Cytokine‐mediated blood brain barrier disruption as a conduit for cancer/chemotherapy‐associated neurotoxicity and cognitive dysfunction

Wardill, Hannah R.; Mander, Kimberley A.; Sebille, Ysabella Z.A. Van; Gibson, Rachel J.; Logan, Richard M.; Bowen, Joanne M.; Sonis, Stephen T.

doi:10.1002/ijc.30252

Cited by 124 publications

(91 citation statements)

References 114 publications

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“…The side effects of chemotherapeutics were mostly attributed to their toxicity to cells in normal organs and tissues (48,49). The inflammatory reactions following the chemotherapy were always considered as a consequence, but not the reason, of such cytotoxicity (50). Nevertheless, our present finding that the product of gut microflora leaking from the intestinal tract promoted systemic inflammation during the treatment with chemotherapeutics suggested that inflammation could directly derive from chemotherapy and might play a significant role in inducing systemic toxicity.…”

Section: Discussionmentioning

confidence: 68%

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

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Doxorubicin is one of the most effective chemotherapeutic agents used for cancer treatment, but it causes systemic inflammation and serious multiorgan side effects in many patients. In this study, we report that upregulation of the proinflammatory Toll-like receptor TLR4 in macrophages by doxorubicin is an important step in generating its toxic side effects. In patient serum, doxorubicin treatment resulted in leakage of endotoxin and inflammatory cytokines into circulation. In mice, doxorubicin damaged the intestinal epithelium, which also resulted in leakage of endotoxin from the gut flora into circulation. Concurrently, doxorubicin increased TLR4 expression in macrophages both in vitro and in vivo, which further enhanced the sensitivity of these cells to endotoxin. Either depletion of gut microorganisms or blockage of TLR4 signaling effectively decreased doxorubicininduced toxicity. Taken together, our findings suggest that doxorubicin-triggered leakage of endotoxin into the circulation, in tandem with enhanced TLR4 signaling, is a candidate mechanism underlying doxorubicin-induced systemic inflammation. Our study provides new insights for devising relevant strategies to minimize the adverse effects of chemotherapeutic agents such as doxorubicin, which may extend its clinical uses to eradicate cancer cells. Cancer Res; 76(22); 6631-42. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 68%

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

et al. 2016

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“…Thus, it is possible that the CNS abnormalities observed in ME/CFS patients can be explained, at least in part, by the ability of leptin and resistin to cross and/or disrupt the bloodbrain barrier (46). Moreover, systemic inflammation, such as that found in our patients, has been invoked as a mechanism for neuroinflammation in other neurodegenerative disease models (47)(48)(49). In animal models, systemic administration of LPS alone has been shown to result in neuroinflammation (45,50).…”

Section: Discussionmentioning

confidence: 85%

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Montoya

Holmes

Anderson

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

308

265

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Although some signs of inflammation have been reported previously in patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), the data are limited and contradictory. High-throughput methods now allow us to interrogate the human immune system for multiple markers of inflammation at a scale that was not previously possible. To determine whether a signature of serum cytokines could be associated with ME/CFS and correlated with disease severity and fatigue duration, cytokines of 192 ME/CFS patients and 392 healthy controls were measured using a 51-multiplex array on a Luminex system. Each cytokine’s preprocessed data were regressed on ME/CFS severity plus covariates for age, sex, race, and an assay property of newly discovered importance: nonspecific binding. On average, TGF-β was elevated (P = 0.0052) and resistin was lower (P = 0.0052) in patients compared with controls. Seventeen cytokines had a statistically significant upward linear trend that correlated with ME/CFS severity: CCL11 (Eotaxin-1), CXCL1 (GROα), CXCL10 (IP-10), IFN-γ, IL-4, IL-5, IL-7, IL-12p70, IL-13, IL-17F, leptin, G-CSF, GM-CSF, LIF, NGF, SCF, and TGF-α. Of the 17 cytokines that correlated with severity, 13 are proinflammatory, likely contributing to many of the symptoms experienced by patients and establishing a strong immune system component of the disease. Only CXCL9 (MIG) inversely correlated with fatigue duration.

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“…can protect rats from Doxo-induced inflammation, cardiac fibrosis and damage, and from I/R heart injury. It is well known that Doxo can cause toxicity and inflammation in several organs, including the heart, liver and intestine (39,54). In particular, Doxo can cause the release of proinflammatory cytokines in the blood of patients, such as IL-1b and TNF-a (39), and the release of ROS, cTnT, and LDH, markers of cytotoxic and cardiotoxic responses (1,(40)(41)(42).…”

Section: Discussionmentioning

confidence: 99%

Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity

et al. 2019

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The clinical use of doxorubicin (Doxo), a widely used anticancer chemotherapeutic drug, is limited by dose‐dependent cardiotoxicity. We have investigated whether chromogranin A (CgA), a cardioregulatory protein released in the blood by the neuroendocrine system and by the heart itself, may contribute to regulation of the cardiotoxic and antitumor activities of Doxo. The effects of a physiologic dose of full‐length recombinant CgA on Doxo‐induced cardiotoxicity and antitumor activity were investigated in rats using in vivo and ex vivo models and in murine models of melanoma, fibrosarcoma, lymphoma, and lung cancer, respectively. The effect of Doxo on circulating levels of CgA was also investigated. In vivo and ex vivo mechanistic studies showed that CgA can prevent Doxo‐induced heart inflammation, oxidative stress, apoptosis, fibrosis, and ischemic injury. On the other hand, CgA did not impair the anticancer activity of Doxo in all the murine models investigated. Furthermore, we observed that Doxo can reduce the intracardiac expression and release of CgA in the blood (i.e., an important cardioprotective agent). These findings suggest that administration of low‐dose CgA to patients with low levels of endogenous CgA might represent a novel approach to prevent Doxo‐induced adverse events without impairing antitumor effects.—Rocca, C., Scavello, F., Colombo, B., Gasparri, A. M., Dallatomasina, A., Granieri, M. C., Amelio, D., Pasqua, T., Cerra, M. C., Tota, B., Corti, A., Angelone, T. Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity. FASEB J. 33, 7734–7747 (2019). http://www.fasebj.org

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Cytokine‐mediated blood brain barrier disruption as a conduit for cancer/chemotherapy‐associated neurotoxicity and cognitive dysfunction

Cited by 124 publications

References 114 publications

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

Doxorubicin-Induced Systemic Inflammation Is Driven by Upregulation of Toll-Like Receptor TLR4 and Endotoxin Leakage

Cytokine signature associated with disease severity in chronic fatigue syndrome patients

Physiological levels of chromogranin A prevent doxorubicin‐induced cardiotoxicity without impairing its anticancer activity

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