title: Nigericin decreases the viability of multidrug-resistant cancer cells and lung tumorspheres and potentiates the effects of cardiac glycosides.
abstract: Multiple factors including tumor heterogeneity and intrinsic or acquired resistance have been associated with drug resistance in lung cancer. Increased stemness and the plasticity of cancer cells have been identified as important mechanisms of resistance; therefore, treatments targeting cancer cells independent of stemness phenotype would be much more effective in treating lung cancer. In this article, we have characterized the anticancer effects of the antibiotic Nigericin in cells displaying varying degrees of stemness and resistance to anticancer drugs, arising from (1) routine culture conditions, (2) prolonged periods of serum starvation. These cells are highly resistant to conventional anticancer drugs such as Paclitaxel, Hydroxyurea, Colchicine, Obatoclax, Wortmannin, and LY294002, and the multidrug-resistant phenotype of cells growing under prolonged periods of serum starvation is likely the result of extensive rewiring of signaling pathways, and (3) lung tumorspheres that are enriched for cancer stem-like cells. We found that Nigericin potently inhibited the viability of cells growing under routine culture conditions, prolonged periods of serum starvation, and lung tumorspheres. In addition, we found that Nigericin downregulated the expression of key proteins in the Wnt canonical signaling pathway such as LRP6, Wnt5a/b, and β-catenin, but promotes β-catenin translocation into the nucleus. The antitumor effects of Nigericin were potentiated by the Wnt activator HLY78 and by therapeutic levels of the US Food and Drug Administration-approved drug Digitoxin and its novel synthetic analog MonoD. We believe that Nigericin may be used in a co-therapy model in combination with other novel chemotherapeutic agents in order to achieve potent inhibition of cancers that display varying degrees of stemness, potentially leading to sustained anticancer effects.
authors.affiliation: 1 Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Juan Sebastian
authors.initials: JS
authors.lastname: Yakisich
authors.affiliation: 1 Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Azad
authors.affiliation: 1 Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Kaushik
authors.affiliation: 2 Department of Chemistry, Northeastern University, Boston, MA, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: O'Doherty
authors.affiliation: 1 Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, VA, USA.
authors.forename: Anand Krishnan V
authors.initials: AK
authors.lastname: Iyer
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D052117:Benzodioxoles / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009550:Nigericin / Q000008:administration & dosage*; D010617:Phenanthridines / Q000008:administration & dosage*; D060449:Wnt Signaling Pathway / Q000187:drug effects
chemical_list: C584141:4-ethyl-5-methyl-5,6-dihydro(1,3)dioxolo(4,5-j)phenanthridine; D000970:Antineoplastic Agents; D052117:Benzodioxoles; D010617:Phenanthridines; D009550:Nigericin
keywords: Digitoxin; Lung cancer; Nigericin; Wnt/β-catenin; chemoresistance; stem cells; stemness; tumorspheres