A Synergistic Combination of Niclosamide and Doxorubicin as an Efficacious Therapy for All Clinical Subtypes of Breast Cancer

Abstract

Drug resistance is one of the major hurdles in the success of cancer chemotherapy. Notably, aberrantly expressed Wnt/β-catenin signaling plays a major role in the initiation and maintenance of oncogenesis along with development of chemoresistance. Therefore, the combinatorial approach of targeting Wnt/β-catenin pathway along with using a chemotherapeutic agent seems to be a promising strategy to improve cancer therapy. In the present study, we evaluated the combination of niclosamide (Nic), an FDA-approved antihelminthic drug repurposed as a Wnt signaling inhibitor, and doxorubicin (Dox), a conventional anticancer agent, in all clinical subtypes of breast cancer viz. triple negative breast cancer, HER2 positive breast cancer, and hormone receptor positive breast cancer. The results demonstrated that the combination induced apoptosis and caused synergistically enhanced death of all breast cancer cell types at multiple combinatorial concentrations using both the sequential and concurrent treatment regimens. Mechanistically, downregulation of Wnt/β-catenin signaling and cell cycle arrest at G0/G1 phase by Nic and increase in reactive oxygen species by both Nic and Dox along with the inherent cytotoxicity of Dox mediated the synergism between the two drugs in both the treatment regimens. Overall, the combination of Nic and Dox holds promise to be developed as an efficient therapeutic option for breast cancer irrespective of its clinical subtype.

Disturbance of the Warburg effect by dichloroacetate and niclosamide suppresses the growth of different sub-types of malignant pleural mesothelioma in vitro and in vivo

“…Synergism has been reported when DCA is combined with different drugs for anti-cancer research: DCA/cisplatin or gefitnib or elotinib (Al-Azawi et al, 2021), DCA/metformin (Kim et al, 2021;Klose et al, 2021;Korsakova et al, 2021), DCA/3-bromopyruvate (Nikravesh et al, 2021), DCA/sorafenib (Sun et al, 2021), DCA/PX-478 (Parczyk et al, 2021) and DCA/ erlotinib (Dyrstad et al, 2021). Said synergistic effect has also been observed when Nic is combined with other agents: Nic/ gemcitabine (Guo et al, 2022b), Nic/metformin (Kang et al, 2021) and Nic/doxorubicin (Lohiya and Katti, 2021). We show a novel combination of DCA with Nic that synergistically suppressed tumor growth in MPM cell line and xenograft models.…”

Mesoporous Silica Nanoparticle-Based Combination of Niclosamide and Doxorubicin: Effect of Treatment Regimens on Breast Cancer Subtypes

“…4,6,7 We combined Nic with Dox (a conventional anticancer agent) to develop a combination therapy to improve the therapeutic outcome of breast cancer patients. 24 However, it is known that systemically administered free drugs have poor biodistribution, are nonspecific, and cause many side effects. 9 NP-mediated drug delivery systems have been shown to improve drug biodistribution, help achieve spatiotemporal control on the drug release, impart stability to the drug, and reduce its side effects.…”

“…The reduced success of single-agent therapies has led to the development of combination therapies for the better management of cancer. In this regard, targeting dysregulated cell signaling pathways along with using a conventional anticancer agent has attracted a lot of importance as dysregulated cell signaling pathways drive cancer and impart chemoresistance to cancer cells. − Wnt/β-catenin signaling is one such pathway which is aberrantly expressed in all clinical subtypes of breast cancer and is responsible for poor clinical outcomes in breast cancer patients, making it a potential target to improve breast cancer therapy. − Nic, an FDA-approved antihelminthic, has shown promising anticancer properties and is able to efficiently downregulate Wnt/β-catenin signaling in multiple cancer cells, including breast cancer. ,, We combined Nic with Dox (a conventional anticancer agent) to develop a combination therapy to improve the therapeutic outcome of breast cancer patients . However, it is known that systemically administered free drugs have poor biodistribution, are nonspecific, and cause many side effects .…”

“…These combinations were NPs containing 1, 2, 5, and 6 μM Dox combined each with 25 and 30 μM Nic-NPs and 20 μM Nic combined with 6 μM Dox (Figures 9E and S4B). Further, since free drug concurrent therapy was not very efficacious in MCF7 cells, 24 formulation-based concurrent therapy was not studied in these cells.…”

Drug Repurposing to Enhance Antitumor Response to PD-1/PD-L1 Immune Checkpoint Inhibitors

“…In brief, NCS is a good candidate for repurposing in oncology, but the active principle should probably be reformulated because it has a poor aqueous solubility and a low bioavailability. The use of cyclodextrin–NCS complexes, polymeric micelles, or specific nanoparticles containing NCS have been proposed to improve the anticancer efficacy of the compound [ 85 , 86 , 99 , 100 ].…”