2. Academic Validation
  3. CCI52 sensitizes tumors to 6-mercaptopurine and inhibits MYCN-amplified tumor growth

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

  • Biochem Pharmacol. 2020 Feb;172:113770. doi: 10.1016/j.bcp.2019.113770.
Tony Huynh 1,  Jayne Murray 1,  Claudia L Flemming 1,  Alvin Kamili 2,  Ute Hofmann 3,  Leanna Cheung 1,  Elizabeth A Roundhill 1,  Denise M T Yu 1,  Hannah T Webber 1,  Matthias Schwab 4,  Michelle J Henderson 1,  Michelle Haber 1,  Murray D Norris 5,  Jamie I Fletcher 6
Affiliations

Affiliations

  • 1 Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia.
  • 2 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.
  • 3 Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, and University of Tuebingen, Tuebingen, Germany.
  • 4 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.
  • 5 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.
  • 6 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.
PMID: 31862449 DOI: 10.1016/j.bcp.2019.113770
Abstract

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.

Keywords

6-Mercaptopurine; Chemotherapy; MRP4; Neuroblastoma; Sensitizer.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-101453
    99.72%, MRP4 Inhibitor