Anti-cancer effect of clofazimine as a single agent and in combination with cisplatin on U266 multiple myeloma cell line

Durusu, Ipek Zeynep; Husnugil, Hazal Hepsen; Ataş, Heval; Biber, Ayşenur; Gerekçi, Selin; Güleç, Ezgi A.; Özen, Can

doi:10.1016/j.leukres.2017.01.019

Cited by 15 publications

(14 citation statements)

References 39 publications

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“…Intriguingly, Durusu et al (42) have shown that CLF induces cell death in the MM cell line U266, in which we observed no detectable effect, presumably because of the lack of AHR expression. This discrepancy is most likely due to the CLF dosage used in the former study, which was 5 times greater than the one used here (10 μM vs. 2 μM).…”

Section: Methodscontrasting

confidence: 64%

“…The potential of CLF as an antitumor drug has been previously explored, and its effects in cultured cells and tumor xenografts have been attributed to its ability to either inhibit the Kv1.3 potassium channel (40)(41)(42), interfere with the Wnt signaling pathway (43), or enhance the activity of phospholipase A 2 (44). At least some of these effects may be explained by CLF-dependent inhibition of polyamines, as polyamines have been previously shown to inhibit the activity of phospholipases A2 and C (100).…”

Section: Methodsmentioning

confidence: 99%

“…Clofazimine (CLF) is a well-tolerated, riminophenazine-based agent approved by the US FDA for the treatment of leprosy and tuberculosis (38,39). Suppression of transformed phenotypes by CLF has been previously reported to impinge on a variety of pathways and targets (40)(41)(42)(43)(44); however, CLF antitumor efficacy has not been evaluated in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Bianchi‐Smiraglia¹,

Bagati²,

Fink³

et al. 2018

Journal of Clinical Investigation

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Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

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Section: Methodscontrasting

confidence: 64%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Bianchi‐Smiraglia¹,

Bagati²,

Fink³

et al. 2018

Journal of Clinical Investigation

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“…Whether baclofen has any anticancer effects or not remains unknown owing to a lack of relevant research. Prestwick-685, also named clofazimine in PubChem, was identified to be associated with breast cancer ( 53 ) and lung cancer ( 54 ). Recently, Durusu et al ( 54 ) provided novel evidence for the anticancer effect of clofazimine, which implies that clofazimine also requires further investigation regarding cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Prestwick-685, also named clofazimine in PubChem, was identified to be associated with breast cancer ( 53 ) and lung cancer ( 54 ). Recently, Durusu et al ( 54 ) provided novel evidence for the anticancer effect of clofazimine, which implies that clofazimine also requires further investigation regarding cancer treatment. Compared with clofazimine, it appears that menadione, which is also known as vitamin K3, has attracted more attention from the perspective of cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Novel drug candidates for treating esophageal carcinoma: A study on differentially expressed genes, using connectivity mapping and molecular docking

et al. 2018

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Patients with esophageal carcinoma (ESCA) have a poor prognosis and high mortality rate. Although standard therapies have had effect, there is an urgent requirement to develop novel options, as increasing drug tolerance has been identified in clinical practice. In the present study, differentially expressed genes (DEGs) of ESCA were identified in The Cancer Genome Atlas and Genotype-Tissue Expression databases. Functional and protein-protein interaction (PPI) analyses were performed. The Connectivity Map (CMAP) was selected to predict drugs for the treatment of ESCA, and their target genes were acquired from the Search Tool for Interactions of Chemicals (STITCH) by uploading the Simplified Molecular-Input Line-Entry System structure. Additionally, significant target genes and ESCA-associated hub genes were extracted using another PPI analysis, and the corresponding drugs were added to construct a network. Furthermore, the binding affinity between predicted drug candidates and ESCA-associated hub genes was calculated using molecular docking. Finally, 827 DEGs (|log2 fold-change|≥2; q-value <0.05), which are principally involved in protein digestion and absorption (P<0.005), the plasminogen-activating cascade (P<0.01), as well as the ‘biological regulation’ of the Biological Process, ‘membrane’ of the Cellular Component and ‘protein binding’ of the Molecular Function categories, were obtained. Additionally, 11 hub genes were obtained from the PPI network (all degrees ≥30). Furthermore, the 15 first screen drugs were extracted from CMAP (score <−0.85) and the 9 second screen drugs with 70 target genes were extracted from STITCH. Furthermore, another PPI analysis extracted 51 genes, and apigenin, baclofen, Prestwick-685, menadione, butyl hydroxybenzoate, gliclazide and valproate were selected as drug candidates for ESCA. Those molecular docking results with a docking score of >5.52 indicated the significance of apigenin, Prestwick-685 and menadione. The results of the present study may lead to novel drug candidates for ESCA, among which Prestwick-685 and menadione were identified to be significant new drug candidates.

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Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis

Yang

Zhang

et al. 2022

Cell. Mol. Life Sci.

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Anti-cancer effect of clofazimine as a single agent and in combination with cisplatin on U266 multiple myeloma cell line

Cited by 15 publications

References 39 publications

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Novel drug candidates for treating esophageal carcinoma: A study on differentially expressed genes, using connectivity mapping and molecular docking

Phenazine derivatives attenuate the stemness of breast cancer cells through triggering ferroptosis

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