Anti-leprosy drug clofazimine inhibits growth of triple-negative breast cancer cells via inhibition of canonical Wnt signaling

Koval, Alexey; Vlasov, Peter K.; Shichkova, Polina; Khunderyakova, S.; Markov, Yuri; Panchenko, J.; Volodina, Anastasia; Kondrashov, Fyodor A.; Katanaev, Vladimir L.

doi:10.1016/j.bcp.2013.12.007

Cited by 64 publications

(75 citation statements)

References 34 publications

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“…The highest ranking scores were found for Cinnarizine, Digitoxigenin and Clofazimine. Cinnarizine has already been shown to be effective in vitro against lymphoma and multiple myeloma42 and to inhibit melanogenesis in mouse B16 melanoma cells43, and Clofazimine was found effective in preclinical models of pancreatic ductal adenocarcinoma and triple-negative breast cancer4445.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

Fagone

Caltabiano

Russo

et al. 2017

Sci Rep

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Melanoma of the uveal tract accounts for approximately 5% of all melanomas and represents the most common primary intraocular malignancy. Despite improvements in diagnosis and more effective local therapies for primary cancer, the rate of metastatic death has not changed in the past forty years. In the present study, we made use of bioinformatics to analyze the data obtained from three public available microarray datasets on uveal melanoma in an attempt to identify novel putative chemotherapeutic options for the liver metastatic disease. We have first carried out a meta-analysis of publicly available whole-genome datasets, that included data from 132 patients, comparing metastatic vs. non metastatic uveal melanomas, in order to identify the most relevant genes characterizing the spreading of tumor to the liver. Subsequently, the L1000CDS2 web-based utility was used to predict small molecules and drugs targeting the metastatic uveal melanoma gene signature. The most promising drugs were found to be Cinnarizine, an anti-histaminic drug used for motion sickness, Digitoxigenin, a precursor of cardiac glycosides, and Clofazimine, a fat-soluble iminophenazine used in leprosy. In vitro and in vivo validation studies will be needed to confirm the efficacy of these molecules for the prevention and treatment of metastatic uveal melanoma.

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Section: Discussionmentioning

confidence: 99%

Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

Fagone

Caltabiano

Russo

et al. 2017

Sci Rep

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“…For example, clofazimine has recently been identified in a large-scale screening as an inhibitor of Wnt signaling [55], the pathway playing an important role in PDAC tumor initiation and progression [56, 57]. Clofazimine was shown to decrease proliferation of HTB19 triple-negative breast cancer cells whose growth is Wnt pathway-dependent.…”

Section: Discussionmentioning

confidence: 99%

“…Clofazimine was shown to decrease proliferation of HTB19 triple-negative breast cancer cells whose growth is Wnt pathway-dependent. The authors also reported that clofazimine exerted a significantly smaller effect on non-cancerous mammary epithelial cells (HMEC) than on HTB19 cells, providing thus a further case of selective action on tumoral versus non-tumoral cells [55]. In addition, clofazimine has been shown to exert an inhibitory action on ABCB1/MDR1/P-glycoproteins (Pgp) [58], although this aspect is particularly relevant when applied together with chemotherapeutics to chemo-resistant cells (e.g.…”

Section: Discussionmentioning

confidence: 99%

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Zaccagnino¹,

Managò

Leanza

et al. 2016

Oncotarget

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Pancreatic ductal adenocarcinoma (PDAC) represents the most common form of pancreatic cancer with rising incidence in developing countries. Unfortunately, the overall 5-year survival rate is still less than 5%. The most frequent oncogenic mutations in PDAC are loss-of function mutations in p53 and gain-of-function mutations in KRAS. Here we show that clofazimine (Lamprene), a drug already used in the clinic for autoimmune diseases and leprosy, is able to efficiently kill in vitro five different PDAC cell lines harboring p53 mutations. We provide evidence that clofazimine induces apoptosis in PDAC cells with an EC50 in the μM range via its specific inhibitory action on the potassium channel Kv1.3. Intraperitoneal injection of clofazimine resulted in its accumulation in the pancreas of mice 8 hours after administration. Using an orthotopic PDAC xenotransplantation model in SCID beige mouse, we show that clofazimine significantly and strongly reduced the primary tumor weight. Thus, our work identifies clofazimine as a promising therapeutic agent against PDAC and further highlights ion channels as possible oncological targets.

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“…Wnt signaling is widely accepted as one of the most common sources for pro-proliferation signaling in TNBC cells, and the FZD7 protein may represent a novel target or biomarker for TNBC treatment [79]. XAV939 and clofazimine have been identified as Wnt inhibitors and promising anti-TNBC drugs, but neither of them have yet been used in advanced clinical trials [80,81]. Fortunately, tannins, isolated from Syzygium guineense, directly inactivates the stabilization and transcription of Wnt3a-induced β-catenin expression, which may be pursued for novel therapies [82].…”

Section: Triple-negative Breast Cancermentioning

confidence: 99%

Natural products against renin-angiotensin system for antifibrosis therapy

Yang

Chen

Liu

et al. 2019

European Journal of Medicinal Chemistry

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Anti-leprosy drug clofazimine inhibits growth of triple-negative breast cancer cells via inhibition of canonical Wnt signaling

Cited by 64 publications

References 34 publications

Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

Identification of novel chemotherapeutic strategies for metastatic uveal melanoma

Tumor-reducing effect of the clinically used drug clofazimine in a SCID mouse model of pancreatic ductal adenocarcinoma

Natural products against renin-angiotensin system for antifibrosis therapy

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