Human mesenchymal stem cells are resistant to cytotoxic and genotoxic effects of cisplatin in vitro

Bellagamba, Bruno Corrêa; Abreu, Bianca Regina Ribas de; Grivicich, Ivana; Markarian, Carolina Franke; Chem, Eduardo Mainieri; Camassola, Melissa; Nardi, Nance Beyer; Dihl, Rafael Rodrigues

doi:10.1590/1678-4685-gmb-2015-0057

Cited by 32 publications

(24 citation statements)

References 38 publications

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“…Similar to alkylating agents, platinum‐based drugs bind to DNA bases, causing intrastrand and interstrand crosslinks . The effects of cisplatin on MSCs have been studied in vitro , and it has been reported that MSCs were highly resistant compared to ovarian cancer cells, peripheral blood lymphocytes and leukemia cells . Similar results have been obtained ex vivo where MSCs derived from bone marrow samples of patients treated with cisplatin were viable and able to proliferate .…”

Section: Effects Of Chemotherapeutic Anti‐cancer Agents On Mscsmentioning

confidence: 63%

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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Section: Effects Of Chemotherapeutic Anti‐cancer Agents On Mscsmentioning

confidence: 63%

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

Rühle

Huber

Saffrich

et al. 2018

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Indeed, embryonic or normal tissue-derived stem cells and the patient’s own adult stem cells can be obtained and differentiated into various target tissues, including cardiomyocytes, hepatocytes, or neurons, for in vitro potential toxicity screening 21 . Especially, MSCs have been used for assessing the toxicity of various chemicals such as anesthetics 22 , 23 , chemotherapeutic drugs 24 , 25 , endocrine disruptors 26 , nanoparticles 27 , 28 , and other industrial chemicals including cosmetic ingredients or detergent 29 , 30 . Nevertheless, the comparison among the toxicological studies using MSCs is challenging, since laboratories around the world lack internationally standardized methods for isolation and in vitro expansion of MSCs, resulting in significant functional heterogeneity and inconsistent testing results.…”

Section: Discussionmentioning

confidence: 99%

SERPINB2 is a novel indicator of stem cell toxicity

et al. 2018

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The toxicological evaluation of potential drug candidates is very important in the preclinical phase of drug development. Toxic materials may cause serious decline in stem cell function and loss of stemness. Indeed, we found that toxic exposure more profoundly suppressed the growth of stem cells than terminally differentiated fibroblasts. Importantly, toxic exposure suppressed stem cell migration and multi-lineage differentiation potential in vitro and in vivo. Moreover, early-response genes involved in stem cell properties such as self-renewal and differentiation capabilities can be used as specific markers to predict toxicity. In the present study, we also identified a labile toxic response gene, SERPINB2, which is significantly increased in response to various toxic agents in human stem cells in vitro and in vivo. Consistently, self-renewal, migration, and multi-lineage differentiation potential were markedly decreased following SERPINB2 overexpression. To the best of our knowledge, this is the first study to focus on the functions of SERPINB2 on the regenerative potential of stem cells in response to various existing chemicals, and the findings will facilitate the development of promising toxicity test platforms for newly developed chemicals.

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“…Similar anti-proliferative and apoptotic effects were reported in MSC after treatment with doxorubicin [ 22 ] and bleomycin [ 20 ]. However, adipose derived MSC were reported to be resistant to toxic effects of cisplatin, vincristine and camptothecin [ 3 , 15 ] and bone marrow derived MSC were resistant to cisplatin [ 19 ] and paclitaxel [ 4 ] induced apoptosis. In our study, we observed a significant reduction in osteogenic and adipogenic differentiation of CYT, DAU and VIN treated MSC immediately after treatment.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells show functional defect and decreased anti-cancer effect after exposure to chemotherapeutic drugs

et al. 2018

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BackgroundMesenchymal stem cells (MSC) are used for several therapeutic applications to improve the functions of bone, cardiac, nervous tissue as well as to facilitate the repopulation of hematopoietic stem cells. MSC give rise to the non-hematopoietic stromal cells of the bone marrow and are important for the maintenance of normal hematopoiesis. Chemotherapeutic drugs used for treatment of leukemia extensively damage the stromal cells and alter their gene expression profiles.MethodsWe determined the changes in adipogenic, osteogenic differentiation, phenotypic and gene expression in MSC during treatment with chemotherapeutic drugs cytarabine, daunorubicin and vincristine. We also tested anti-cancer effects of drug treated MSC on leukemia cells.ResultsTreatment with the chemotherapeutic drugs resulted in functional defects in MSC, leading to reduced proliferation, osteogenic and adipogenic differentiation. The drug treated MSC also showed decreased expression of cell surface receptors, and the changes in proliferation, phenotype and differentiation defect was partially reversible after withdrawing the drugs from the cells. The drug treated MSC showed increased expression of cytokines, IL6, FGF2 and TNFA but reduced levels of differentiation markers SOX9 and ACTC1. Drug treated MSC also contributed to reduced anti-cancer effects in leukemia cells.ConclusionsChemotherapeutic drug treatment altered the phenotype, osteogenic and adipogenic differentiation potential of MSC and modified the gene expression profile of the cells to render them more chemoprotective of the leukemic cells. Thus, additional therapeutic efforts to target the stromal cell population will help in preventing chemoresistance, disease relapse in leukemia and to maintain a healthy bone marrow stroma.Electronic supplementary materialThe online version of this article (10.1186/s12929-018-0407-7) contains supplementary material, which is available to authorized users.

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Human mesenchymal stem cells are resistant to cytotoxic and genotoxic effects of cisplatin in vitro

Cited by 32 publications

References 38 publications

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

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

SERPINB2 is a novel indicator of stem cell toxicity

Mesenchymal stem cells show functional defect and decreased anti-cancer effect after exposure to chemotherapeutic drugs

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