title: Sweat but no gain: inhibiting proliferation of multidrug resistant cancer cells with "ersatzdroges".
abstract: ATP-binding cassette (ABC) drug transporters consuming ATPs for drug efflux is a common mechanism by which clinical cancers develop multidrug resistance (MDR). We hypothesized that MDR phenotypes could be suppressed by administration of "ersatzdroges," nonchemotherapy drugs that are, nevertheless, ABC substrates. We reasoned that, through prolonged activation of the ABC pumps, ersatzdroges will force MDR cells to divert limited resources from proliferation and invasion thus delaying disease progression. We evaluated ABC substrates as ersatzdroge by comparing their effects on proliferation and survival of MDR cell lines (MCF-7/Dox and 8226/Dox40) with the effects on the drug-sensitive parental lines (MCF-7 and 8226/s, respectively) in glucose-limited condition. The changes in glucose and energy demands were also examined in vitro and in vivo. MCF-7/Dox showed higher ATP demand and susceptibility to glucose resource limitation. Ersatzdroges significantly decreased proliferation of MCF-7/Dox when the culture media contained physiological glucose concentrations (1.0 g/L) or less, but had no effect on MCF-7. Similar evidence was obtained from 8226/Dox40 and 8226/s comparison. In vivo 18F-FDG-PET imaging demonstrated that glucose uptake was increased by systemic administration of an ersatzdroge in tumors composed of MDR. These results suggest that administration of ersatzdroges, by increasing the metabolic cost of resistance, can suppress proliferation of drug-resistance phenotypes. This provides a novel and relatively simple application model of evolution-based strategy, which can exploit the cost of resistance to delay proliferation of drug-resistant cancer phenotypes. Furthermore, suggested is the potential of ersatzdroges to identify tumors or regions of tumors that express the MDR phenotype.
authors.affiliation: Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
authors.forename: Yoonseok
authors.initials: Y
authors.lastname: Kam
authors.forename: Tuhin
authors.initials: T
authors.lastname: Das
authors.forename: Haibin
authors.initials: H
authors.lastname: Tian
authors.forename: Parastou
authors.initials: P
authors.lastname: Foroutan
authors.forename: Epifanio
authors.initials: E
authors.lastname: Ruiz
authors.forename: Gary
authors.initials: G
authors.lastname: Martinez
authors.forename: Susan
authors.initials: S
authors.lastname: Minton
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Gillies
authors.forename: Robert A
authors.initials: RA
authors.lastname: Gatenby
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D017291:Clarithromycin / Q000494:pharmacology / Q000627:therapeutic use; D016572:Cyclosporine / Q000494:pharmacology / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004917:Erythromycin / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015870:Gene Expression; D006801:Humans; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D047368:Tumor Burden; D014700:Verapamil / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D004917:Erythromycin; D016572:Cyclosporine; D014700:Verapamil; D017291:Clarithromycin
keywords: ABCB1 transporters; breast cancer; multidrug resistance