Abstract
Growth competition assays using barcoded yeast deletion-mutants reveal the molecular targets of nitrogen containing bisphosphonates used for the treatment of bone cancers and osteoporosis.
Highlights
Nitrogen-containing bisphosphonates are the elected drugs for the treatment of diseases in which excessive bone resorption occurs, for example, osteoporosis and cancer-induced bone diseases
The dataset obtained from the yeast screen was validated in a mammalian system, allowing the discovery of new biological processes involved in the cellular response to nitrogencontaining bisphosphonates and opening up opportunities for development of new anticancer drugs
Among the strains showing a marked haploinsufficient profile in the presence of the three drugs, we found genes related to proton pumps, which were suggested as nitrogencontaining bisphosphonates (N-BPs) targets before the discovery of farnesyl pyrophosphate synthase (FPPS)'s involvement [18]
Summary
Nitrogen-containing bisphosphonates are the elected drugs for the treatment of diseases in which excessive bone resorption occurs, for example, osteoporosis and cancer-induced bone diseases. The only known target of nitrogen-containing bisphosphonates is farnesyl pyrophosphate synthase, which ensures prenylation of prosurvival proteins, such as Ras. it is likely that the action of nitrogen-containing bisphosphonates involves additional unknown mechanisms. To identify novel targets of nitrogen-containing bisphosphonates, we used a genomewide high-throughput screening in which 5,936 Saccharomyces cerevisiae heterozygote barcoded mutants were grown competitively in the presence of sub-lethal doses of three nitrogen-containing bisphosphonates (risedronate, alendronate and ibandronate). Little is known about the molecular mechanisms underlying these effects In this context, we performed a large-scale competition experiment with different yeast mutants in the presence of sub-lethal doses of N-BPs to unravel their secondary cellular targets and to understand the molecular changes occurring in cells exposed to such compounds
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