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. Epub 2019 Dec 17.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimetabolites, Antineoplastic / administration & dosage
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Mercaptopurine / administration & dosage*
  • Mercaptopurine / pharmacology*
  • Mice
  • Mice, Transgenic
  • Molecular Structure
  • N-Myc Proto-Oncogene Protein / genetics
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neoplasms, Experimental / drug therapy
  • Neuroblastoma / drug therapy*
  • Neuroblastoma / pathology
  • Thiazoles / adverse effects
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • Antimetabolites, Antineoplastic
  • MYCN protein, mouse
  • N-Myc Proto-Oncogene Protein
  • Thiazoles
  • Mercaptopurine