Identification of Niclosamide as a Novel Anticancer Agent for Adrenocortical Carcinoma

Abstract

Purpose Adrenocortical carcinoma (ACC) is a rare and aggressive cancer, and no current effective therapy is available for locally advanced and metastatic ACC. Drug repurposing is an emerging approach for identifying new indications for existing drugs, especially for rare cancers such as ACC. The objective of this study was to use quantitative high-throughput screening to identify agents with antineoplastic activity against ACC. Experimental Design A screening of 4,292 compounds was performed on three ACC cell lines: BD140A, SW-13, and NCI-H295R. Results Twenty-one active compounds were identified, with an efficacy of >80% in all three cell lines. Of these, niclosamide showed higher efficacy and lower IC50 than established anti-ACC drugs. We then validated niclosamide-inhibited cellular proliferation in all three ACC cell lines. Next, we investigated the mechanism by which niclosamide inhibited ACC cell proliferation, and found that it induced caspase-dependent apoptosis and G1 cell cycle arrest. Niclosamide also decreased cellular migration and reduced the level of mediators of epithelial-to-mesenchymal transition, such as N-cadherin and vimentin. Furthermore, niclosamide treatment resulted in decreased expression of β-catenin. We also evaluated the effect of niclosamide on energy metabolism in ACC cell lines and found it resulted in mitochondrial uncoupling. Niclosamide treatment inhibited ACC tumor growth with no observed toxicity in mice in vivo. Conclusions Our findings suggest that niclosamide has anti-ACC activity through its inhibition of multiple altered cellular pathways and cellular metabolism in ACC. Our results provide a preclinical rationale for evaluating niclosamide therapy in a clinical trial for ACC.

Niclosamide, a Drug with Many (Re)purposes

“…The disease that has received by far the most attention in the repurposing of niclosamide is cancer. To date, niclosamide has been shown to exhibit anticancer activity against colon, breast, prostate, glioblastoma, osteosarcoma, ovarian, leukemia, adrenocortical carcinoma, lung, and oral cancers …”

Repurposing of Anthelminthics as Anticancer Drugs

“…Furthermore, niclosamide showed significant antitumor activity against a panel of cervical cancer cell lines via inhibition of mitochondrial respiration and the mammalian target of rapamycin (mTOR) signaling pathway [42]. In adrenocortical carcinoma, niclosamide has anticancer activity through its inhibition of multiple cellular pathways and impairment of the cellular metabolism [43].…”

“…Signaling pathways Cancer cells [45], osteosarcoma [37], STAT3 CSCs [46], Wnt/β-catenin ovarian cancer [43], prostate cancer [36], NSCLC/ c-Jun-ROS [35], colorectal cancer/TNIK [30].…”

Niclosamide inhibits the cell proliferation and enhances the responsiveness of esophageal cancer cells to chemotherapeutic agents

“…The mechanism of niclosamide action is through the inhibition of glucose uptake, oxidative phosphorylation, and anaerobic metabolism in the target worms (7). Except for antiprotozoal function, the antineoplastic effects of niclosamide has been revealed in many human cancer cells, including adrenocortical carcinoma (8), breast (9)(10)(11), colorectal (12,13) and cervical cancer (14), glioblastoma (15), hepatocellular carcinoma (16,17), head and neck (18,19) and lung cancer (20,21), leukemia (22,23), nasopharyngeal cancer (24), osteosarcoma (25), oral squamous cell carcinoma (26,27), ovarian (28)(29)(30), prostate (31)(32)(33), renal (34) and thyroid cancer (35). Niclosamide treatment was reported to induce apoptosis of cancer cells in vitro (7,10,23) and suppress tumor size in animal studies (11,29).…”