Etoposide Attenuates Zymosan-Induced Shock in Mice

Remichkova, Mimi; Yordanov, M.; Dimitrova, Petya

doi:10.1007/s10753-007-9049-8

Cited by 8 publications

(7 citation statements)

References 30 publications

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“…Although tumor cells may be particularly prone to etoposide, normal cells are also impacted. 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.…”

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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“…of toll-like receptors. In particular, TLR4 binds bacterial LPS, while TLR2/TLR6 binds fungal zymosan, albeit the infection induced by either of them leads to an excessive immune response manifesting itself by a massive production of proinflammatory cytokines and NO (Kłuciński and Martirosian, 2005;Remichkova et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Modulation of zymosan-induced peritonitis by riboflavin co-injection, pre-injection or post-injection in male Swiss mice

2012

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“…The importance of this population for the development of zymosan-induced inflammation was previously studied by our group. Treatment with etoposide, a drug that selectively eliminates monocytes, improved the survival and systemic cytotoxicity in shock (16). In the present experiments the administration of tyrphostin AG-490 rendered the frequencies of monocytes to the baseline values (17.3 ± 9.0 in ZY+AG-490; 23.3 ± 3.1 in control group; 55.3 ± 11.0 in ZY group).…”

Section: Monocytesmentioning

confidence: 46%

“…The acute inflammation was provoked in mice with severe combined immunodeficiency (SCID). Previously, we have observed that SCID mice are more sensitive than normal BALB/c mice to zymosan-induced shock (16). The dose of 0.8 mg/g body weight caused 60% mortality in SCID mice within 48 h. All animals had peritonitis, increased body temperature, ruffled fur, diarrhea and conjunctivitis.…”

Section: Monocytesmentioning

confidence: 87%

Effect of Tyrosine Kinase Inhibitor AG-490 on the Development of Aseptic Shock

Gyurkovska

Ivanovska

Saso

et al. 2009

Biotechnology & Biotechnological Equipment

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Recently, protein kinase inhibitors are used to limit the uncontrolled immune responses in cancer and autoimmune diseases. Tyrphostin AG-490 is a novel benzylidine malononitrile analogue that inhibits the activity of Janus activation kinase 2 (JAK2). In the present study we investigate the effect of the drug on the development of aseptic shock. The acute inflammation was provoked in mice with severe combined immunodeficiency (SCID) by intraperitoneal injection of 0.8 mg/g body weight of zymosan. Tyrphostin AG-490 was administrated intraperitoneally in a dose of 5 mg/kg. Blood, liver and spleens were collected on day 21 of shock. The white blood cell differential count showed that the percentage of polymorphonuclear cells in peripheral blood was not affected by administration. The proportion of blood monocytes increased 2 times in shock mice and returned to the baseline value in AG-490-treated mice. At the late phase of zymosan-induced inflammation SCID mice had enlarged spleens and increased numbers of splenocytes that were significantly reduced by AG-490 administration.Interestingly, the elevated number of hepatocytes and the enhanced ability of hepatocytes to produce nitric oxide (NO) in response to zymosan restimulation in vitro were observed in the group of AG-490-treated mice with shock. These data suggest that the inhibition of JAK2 kinase can stimulate the NO inflammatory pathway in liver when functional T and B cells are missing. Our study has performed an evidence for the decisive role of T and B cells for the resolution of inflammation and cell repair in the liver.

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Etoposide Attenuates Zymosan-Induced Shock in Mice

Cited by 8 publications

References 30 publications

The skeletal impact of the chemotherapeutic agent etoposide

The skeletal impact of the chemotherapeutic agent etoposide

Modulation of zymosan-induced peritonitis by riboflavin co-injection, pre-injection or post-injection in male Swiss mice

Effect of Tyrosine Kinase Inhibitor AG-490 on the Development of Aseptic Shock

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