Abstract
ABCC10, also known as multidrug-resistant protein 7 (MRP7), is the tenth member of the C subfamily of the ATP-binding cassette (ABC) superfamily. ABCC10 mediates multidrug resistance (MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs. The ABCC10 transporter is a 171-kDa protein that is localized on the basolateral cell membrane. ABCC10 is a broad-specificity transporter of xenobiotics, including antitumor drugs, such as taxanes, epothilone B, vinca alkaloids, and cytarabine, as well as modulators of the estrogen pathway, such as tamoxifen. In recent years, ABCC10 inhibitors, including cepharanthine, lapatinib, erlotinib, nilotinib, imatinib, sildenafil, and vardenafil, have been reported to overcome ABCC10-mediated MDR. This review discusses some recent and clinically relevant aspects of the ABCC10 drug efflux transporter from the perspective of current chemotherapy, particularly its inhibition by tyrosine kinase inhibitors and phosphodiesterase type 5 inhibitors.
Highlights
ABCC10, known as multidrug-resistant protein 7 (MRP7), is the tenth member of the C subfamily of the ATP-binding cassette (ABC) superfamily
Studies to date have consistently focused on the three major ABC transporters involved in producing multidrug resistance (MDR) in most cancer cells: ABCB1 (MDR1, known as P-glycoprotein or P-gp), ABCC1, and ABCG2[3,4,5,6,7]
ABCC10 mRNA is highly expressed in various tissues, including the kidneys, brain, and colon, suggesting that it is involved in the transport of drugs and other endogenous molecules[15]
Summary
Discovery of ABCC10 as a new member of ABCC subfamily[9] cDNA cloning and genomic organization of the murine Abcc10A and Abcc10B[57] ABCC10 is a lipophilic anion transporter involved in phase III of detoxification[12] First report of ABCC10 as a resistance factor to anticancer drugs like paclitaxel, docetaxel, vincristine, and vinblastine[10] ABCC10 gene expression found to be the highest in the pancreas[14] Peptide derived from ABCC10 reported as an immunoregulator[58] ABCC10 is a resistance factor for docetaxel in salivary gland adenocarcinoma[21] ABCC10 is established as a biomarker for paclitaxel resistance in non-small cell lung cancer[18] ABCC10 is a resistance factor for vinorelbine in non-small cell lung cancer[17] ABCC10 is a resistance factor for epothilone B, and ABCC10 transport does not involve glutathione, unlike ABCB1 and ABCC1[22] Cepharanthine, a herbal extract, reverses ABCC10-mediated paclitaxel resistance[24] BCR-Abl tyrosine kinase inhibitors, imatinib and nilotinib, inhibit efflux function of ABCC10 efflux transporter[28]. Epidermal growth factor receptor tyrosine kinase inhibitors, erlotinib and lapatinib, inhibit efflux function of ABCC10 efflux transporter[33] Docetaxel intermittently increases simultaneous ABCC10 and ABCB1 gene expression[59] ABCC10 transcript was detected in acute myeloid leukemia cell lines[19] ABCC10 termed as "endogenous resistance factor" for taxanes that confer paclitaxel resistance in vivo in Abcc10-knockout mice[12]. The mortality of the Abcc10-knockout mice was found to be significantly increased due to neutropenia and marked bone marrow toxicity after paclitaxel treatment[13] These results suggest that ABCC10 protects cells against paclitaxel toxicity. Accumulation and efflux studies have indicated that cepharanthine significantly increases the intracellular accumulation of [3H]-paclitaxel and inhibits the efflux of [3H]-paclitaxel from ABCC10-transfected cells, but not in the cells lacking the ABCC10 transporter[24]. The transport of E217βG is competitively inhibited by cepharanthine with a Ki value of 4.86 μmol/L[24]
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