Niclosamide enhances the cytotoxic effect of cisplatin in cisplatin-resistant human lung cancer cells via suppression of lung resistance-related protein and c-myc

Abstract

Lung cancer is a leading cause of cancer-associated mortality worldwide. The cisplatin (DDP)-based chemotherapy remains the foundation of treatment for the majority of patients affected by advanced non-small cell lung cancer (NSCLC). However, DDP-resistance limits the clinical utility of this drug in patients with advanced NSCLC. The aim of the present study was to investigate the inhibitory effect of niclosamide on human lung cancer cell growth and to investigate the possible underlying mechanism. The effects of niclosamide on the proliferation of human lung adenocarcinoma (A549) and DDP-resistant (CR) human lung adenocarcinoma (A549/DDP) cells were examined by Cell Counting kit-8 assay. The impact of niclosamide on the apoptosis of A549/DDP cells was detected by Annexin V-fluorescein isothiocyanate/propidium iodide assay. The expression levels of cisplatin-resistant-associated molecules (lung resistance-related protein and c-myc) following niclosamide treatment in A549/DDP cells were evaluated by western blot analysis. The results indicated that niclosamide in combination with DDP demonstrated a synergistic effect in A549/DDP cells and directly induced apoptosis, which may be associated with caspase-3 activation. Furthermore, niclosamide decreased the expression level of c-myc protein, which may influence DDP sensitivity of A549/DDP cells. Thus, the present study indicates that niclosamide combined with DDP exerts a synergistic effect in cisplatin-resistant lung cancer cells and may present as a promising drug candidate in lung cancer therapy.

Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres

“…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 ). Moreover, niclosamide enhanced the anti-proliferative activities of oxaliplatin in human colorectal cancer (Osada et al 2011 ) and of cisplatin in lung cancer (Zuo et al 2018 ). Wieland et al also reported that niclosamide acts as a natural inducer of NFKBIA and combined treatment of niclosamide and TMZ synergistically inhibited cellular viability in NFKBIA ± glioblastoma genotype (Wieland et al 2013 ).…”

Host-targeted niclosamide inhibits C. difficile virulence and prevents disease in mice without disrupting the gut microbiota

“…From the most potent inhibitors of cell-rounding in this class, niclosamide was selected for further characterization based on its impeccable safety profile in humans, and known preferential distribution in the lower GI after oral dosing 26 , which we anticipated would be beneficial for targeting the gut-damaging toxins of C. difficile . Niclosamide is a remarkably well-studied molecule that has been shown to have a number of other biological activities in vitro that have prompted other investigations into translation into diseases including cancer 45 – 49 , diabetes 50 as well as other infectious diseases 22 . In most cases, however, the low systemic exposure of niclosamide, which is likely a major contributor to its overall safety, has hampered its use for indications outside of the GI tract.…”

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

“…Furthermore, niclosamide was also revealed to exert a synergistic effect with numerous cancer drugs in human cancer cells. Compared with cancer drug treatment alone, the combination treatment of niclosamide with bicalutamide, cisplatin, paclitaxel, carboplatin, erlotinib, dasatinib, or sorafenib exhibited an improved antineoplastic efficacy in prostate (32), lung (52), cervical (14), ovarian (30), colon (53), chronic myeloid leukemia (22) and renal cancer (34), respectively. To date, the frontline chemotherapeutic agents for advanced esophageal cancer cells are 5-FU, cisplatin, and paclitaxel.…”