Rifampicin as an Oral Angiogenesis Inhibitor Targeting Hepatic Cancers

Shichiri, Masayoshi; Fukai, Nozomi; Kono, Yutaka; Tanaka, Yujiro

doi:10.1158/0008-5472.can-08-3417

Cited by 34 publications

(27 citation statements)

References 44 publications

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“…Cotreatment with an anti-IGFBP1 antibody reduced this increase to approximately 2-fold, whereas an anti-IGFBP3 antibody did not reduce it. RIF, at concentrations greater than 100 mg/ml, has been reported to inhibit growth in various human cancer cells (Shichiri et al, 2009). No significant differences in cell growth were observed during treatments and cotreatments in our present experiments (unpublished data).…”

Section: Pxr Targets the Distal Enhancer Region To Represssupporting

confidence: 49%

Pregnane X Receptor RepressesHNF4αGene to Induce Insulin-Like Growth Factor–Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells

2015

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Upon treatment with the pregnane X receptor (PXR) activator rifampicin (RIF), human hepatocellular carcinoma HepG2-derived ShP51 cells that stably express PXR showed epithelialmesenchymal transition (EMT)-like morphological changes and migration. Our recent DNA microarrays have identified hepatocyte nuclear factor (HNF) 4a and insulin-like growth factorbinding protein (IGFBP) 1 mRNAs to be downregulated and upregulated, respectively, in RIF-treated ShP51 cells, and these regulations were confirmed by the subsequent real-time polymerase chain reaction and Western blot analyses. Using this cell system, we demonstrated here that the PXR-HNF4a-IGFBP1 pathway is an essential signal for PXR-induced morphological changes and migration. First, we characterized the molecular mechanism underlying the PXR-mediated repression of the HNF4a gene. Chromatin conformation capture and chromatin immunoprecipitation (ChIP) assays revealed that PXR activation by RIF disrupted enhancer-promoter communication and prompted deacetylation of histone H3 in the HNF4a P1 promoter. Cell-based reporter and ChIP assays showed that PXR targeted the distal enhancer of the HNF4a P1 promoter and stimulated dissociation of HNF3b from the distal enhancer. Subsequently, small interfering RNA knockdown of HNF4a connected PXR-mediated gene regulation with the PXRinduced cellular responses, showing that the knockdown resulted in the upregulation of IGFBP1 and EMT-like morphological changes without RIF treatment. Moreover, recombinant IGFBP1 augmented migration, whereas an anti-IGFBP1 antibody attenuated both PXR-induced morphological changes and migration in ShP51 cells. PXR indirectly activated the IGFBP1 gene by repressing the HNF4a gene, thus enabling upregulation of IGFBP1 to change the morphology of ShP51 cells and cause migration. These results provide new insights into PXR-mediated cellular responses toward xenobiotics including therapeutics.

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Section: Pxr Targets the Distal Enhancer Region To Represssupporting

confidence: 49%

Pregnane X Receptor RepressesHNF4αGene to Induce Insulin-Like Growth Factor–Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells

2015

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“…Because these drugs have an excellent side-effect profile, the addition to a metronomic chemotherapy would therefore be easy to perform. Other approved drugs like nitroxolene [119] and rifampicin [120] have been described to feature anti-angiogenic properties. Nitroxolene is approved for the prophylaxis of bladder infection, thus continuous application should not be a problem.…”

Section: Metronomic Therapies With Non-cytotoxic/-static Drugsmentioning

confidence: 99%

Metronomic anti-cancer therapy – an ongoing treatment option for advanced cancer patients

Mross¹,

Neumarkt²

2012

J Cancer Ther Res

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The therapeutic concept of administering agents (cytotoxic/-static,non-cytotoxic and/or targeted drugs) continuously at lower doses -relative to MTDs in the case of cytostatic and cytotoxic drugs or continuously at tolerable doses as in the case of targeted drugs without drug-free breaks over extended periods -known as 'metronomic therapy' (MT), is increasingly being recognized as an experimental option for treating cancer. In comparison with MTD-defined chemotherapy (CHT) regimens, metronomic therapy has demonstrated reduced toxicity. More importantly, several phase II trials have shown that metronomic therapies showed anti-cancer activity in different cancer types with different drugs. The mechanistic basis of metronomic therapy using cytotoxic/static drugs is believed to be primarily anti-angiogenic, either by direct killing or inhibiting endothelial cells (ECs) in the tumor vasculature, killing bone-marrow-derived endothelial progenitor cells, stimulating the immune system, directly affecting tumor cells through a drug-driven effect as well as specificly inhibiting a target when targeting drugs were used in additional to metronomic therapy. The induction of senescence in cancer is another possible explanation for the principles behind 'metronomic therapy' .

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“…32 In vivo, rifampicin suppresses hyperoxia-induced retinal neovascularization 33 and tumor angiogenesis. 34 Thereby, it should be noted that its antiangiogenic properties seem to be comparable with the well established angiogenesis inhibitor, endostatin. 32 Although the antiangiogenic activity of rifampicin might markedly affect the incorporation and long-term stabilization of implanted vascular prostheses, there might be also specific applications in vascular surgery that would benefit from this mode of action.…”

Section: Discussionmentioning

confidence: 97%

Perigraft vascularization and incorporation of implanted Dacron prostheses are affected by rifampicin coating

Moussavian

Laschke

Schlachtenberger

et al. 2016

Journal of Vascular Surgery

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Our novel findings show that early perigraft vascularization and incorporation of implanted Dacron prostheses are affected by the rifampicin coating. Because rapid graft vascularization and incorporation are thought to reduce the risk of infection, the use of Dacron-Rifamp Dacron grafts for antibacterial prophylaxis should be reconsidered particularly in cases of elective arterial reconstruction in a noninfected environment.

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Rifampicin as an Oral Angiogenesis Inhibitor Targeting Hepatic Cancers

Cited by 34 publications

References 44 publications

Pregnane X Receptor RepressesHNF4αGene to Induce Insulin-Like Growth Factor–Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells

Pregnane X Receptor RepressesHNF4αGene to Induce Insulin-Like Growth Factor–Binding Protein IGFBP1 that Alters Morphology of and Migrates HepG2 Cells

Metronomic anti-cancer therapy – an ongoing treatment option for advanced cancer patients

Perigraft vascularization and incorporation of implanted Dacron prostheses are affected by rifampicin coating

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