Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway

Zhu, Yiping; Zuo, Weiqiong; Chen, Lijuan; Bian, Shasha; Jing, Jiayu; Gan, Cailin; Wu, Xiuli; Liu, Hongyao; Su, Xingping; Hu, Wanglai; Guo, Yuqi; Wang, Yue; Ye, Tinghong

doi:10.1016/j.bcp.2019.08.012

Cited by 34 publications

(17 citation statements)

References 35 publications

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“…354 An increasing number of studies have shown niclosamide has an anti-metastasis effect in oral squamous cell carcinoma, hepatocellular carcinoma, melanoma, and human thyroid cancer. [355][356][357][358] A Phase II clinical trial of niclosamide, in which the drug was applied to patients with colorectal cancer metastases, has been conducted to assess the drug safety and efficacy (NCT02519582). Clinical trials have also been conducted for the treatment of prostate cancer (NCT02532114) (NCT03123978).…”

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

392

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

392

315

View full text Add to dashboard Cite

show abstract

“…A recent study reported that niclosamide, a potent radiosensitizer, acts by inhibiting STAT3 and Bcl-2 and by increasing the production of reactive oxygen species (ROS) in triple-negative breast cancer ( 17 ). Another study demonstrated that niclosamide inhibits the growth of melanoma cell lines (A375 and B16-F10) and induces mitochondrial apoptosis, which impairs cell migration and invasion, reduces expression of phosphorylated STAT3 at Tyr705 and inhibits matrix metalloproteinase-2 and −9 expression ( 18 ). Conversely, the present study demonstrated that the anthelmintic agent niclosamide may be repurposed to treat chemoresistant HER2-positive breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin‑resistant human epidermal growth factor receptor 2‑positive breast cancer

et al. 2021

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Chemotherapy-resistant breast cancer displays aggressive clinical behavior, is poorly differentiated and is associated with the occurrence of epithelial-mesenchymal transition and the presence of cancer stem cells. The anthelmintic drug niclosamide has been shown to have numerous clinical applications in the treatment of malignant tumors, in addition to its traditional use in tapeworm disease. Our previous study demonstrated that niclosamide had an antiproliferative effect and could inhibit the stem-like phenotype of the breast cancer cells, suggesting that it might have the potential to be used in the treatment of triple-negative breast cancer. However, the specific function and underlying mechanism of action of niclosamide in chemoresistant human epidermal growth factor receptor 2 (HER2)-positive breast cancer remain unknown. The present study aimed to determine whether niclosamide can inhibit cell proliferation, invasion and epithelial-to-mesenchymal transition, as well as the stem-like phenotype in cisplatin-resistant HER2-positive breast cancer. Alamar Blue and Annexin V/7-AAD staining, mammosphere formation and Transwell assays were performed to assess the viability, apoptosis, stem-like phenotype and invasion ability of breast cancer cell lines, respectively. Signaling molecule expression was detected via western blotting and a xenograft model was used to verify the inhibitory effect of niclosamide in vivo. The results from the present study demonstrated that niclosamide inhibited the resistance of HER2-positive breast cancer to cisplatin both in vitro and in vivo. Furthermore, niclosamide combined with cisplatin could inhibit breast cancer cell invasion, epithelial-mesenchymal transition and cell stemness. The inhibitory effect of niclosamide was mediated by apoptosis induction and Bcl-2 downregulation. Taken together, the results of the present study suggested that niclosamide combined with cisplatin may be considered as a novel treatment for chemoresistant HER2-positive breast cancer.

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“…In addition, the IC 50 for skeletal myoblast cytotoxicity was lower than in cancer cells. Previous studies of Ni anti-cancer activity have tended to utilize cancer cell xenograft models [ 61 ], including patient derived xenografts [ 62 ]. These models may not fully recapitulate cancer cachexia, which is observed in advanced metastasis and requires a fully functional immune system [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy

et al. 2021

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Skeletal muscle atrophy is a feature of aging (termed sarcopenia) and various diseases, such as cancer and kidney failure. Effective drug treatment options for muscle atrophy are lacking. The tapeworm medication, niclosamide is being assessed for repurposing to treat numerous diseases, including end-stage cancer metastasis and hepatic steatosis. In this study, we investigated the potential of niclosamide as a repurposing drug for muscle atrophy. In a myotube atrophy model using the glucocorticoid, dexamethasone, niclosamide did not prevent the reduction in myotube diameter or the decreased expression of phosphorylated FOXO3a, which upregulates the ubiquitin-proteasome pathway of muscle catabolism. Treatment of normal myotubes with niclosamide did not activate mTOR, a major regulator of muscle protein synthesis, and increased the expression of atrogin-1, which is induced in catabolic states. Niclosamide treatment also inhibited myogenesis in muscle precursor cells, enhanced the expression of myoblast markers Pax7 and Myf5, and downregulated the expression of differentiation markers MyoD, MyoG and Myh2. In an animal model of muscle atrophy, niclosamide did not improve muscle mass, grip strength or muscle fiber cross-sectional area. Muscle atrophy is also feature of cancer cachexia. IC50 analyses indicated that niclosamide was more cytotoxic for myoblasts than cancer cells. In addition, niclosamide did not suppress the induction of iNOS, a key mediator of atrophy, in an in vitro model of cancer cachexia and did not rescue myotube diameter. Overall, these results suggest that niclosamide may not be a suitable repurposing drug for glucocorticoid-induced skeletal muscle atrophy or cancer cachexia. Nevertheless, niclosamide may be employed as a compound to study mechanisms regulating myogenesis and catabolic pathways in skeletal muscle.

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Repurposing of the anti-helminthic drug niclosamide to treat melanoma and pulmonary metastasis via the STAT3 signaling pathway

Cited by 34 publications

References 35 publications

Overcoming cancer therapeutic bottleneck by drug repurposing

Overcoming cancer therapeutic bottleneck by drug repurposing

Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatin‑resistant human epidermal growth factor receptor 2‑positive breast cancer

Investigation of niclosamide as a repurposing agent for skeletal muscle atrophy

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