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

SIMPLE SUMMARY: Chemotherapy is the gold standard treatment option for metastatic cancers. However, the efficacy of chemotherapy is limited due to the development of resistance. The aberrantly expressed Wnt/β-catenin signaling pathway acts as one of the major cancer drivers that also causes the development of resistance. Therefore, in this study, we explored the combinatorial approach of downregulating the Wnt/β-catenin pathway along with using a chemotherapeutic agent as a strategy to overcome drug resistance and improve cancer therapy. We evaluated the combinatorial efficacy of Niclosamide (an antihelminthic repurposed as a Wnt signaling inhibitor) and Doxorubicin (first-line treatment for multiple cancers in the clinic) against breast cancer. The combination showed synergistically enhanced death of all three clinical subtypes of breast cancer cells in both the sequential and concurrent treatment regimens and holds the potential to be developed as an efficient therapeutic option for breast cancer irrespective of its clinical subtype. 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.