V-ATPase as an effective therapeutic target for sarcomas
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- 作者：Francesca Perut ; Sofia Avnet ; Caterina Fotia ; Serena Rubina Bagl矛o ; Manuela Salerno ; Shigekuni Hosogi ; Katsuyuki Kusuzaki ; Nicola Baldini
- 关键词：ESOM ; esomeprazole ; OS ; osteosarcoma ; RS ; rhabdomyosarcoma ; CS ; chondrosarcoma
- 刊名：Experimental Cell Research
- 出版年：1 January, 2014
- 年：2014
- 卷：320
- 期：1
- 页码：21-32
- 全文大小：4204 K
文摘
Malignant tumors show intense glycolysis and, as a consequence, high lactate production and proton efflux activity. We investigated proton dynamics in osteosarcoma, rhabdomyosarcoma, and chondrosarcoma, and evaluated the effects of esomeprazole as a therapeutic agent interfering with tumor acidic microenvironment. All sarcomas were able to survive in an acidic microenvironment (up to 5.9-6.0 pH) and abundant acidic lysosomes were found in all sarcoma subtypes. V-ATPase, a proton pump that acidifies intracellular compartments and transports protons across the plasma membrane, was detected in all cell types with a histotype-specific expression pattern.
Esomeprazole administration interfered with proton compartmentalization in acidic organelles and induced a significant dose-dependent toxicity. Among the different histotypes, rhabdomyosarcoma, expressing the highest levels of V-ATPase and whose lysosomes are most acidic, was mostly susceptible to ESOM treatment.