Niclosamide, an oral antihelmintic drug, exhibits antimetastatic activity in hepatocellular carcinoma cells through downregulating twist‐mediated CD10 expression

Abstract

Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, especially, in eastern Asia, and its prognosis is poor once metastasis occurs. Niclosamide, a US Food and Drug Administration-approved antihelmintic drug, was shown to inhibit the growth of various cancers including HCC, but the effect of niclosamide on cell motility and the underlying mechanism have not yet been completely defined. The present study demonstrated that niclosamide, at 0-40 nM, concentration-dependently inhibited wound closure and the migratory/invasive capacities of human Huh7 and SK-Hep-1 HCC cells without exhibiting cytotoxicity. A protease array analysis showed that CD10 was dramatically downregulated in Huh7 cells after niclosamide treatment. Western blot and flow cytometric assays further demonstrated that CD10 expression was concentration-dependently downregulated in Huh7 and SK-Hep-1 cells after niclosamide treatment. Mechanistic investigations found that niclosamide suppressed Twist-mediated CD10 transactivation. Moreover, knockdown of CD10 expression by CD10 small interfering RNA in HCC cells suppressed cell migratory/invasive abilities and overexpression of CD10 relieved the migration inhibition induced by niclosamide. Taken together, our results indicated that niclosamide could be a potential agent for inhibiting metastasis of HCC, and CD10 is an important target of niclosamide for suppressing the motility of HCC cells.

Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

“…Firstly, we found that niclosamide significantly reduced proliferation of GBM TSs in a dose dependent manner. Chien et al ( 2018 ) reported that niclosamide inhibited invasiveness but could not alter cell viability in hepatocellular carcinoma. However, several studies have revealed that niclosamide inhibits the proliferation of cancer cells in colon (Sack et al 2011 ), breast (Londono-Joshi et al 2014 ), prostate (Lu et al 2011 ), and lung cancers (Stewart et al 2016 ), as well as GBM (Wieland et al 2013 ).…”

Overcoming cancer therapeutic bottleneck by drug repurposing

“…354 An increasing number of studies have shown niclosamide has an anti-metastasis effect in oral squamous cell carcinoma, hepatocellular carcinoma, melanoma, and human thyroid cancer. [355][356][357][358] A Phase II clinical trial of niclosamide, in which the drug was applied to patients with colorectal cancer metastases, has been conducted to assess the drug safety and efficacy (NCT02519582). Clinical trials have also been conducted for the treatment of prostate cancer (NCT02532114) (NCT03123978).…”

Kaempferol inhibits the cell migration of human hepatocellular carcinoma cells by suppressing MMP‐9 and Akt signaling

“…Several studies have reported that the MAPK signaling is known to regulate MMP‐9 expression and play a vital role in HCC metastasis 45–47 . Western blot revealed that kaempferol (0, 25, 50, 75, and 100 μM) had no obvious influence on the expressions of p‐p‐38, total p‐38, p‐ERK1/2, total ERK1/2, p‐JNK1/2 and total JNK1/2 in Huh‐7 and SK‐Hep‐1 cells (Figure 6A and B).…”