Abstract
The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions. Under physiological conditions, ABC transporters are involved in cellular trafficking of hormones, lipids, ions, xenobiotics, and several other molecules, including a broad spectrum of chemical substrates and chemotherapeutic drugs. In cancers, ABC transporters have been intensely studied over the past decades, mostly for their involvement in the multidrug resistance (MDR) phenotype. This review provides an overview of ABC transporters, both related and unrelated to MDR, which have been studied in osteosarcoma and Ewing’s sarcoma. Since different backbone drugs used in first-line or rescue chemotherapy for these two rare bone sarcomas are substrates of ABC transporters, this review particularly focused on studies that have provided findings that have been either translated to clinical practice or have indicated new candidate therapeutic targets; however, findings obtained from ABC transporters that were not directly involved in drug resistance were also discussed, in order to provide a more complete overview of the biological impacts of these molecules in osteosarcoma and Ewing’s sarcoma. Finally, therapeutic strategies and agents aimed to circumvent ABC-mediated chemoresistance were discussed to provide future perspectives about possible treatment improvements of these neoplasms.
Highlights
The most common mechanism leading to multidrug resistance (MDR) in human tumors is the increased activity or overexpression of ATP-binding cassette (ABC) proteins that reduce the levels of chemotherapeutic drugs accumulation within cells [5]
While ATP-binding cassette subfamily B member 1 (ABCB1) increased along with the degree of doxorubicin resistance in preclinical models of U-2OS cells, ATP-binding cassette subfamily A member 1 (ABCA1) was shown to be progressively downregulated. This ratio was proven to derive from the activation of Ras, which was dependent on the endogenous rate of synthesis of farnesyl pyrophosphate (FPP), an upstream metabolite of cholesterol
The discovery of non-coding RNAs opened the field for the identification of multiple mechanisms mediated by microRNAs and long ncRNAs, which control the expression of ABCB1 and mediate drug resistance
Summary
The ATP-binding cassette (ABC) transporter superfamily consists of several proteins with a wide repertoire of functions, including the transport of a broad spectrum of chemical substrates and chemotherapeutic drugs. The most common mechanism leading to MDR in human tumors is the increased activity or overexpression of ABC proteins that reduce the levels of chemotherapeutic drugs accumulation within cells [5]. OStogether and ES tumor cells, as well as the most common primary tumors of bone, they are rare neoplasms [6] ABC-mediated chemoresistance or to sensitize bone tumor cells to conventional in this review in relation to their expression and activity in OS and ES tumor cells, as well chemotherapeutic drugs are reviewed. Potential therapeutic strategies and novel agents used to circumvent the ABCmediated chemoresistance or to sensitize bone tumor cells to conventional chemotherapeutic drugs are reviewed
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