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Glabridin Prevents Doxorubicin-Induced Cardiotoxicity Through Gut Microbiota Modulation and Colonic Macrophage Polarization in Mice.

ABSTRACT: The chemotherapeutic drug doxorubicin (DOX) provokes a dose-related cardiotoxicity. Thus, there is an urgent need to identify the underlying mechanisms and develop strategies to overcome them. Here we demonstrated that glabridin (GLA), an isoflavone from licorice root, prevents DOX-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization in mice. GLA reduced DOX-induced leakage of myocardial enzymes including aminotransferase, creatine kinase, lactate dehydrogenase, and creatine kinase-MB. GLA downregulated pro-apoptotic proteins (Bax, cleaved-caspase 9 and cleaved-caspase 3) and upregulated anti-apoptotic proteins (HAX-1 and Bcl-2) in the cardiac tissues. In addition, GLA modulated DOX-induced dysbiosis of gut microbiota and thereby decreased the ratio of M1/M2 colonic macrophage, accompanied by the downregulated lipopolysaccharide (LPS) and upregulated butyrate in the feces and peripheral blood. The leakage of myocardial enzymes induced by the DOX was decreased by antibiotics treatment, but not altered by co-treatment with the GLA and antibiotics. The ratio of M1/M2 colonic macrophage and leakage of myocardial enzymes reduced by the GLA were greatly increased by the Desulfovibrio vulgaris or LPS but decreased by the butyrate. Depletion of the macrophage attenuated DOX-induced cardiotoxicity but failed to further affect the effects of GLA. Importantly, GLA decreased production of M1 cytokines (IL-1β and TNF-α) but increased production of M2 cytokines (IL-10 and TGF-β) in the colonic macrophage with the downregulation of NF-κB and the upregulation of STAT6. In summary, GLA prevents DOX-induced cardiotoxicity through gut microbiota modulation and colonic macrophage polarization, and may serve as a potential therapeutic strategy for the DOX-induced cardiotoxicity.

SUBMITTER: Huang K

PROVIDER: S-EPMC6387923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCyclic nucleotides play critical roles in cardiovascular biology and disease. PDE10A (phosphodiesterase 10A) is able to hydrolyze both cAMP and cGMP. PDE10A expression is induced in various human tumor cell lines, and PDE10A inhibition suppresses tumor cell growth. Chemotherapy drug such as doxorubicin (DOX) is widely used in chemotherapy. However, cardiotoxicity of DOX remains to be a serious clinical complication. In the current study, we aim to determine the role of PDE10A and the effect of PDE10A inhibition on cancer growth and cardiotoxicity induced by DOX.MethodsWe used global PDE10A knockout (KO) mice and PDE10A inhibitor TP-10 to block PDE10A function. DOX-induced cardiotoxicity was evaluated in C57Bl/6J mice and nude mice with implanted ovarian cancer xenografts. Isolated adult mouse cardiomyocytes and a human ovarian cancer cell line were used for in vitro functional and mechanistic studies.ResultsWe found that PDE10A deficiency or inhibition alleviated DOX-induced myocardial atrophy, apoptosis, and dysfunction in C57Bl/6J mice. RNA sequencing study revealed a number of PDE10A-regulated signaling pathways involved in DOX-induced cardiotoxicity. PDE10A inhibition increased the death, decreased the proliferation, and potentiated the effect of DOX on various human cancer cells. Importantly, in nude mice with implanted ovarian cancer xenografts, PDE10A inhibition attenuated tumor growth while protecting DOX-induced cardiotoxicity. In isolated cardiomyocytes, PDE10A contributed to DOX-induced cardiomyocyte death via increasing Top2β (topoisomerase 2β) expression, mitochondrial dysfunction, and DNA damage by antagonizing cGMP/PKG (protein kinase G) signaling. PDE10A contributed to cardiomyocyte atrophy via potentiating FoxO3 (forkhead box O3) signaling via both cAMP/PKA (protein kinase A)- and cGMP/PKG-dependent signaling.ConclusionsTaken together, our study elucidates a novel role for PDE10A in cardiotoxicity induced by DOX and cancer growth. Given that PDE10A has been already proven to be a safe drug target, PDE10A inhibition may represent a novel therapeutic strategy in cancer therapy, with effects preventing DOX-induced cardiotoxicity and simultaneously antagonizing cancer growth.

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Glabridin Prevents Doxorubicin-Induced Cardiotoxicity Through Gut Microbiota Modulation and Colonic Macrophage Polarization in Mice.

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