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25.05.2019 | Original Article | Ausgabe 3/2019

Cancer Chemotherapy and Pharmacology 3/2019

Identification of dinactin, a macrolide antibiotic, as a natural product-based small molecule targeting Wnt/β-catenin signaling pathway in cancer cells

Zeitschrift:
Cancer Chemotherapy and Pharmacology > Ausgabe 3/2019
Autoren:
Aehtesham Hussain, Mohd Saleem Dar, Nasima Bano, Md Mehedi Hossain, Rafia Basit, Aadil Qadir Bhat, Mushtaq A. Aga, Sabeena Ali, Qazi Parvaiz Hassan, Mohd Jamal Dar
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00280-019-03870-x) contains supplementary material, which is available to authorized users.
Aehtesham Hussain and Mohd Saleem Dar contributed equally to this work.

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Abstract

Purpose

Despite the fact that hyper-activation of Wnt/β-catenin signaling pathway has been seen in many cancers, including liver, colorectal and lung carcinoma, no small molecule inhibitors are available that specifically target this pathway. In this study, we analyzed the impact of dinactin (DA), an antibiotic ionophore produced by Streptomyces species, as an effective small molecule targeting Wnt/β-catenin signaling pathway in cancer cells.

Methods

We performed MTT assays to investigate cell viability and proliferation after exposure to small molecules. Protein expression analysis was carried out by western blotting. Top-Flash reporter assays were used to score for β-catenin signaling and cell cycle analysis was carried out by flow cytometry.

Results

In the first set of experiments, DA was seen to selectively inhibit the proliferation of HCT-116 and HepG2 cancer cells, unlike HEK-293 cells (a low tumorigenic cell line), in apoptosis-independent manner. Further, DA was seen to block the G1/S progression and decrease the expression of cyclin D1 in cancer cells. Since cyclin D1 is the downstream target gene of Wnt/β-catenin signaling, we examined the impact of DA on TCF-dependent β-catenin activity using Top-Flash reporter assay. Interestingly, DA significantly decreased Top-Flash activity at lower nano-molar concentrations when compared with salinomycin in HCT-116 and HepG2 cells.

Conclusion

We report the identification of dinactin as a natural product-based small molecule that effectively blocks the Wnt/β-catenin signaling pathway in cancer cells at nano-molar concentration. We anticipate that DA could be developed as a novel drug for anti-cancer therapy and for the management of neuropathic pain.

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