CCI52 sensitizes tumors to 6-mercaptopurine and inhibits MYCN-amplified tumor growth.

Autor: Huynh T; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Murray J; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Flemming CL; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Kamili A; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia., Hofmann U; Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, Tuebingen, Germany., Cheung L; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Roundhill EA; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Yu DMT; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Webber HT; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Schwab M; Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, Tuebingen, Germany; Departments of Clinical Pharmacology, and of Pharmacy and Biochemistry, University Hospital Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Henderson MJ; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Haber M; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia., Norris MD; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; University of New South Wales Centre for Childhood Cancer Research, UNSW Sydney, Kensington, NSW, Australia., Fletcher JI; Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Women's and Children's Health, UNSW Sydney, Kensington, NSW, Australia. Electronic address: jfletcher@ccia.org.au.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2020 Feb; Vol. 172, pp. 113770. Date of Electronic Publication: 2019 Dec 17.
DOI: 10.1016/j.bcp.2019.113770
Abstrakt: The antimetabolite 6-mercaptopurine (6-MP) is an important component in the treatment of specific cancer subtypes, however, the development of drug resistance and dose-limiting toxicities can limit its effectiveness. The therapeutic activity of 6-MP requires cellular uptake, enzymatic conversion to thio-GMP and incorporation of thio-GTP into RNA and DNA, as well as inhibition of de novo purine synthesis by methyl-thio-IMP. Mechanisms that prevent 6-MP entry into the cell, prevent 6-MP metabolism or deplete thiopurine intermediates, can all lead to 6-MP resistance. We previously conducted a high-throughput screen for inhibitors of the multidrug transporter MRP4 using 6-MP sensitivity as the readout. In addition to MRP4-specific inhibitors, we identified a compound, CCI52, that sensitized cell lines to 6-MP independent of this transporter. CCI52 and its more stable analogue CCI52-14 also function as effective chemosensitizers in vivo, substantially extending survival in a transgenic mouse cancer model treated with 6-MP. Chemosensitization was associated with an increase in thio-IMP, suggesting that CCI52 functions directly on 6-MP uptake or metabolism. In addition to its chemosensitizing effects, CCI52 and CCI52-14 inhibited the growth of MYCN-amplified high-risk neuroblastoma cell lines and delayed tumor progression in a MYCN-driven, transgenic mouse model of neuroblastoma. These multifunctional inhibitors may be useful for the further development of anticancer agents and as tools to better understand 6-MP metabolism.
(Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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