Sweat but no gain: Inhibiting proliferation of multidrug resistant cancer cells with ersatzdroges

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. What's new? A common mechanism for acquired resistance to cancer chemotherapy is upregulation of the ABCB1 pump. This study shows that the proliferation of multidrug-resistant ABCB1-expressing cells is decreased significantly with the administration of relatively nontoxic chemotherapy drug substitutes, or ersatzdroges, that serve as pump substrates. In vivo 18-FDG-PET imaging revealed increased glucose uptake by tumors in mice following systemic ersatzdroge administration. The findings suggest that ersatzdroges, by increasing the energy expenditure of resistant cells, expose resistant cell populations and reduce their fitness and ability to proliferate. Since many ersatzdroges are currently available (e.g., Verapamil), the strategy could be applied clinically.