The fungicide ciclopirox inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3-mediated ERK signaling pathway

Luo, Yan; Zhou, Hongyu; Liu, L; Shen, Tao; Chen, Wenxing; Xu, Baoshan; Han, Xiuzhen; Zhang, F; Scott, Rona S.; Alexander, J. Steven; Alam, Antoine; Huang, Shile

doi:10.1038/onc.2010.590

Cited by 31 publications

(35 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ability of LECs transfected with miR-9 mimics or inhibitors to form capillary networks was evaluated by endothelial tube formation assay in the absence or presence of TNF-␣ (20 ng/ml) as described elsewhere with some modifications (38). After 96-well plates were precoated with 40 l of Matrigel per well, they were allowed to polymerize for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Chakraborty

Zawieja

Davis

et al. 2015

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Chakraborty S, Zawieja DC, Davis MJ, Muthuchamy M. MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation. Am J Physiol Cell Physiol 309: C680 -C692, 2015. First published September 9, 2015; doi:10.1152/ajpcell.00122.2015.-The lymphatics have emerged as critical players in the progression and resolution of inflammation. The goal of this study was to identify specific microRNAs (miRNAs) that regulate lymphatic inflammatory processes. Rat mesenteric lymphatic endothelial cells (LECs) were exposed to the proinflammatory cytokine tumor necrosis factor-␣ for 2, 24, and 96 h, and miRNA profiling was carried out by real-time PCR arrays. Our data demonstrate a specific set of miRNAs that are differentially expressed (Ͼ1.8-fold and/or P Ͻ 0.05) in LECs in response to tumor necrosis factor-␣ and are involved in inflammation, angiogenesis, endothelial-mesenchymal transition, and cell proliferation and senescence. We further characterized the expression of miRNA 9 (miR-9) that was induced in LECs and in inflamed rat mesenteric lymphatics. Our results showed that miR-9 overexpression significantly repressed NF-B expression and, thereby, suppressed inflammation but promoted LEC tube formation, as well as expression of the prolymphangiogenic molecules endothelial nitric oxide synthase and VEGF receptor type 3. LEC viability and proliferation and endothelial-mesenchymal transition were also significantly induced by miR-9. This study provides the first evidence of a distinct profile of miRNAs associated with LECs during inflammation. It also identifies the critical dual role of miR-9 in fine-tuning the balance between lymphatic inflammatory and lymphangiogenic pathways.

show abstract

Section: Methodsmentioning

confidence: 99%

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Chakraborty

Zawieja

Davis

et al. 2015

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

show abstract

“…Thus, CPX has been shown to inhibit the proliferation of cells in culture (10–12) and of breast cancer and myeloma xenograft growth in mice (11–13). CPX also inhibits angiogenesis and lymphangiogenesis in established culture models (10, 14). DEF inhibits the growth of HeLa cells derived from cervical carcinoma as well as other cancer cell lines (15), and its analog mimosine slows the growth of subcutaneous lung and pancreatic cancer xenografts in mice (16).…”

Section: Introductionmentioning

confidence: 99%

Blocking eIF5A Modification in Cervical Cancer Cells Alters the Expression of Cancer-Related Genes and Suppresses Cell Proliferation

et al. 2014

View full text Add to dashboard Cite

Cancer etiology is influenced by alterations in protein synthesis that are not fully understood. In this study, we took a novel approach to investigate the role of the eukaryotic translation initiation factor eIF5A in human cervical cancers, where it is widely overexpressed. eIF5A contains the distinctive amino acid hypusine, which is formed by a posttranslational modification event requiring deoxyhypusine hydroxylase (DOHH), an enzyme that can be inhibited by the drugs ciclopirox and deferiprone. We found that proliferation of cervical cancer cells can be blocked by DOHH inhibition with either of these pharmacologic agents, as well as by RNA interference–mediated silencing of eIF5A, DOHH, or another enzyme in the hypusine pathway. Proteomic and RNA analyses in HeLa cervical cancer cells identified two groups of proteins in addition to eIF5A that were coordinately affected by ciclopirox and deferiprone. Group 1 proteins (Hsp27, NM23, and DJ-1) were downregulated at the translational level, whereas group 2 proteins (TrpRS and PRDX2) were upregulated at the mRNA level. Further investigations confirmed that eIF5A and DOHH are required for Hsp27 expression in cervical cancer cells and for regulation of its key target IκB and hence NF-κB. Our results argue that mature eIF5A controls a translational network of cancer-driving genes, termed the eIF5A regulon, at the levels of mRNA abundance and translation. In coordinating cell proliferation, the eIF5A regulon can be modulated by drugs such as ciclopirox or deferiprone, which might be repositioned to control cancer cell growth.

show abstract

“…Recently, preclinical studies have found that this off-patent fungicide possess anticancer effect, by inhibiting cell proliferation, inducing cell death, as well as inhibiting angiogenesis and lymphangiogenesis [5, 7–10, 12]. Most recently, a phase I clinical trial has demonstrated that oral administration of CPX at a dose of 40 mg/m 2 once daily for 5 days is well tolerated in all patients, and induces disease stabilization and/or hematologic improvement in 2/3 patients with advanced hematologic malignancies [6].…”

Section: Discussionmentioning

confidence: 99%

“…These findings strongly support that systemic administration of CPX has a great potential to be repositioned for cancer therapy. To facilitate repurposing CPX for cancer therapy, many groups have investigated the molecular mechanisms underlying its anticancer action [5, 7–10, 12]. Of interest, a recent study has reported that CPX enhances parthenolide-induced cell death in acute myeloid leukemia cells, by inhibiting the phosphorylation of S6K1 (T389), implying inhibition of mTORC1 [13].…”

Section: Discussionmentioning

confidence: 99%

“…CPX inhibits angiogenesis by inhibiting deoxyhypusine hydroxylase activity and vascular endothelial cell growth [10], although this is controversial [11]. CPX inhibits lymphangiogenesis by inhibiting vascular endothelial growth factor receptor-3 (VEGFR-3) expression in lymphatic endothelial cells [12]. Of interest, a recent study has reported that CPX enhances parthenolide-induced cell death in leukemic cells, by inhibiting the phosphorylation of ribosomal p70 S6 kinase 1 (S6K1) on T389, implying inhibition of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) [13].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK

Zhou

Shang

Wang

et al. 2016

Biochemical Pharmacology

View full text Add to dashboard Cite

Ciclopirox olamine (CPX), an off-patent antifungal agent, has recently been identified as a potential anticancer agent. The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation and survival. Little is known about whether and how CPX executes its anticancer action by inhibiting mTOR. Here we show that CPX inhibited the phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two downstream effector molecules of mTOR complex 1 (mTORC1), in a spectrum of human tumor cells, indicating that CPX inhibits mTORC1 signaling. Using rhabdomyosarcoma cells as an experimental model, we found that expression of constitutively active mTOR (E2419K) conferred resistance to CPX inhibition of cell proliferation, suggesting that CPX inhibition of mTORC1 contributed to its anticancer effect. In line with this, treatment with CPX inhibited tumor growth and concurrently suppressed mTORC1 signaling in RD xenografts. Mechanistically, CPX inhibition of mTORC1 was neither via inhibition of IGF-I receptor or phosphoinositide 3-kinase (PI3K), nor by activation of phosphatase and tensin homolog (PTEN). Instead, CPX inhibition of mTORC1 was attributed to activation of AMP-activated protein kinase (AMPK)-tuberous sclerosis complexes (TSC)/raptor pathways. This is supported by the findings that CPX activated AMPK; inhibition of AMPK with Compound C or ectopic expression of dominant negative AMPKα partially prevented CPX from inhibiting mTORC1; silencing TSC2 attenuated CPX inhibition of mTORC1; and CPX also increased AMPK-mediated phosphorylation of raptor (S792). Therefore, the results indicate that CPX exerts the anticancer effect by activating AMPK, resulting in inhibition of mTORC1 signaling.

show abstract

The fungicide ciclopirox inhibits lymphatic endothelial cell tube formation by suppressing VEGFR-3-mediated ERK signaling pathway

Cited by 31 publications

References 40 publications

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

MicroRNA signature of inflamed lymphatic endothelium and role of miR-9 in lymphangiogenesis and inflammation

Blocking eIF5A Modification in Cervical Cancer Cells Alters the Expression of Cancer-Related Genes and Suppresses Cell Proliferation

Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK

Contact Info

Product

Resources

About