PI) and annexin V assay, as well as real‐time polymerase chain reaction, were used. Results BMSCs viability significantly decreased (P < .05) in the cells treated at concentrations of 50 and 100 μM for 24 hours and concentrations of 25, 50, and 100 μM for 48 hours and at all concentrations for 72 hours. The apoptosis of BMSCs (TUNEL positive) was significantly more visible at concentrations of 25 and 50 μM compared with that in the controls (P < .05), while this increased through dose‐dependent processes. Annexin V/PI staining revealed negligible dose‐dependent increases in all the apoptotic cells after 72 hours of incubation, and this apoptosis elevation was significant at 25 and 50 μM (P < .05). Conclusion Resistance to nutlin‐3 was observed in human bone marrow–derived MSCs; nevertheless, further clinical data are required to be obtained with long‐duration exposure to confirm the present findings.

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Mesenchymal stem cells exhibit resistance to topoisomerase inhibition

Cited by 23 publications

References 58 publications

The skeletal impact of the chemotherapeutic agent etoposide

The skeletal impact of the chemotherapeutic agent etoposide

The current understanding of mesenchymal stem cells as potential attenuators of chemotherapy‐induced toxicity

Resistance of human primary mesenchymal stem cells to cytotoxic effects of nutlin‐3 in vitro

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