Itraconazole Induces Regression of Infantile Hemangioma via Downregulation of the Platelet-Derived Growth Factor–D/PI3K/Akt/mTOR Pathway

Chen, Shuang; Zhuang, Kaiwen; Sun, Kai-Yi; Yang, Qin; Ran, Xin; Xu, Xiu-Lian; Chan, Mu; Zheng, Bin; Liu, Yanrong; Zeng, Jun; Dai, Yalin; Pradhan, Sushmita; Ran, Yuping

doi:10.1016/j.jid.2018.12.028

Cited by 27 publications

(24 citation statements)

References 23 publications

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“…317 Recently, Chen et al showed that itraconazole significantly inhibited angiogenesis in infantile hemangioma by downregulation of the PDGF/PI3K/ Akt/mTOR pathway. 318 Such studies have led to increased itraconazole-based clinical usage in the past few years. Studies have implied that itraconazole treatment has benefited many patients with ovarian, pancreatic and other cancers.…”

Section: Non-oncology Drugs In Drug Repurposingmentioning

confidence: 99%

Overcoming cancer therapeutic bottleneck by drug repurposing

Zhang

Zhou

Xie

et al. 2020

Sig Transduct Target Ther

364

315

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Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The "treasure trove" of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono-or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.

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Section: Non-oncology Drugs In Drug Repurposingmentioning

confidence: 99%

Overcoming cancer therapeutic bottleneck by drug repurposing

Zhang

Zhou

Xie

et al. 2020

Sig Transduct Target Ther

364

315

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“…Physiologically, PDGFR-β also promotes proliferation of pericytes and smooth muscle cells during their recruitment to the endothelium. Of note, itraconzole (which is a common anti-fungal drug) has recently been tested as a therapy for IHs, and this drug targets PDGFR-β activation, in turn inhibiting PI3K and Atk 74 .…”

Section: Mxra5mentioning

confidence: 99%

Identification of putative biomarkers for Infantile Hemangiomas and Propranolol treatment via data integration

Gómez-Acevedo

Dai²,

Strub

et al. 2020

Sci Rep

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Infantile hemangiomas (IHs) are the most common benign tumors in early childhood. They show a distinctive mechanism of tumor growth in which a rapid proliferative phase is followed by a regression phase (involution). Propranolol is an approved treatment for IHs, but its mechanism of action remains unclear. We integrated and harmonized microRNA and mRNA transcriptome data from newly generated microarray data on IHs with publicly available data on toxicological transcriptomics from propranolol exposure, and with microRNA data from IHs and propranolol exposure. We identified subsets of putative biomarkers for proliferation and involution as well as a small set of putative biomarkers for propranolol's mechanism of action for IHs, namely EPAS1, LASP1, SLC25A23, MYO1B, and ALDH1A1. Based on our integrative data approach and confirmatory experiments, we concluded that hypoxia in IHs is regulated by EPAS1 (HIF-2α) instead of HIF-1α, and also that propranolol-induced apoptosis in endothelial cells may occur via mitochondrial stress. Infantile hemangiomas (IHs) are the most common benign tumor of the vascular endothelium in infants and are present in 4 to 10% of children younger than 12 months 1,2. They manifest in any part of the body but around 60% of the cases arise in the head and neck 3. IHs have a unique growth pattern that is divided into three phases: proliferation, quiescence and involution 4. Despite the fact that the majority of IHs involute completely by 7 years of age, their hyper-proliferation can cause significant functional and disfiguring consequences and morbidities such as ulceration, bleeding, and pain. It is estimated that up to 40% of the lesions will require either surgical or medical intervention 3,5. Histologically, IHs in the proliferative phase show a lack of organization of blood vessels with densely packed capillaries composed of immature endothelial cells surrounded by pericytes, whereas during involution the capillaries are replaced with fatty and fibrous tissue 6. These findings suggest that the proliferation phase is orchestrated by angiogenesis or growth factors that lead to high mitotic rates. Among such markers reported in the literature are vascular endothelial growth factor A (VEGF-A) 7 , basic fibroblast growth factor (bFGF), proliferating cell nuclear antigen (PCNA), type IV collagenase 8 , and insulin-like growth factor 2 (IGF-2) 9. On the other hand, during the involution phase there is a high expression of antiangiogenic factors (e.g., tissue inhibitor of metalloproteinase TIMP1) 8 and increasing apoptosis of endothelial cells 10. However, high expression of growth factors in both the proliferating and involution phases (e.g. bFGF) makes it difficult to clearly identify causative factors for IHs' development. From the clinical perspective, it is important to find biomarkers that robustly differentiate between proliferation and involution phases on IHs, with the hope that those biomarkers will guide medical decisions towards optimal treatments. Propranolol is a non-selective β-adre...

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“…Other medications such as vincristine, interferon-α and imiquimod may be useful but are rarely used due to their serious side-effects. Recently, the common antifungal agent itraconazole has been found to be useful in the treatment of infantile haemangioma by inhibiting proliferation and promoting apoptosis of infantile primary haemangioma endothelial cells 6…”

Section: Commentmentioning

confidence: 99%