Valosin containing protein (VCP) interacts with macrolide antibiotics without mediating their anti-inflammatory activities

Nujić, Krunoslav; Smith, M. D.; Lee, Michael; Belamarić, Daniela; Tomašković, Linda; Alihodžić, Sulejman; Malnar, Ivica; Polančec, Denis; Schneider, Klaus; Haber, Vesna Eraković

doi:10.1016/j.ejphar.2011.12.022

Cited by 16 publications

(8 citation statements)

References 64 publications

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“…Much of the work in this regard has converged in identifying the NF‐κB signaling cascade as the core regulator of the observed shifts in cytokine profiles following macrolide treatment . While this is clearly important, the molecular target upstream of the NF‐κB cascade on which these drugs act remains unclear . In vitro studies show that AZM accumulates in macrophage lysosomes, where it increases the pH, interacts with membrane lipids, induces phospholipidosis, and alters vesicular trafficking which may affect endocytosis and phagocytosis .…”

Section: Discussionmentioning

confidence: 99%

“…29,[33][34][35] While this is clearly important, the molecular target upstream of the NF-κB cascade on which these drugs act remains unclear. 36 In vitro studies show that AZM accumulates in macrophage lysosomes, where it increases the pH, interacts with membrane lipids, induces phospholipidosis, and alters vesicular trafficking which may affect endocytosis and phagocytosis. 37,38 Other suggested mechanisms indicate that AZM may alter cellular autophagy, or alter the TLR4 signaling pathways by changing endosome trafficking.…”

Section: Discussionmentioning

confidence: 99%

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Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

et al. 2019

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Summary Introduction Azithromycin (AZM) and other macrolide antibiotics are applied as immunomodulatory treatments for CNS disorders. The immunomodulatory and antibiotic properties of AZM are purportedly independent. Aims To improve the efficacy and reduce antibiotic resistance risk of AZM‐based therapies, we evaluated the immunomodulatory and neuroprotective properties of novel AZM derivatives. We semisynthetically prepared derivatives by altering sugar moieties established as important for inhibiting bacterial protein synthesis. Bone marrow‐derived macrophages (BMDMs) were stimulated in vitro with proinflammatory, M1, stimuli (LPS + INF‐gamma) with and without derivative costimulation. Pro‐ and anti‐inflammatory cytokine production, IL‐12 and IL‐10, respectively, was quantified using ELISA. Neuron culture treatment with BMDM supernatant was used to assess derivative neuroprotective potential. Results Azithromycin and some derivatives increased IL‐10 and reduced IL‐12 production of M1 macrophages. IL‐10/IL‐12 cytokine shifts closely correlated with the ability of AZM and derivatives to mitigate macrophage neurotoxicity. Conclusions Sugar moieties that bind bacterial ribosomal complexes can be modified in a manner that retains AZM immunomodulation and neuroprotection. Since the effects of BMDMs in vitro are predictive of CNS macrophage responses, our results open new therapeutic avenues for managing maladaptive CNS inflammation and support utilization of IL‐10/12 cytokine profiles as indicators of macrophage polarization and neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

et al. 2019

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“…However, the molecular mechanism of blocking autophagy flux by AZM and CAM is not well understood. It is reported that macrolide antibiotics interact with valosin-containing proteins (VCPs) without mediating their anti-inflammatory activities [40], and that VCPs are essential for the maturation of autophagosomes [41, 42]. However, transfection of various VCP variants including the AAA-ATPase-deficient form into HEK293T cells did not show any effect on AZM-induced autophagy (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Macrolide Antibiotics Exhibit Cytotoxic Effect under Amino Acid-Depleted Culture Condition by Blocking Autophagy Flux in Head and Neck Squamous Cell Carcinoma Cell Lines

et al. 2016

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Autophagy, a self-digestive system for cytoplasmic components, is required to maintain the amino acid pool for cellular homeostasis. We previously reported that the macrolide antibiotics azithromycin (AZM) and clarithromycin (CAM) have an inhibitory effect on autophagy flux, and they potently enhance the cytocidal effect of various anticancer reagents in vitro. This suggests that macrolide antibiotics can be used as an adjuvant for cancer chemotherapy. Since cancer cells require a larger metabolic demand than normal cells because of their exuberant growth, upregulated autophagy in tumor cells has now become the target for cancer therapy. In the present study, we examined whether macrolides exhibit cytotoxic effect under an amino acid-starving condition in head and neck squamous cancer cell lines such as CAL 27 and Detroit 562 as models of solid tumors with an upregulated autophagy in the central region owing to hypovascularity. AZM and CAM induced cell death under the amino acid-depleted (AAD) culture condition in these cell lines along with CHOP upregulation, although they showed no cytotoxicity under the complete culture medium. CHOP knockdown by siRNA in the CAL 27 cells significantly suppressed macrolide-induced cell death under the AAD culture condition. CHOP-/- murine embryonic fibroblast (MEF) cell lines also attenuated AZM-induced cell death compared with CHOP+/+ MEF cell lines. Using a tet-off atg5 MEF cell line, knockout of atg5, an essential gene for autophagy, also induced cell death and CHOP in the AAD culture medium but not in the complete culture medium. This suggest that macrolide-induced cell death via CHOP induction is dependent on autophagy inhibition. The cytotoxicity of macrolide with CHOP induction was completely cancelled by the addition of amino acids in the culture medium, indicating that the cytotoxicity is due to the insufficient amino acid pool. These data suggest the possibility of using macrolides for “tumor-starving therapy”.

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“…However, both macrolides have reportedly prevented maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes ( 32 ). Valosin-containing protein (VCP)/p97 appears to be another potential target ( 33 ). A recent report demonstrated that AZM and CAM interact with VCP, based on AZM- and CAM-immobilized affinity chromatography ( 33 ).…”

Section: Discussionmentioning

confidence: 99%

“…Valosin-containing protein (VCP)/p97 appears to be another potential target ( 33 ). A recent report demonstrated that AZM and CAM interact with VCP, based on AZM- and CAM-immobilized affinity chromatography ( 33 ). Pathophysiologically, germline mutations in VCP genes account for a spectrum of pathological phenotypes that include inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia, hereditary spastic paraplegia (IBMPFD), and 1–2% of familial amyotrophic lateral sclerosis ( 34 , 35 ).…”

Section: Discussionmentioning

confidence: 99%

Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines

Mukai

Moriya

Hara

et al. 2015

International Journal of Oncology

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Pancreatic cancer is one of the most difficult types of cancer to treat because of its high mortality rate due to chemotherapy resistance. We previously reported that combined treatment with gefitinib (GEF) and clarithromycin (CAM) results in enhanced cytotoxicity of GEF along with endoplasmic reticulum (ER) stress loading in non-small cell lung cancer cell lines. An epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) such as GEF induces autophagy in a pro-survival role, whereas CAM inhibits autophagy flux in various cell lines. Pronounced GEF-induced cytotoxicity therefore appears to depend on the efficacy of autophagy inhibition. In the present study, we compared the effect on autophagy inhibition among such macrolides as CAM, azithromycin (AZM), and EM900, a novel 12-membered non-antibiotic macrolide. We then assessed the enhanced GEF-induced cytotoxic effect on pancreatic cancer cell lines BxPC-3 and PANC-1. Autophagy flux analysis indicated that AZM is the most effective autophagy inhibitor of the three macrolides. CAM exhibits an inhibitory effect but less than AZM and EM900. Notably, the enhancing effect of GEF-induced cytotoxicity by combining macrolides correlated well with their efficient autophagy inhibition. However, this pronounced cytotoxicity was not due to upregulation of apoptosis induction, but was at least partially mediated through necroptosis. Our data suggest the possibility of using macrolides as ‘chemosensitizers’ for EGFR-TKI therapy in pancreatic cancer patients to enhance non-apoptotic tumor cell death induction.

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Valosin containing protein (VCP) interacts with macrolide antibiotics without mediating their anti-inflammatory activities

Cited by 16 publications

References 64 publications

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

Macrolide derivatives reduce proinflammatory macrophage activation and macrophage‐mediated neurotoxicity

Macrolide Antibiotics Exhibit Cytotoxic Effect under Amino Acid-Depleted Culture Condition by Blocking Autophagy Flux in Head and Neck Squamous Cell Carcinoma Cell Lines

Macrolides sensitize EGFR-TKI-induced non-apoptotic cell death via blocking autophagy flux in pancreatic cancer cell lines

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