The combination of reduced MCL-1 and standard chemotherapeutics is tolerable in mice

Cell Death Differ. 2017 Dec;24(12):2032-2043. doi: 10.1038/cdd.2017.125. Epub 2017 Aug 11.

Abstract

A common therapeutic strategy to combat human cancer is the use of combinations of drugs, each targeting different cellular processes or vulnerabilities. Recent studies suggest that addition of an MCL-1 inhibitor to such anticancer drug treatments could be an attractive therapeutic strategy. Thus, it is of great interest to understand whether combinations of conventional anticancer drugs with an MCL-1 inhibitor will be tolerable and efficacious. In order to mimic the combination of MCL-1 inhibition with other cancer therapeutics, we treated Mcl-1+/- heterozygous mice, which have a ~50% reduction in MCL-1 protein in their cells, with a broad range of chemotherapeutic drugs. Careful monitoring of treated mice revealed that a wide range of chemotherapeutic drugs had no significant effect on the general well-being of Mcl-1+/- mice with no overt damage to a broad range of tissues, including the haematopoietic compartment, heart, liver and kidney. These results indicate that MCL-1 inhibition may represent a tolerable strategy in cancer therapy, even when combined with select cytotoxic drugs.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Drug Resistance, Neoplasm
  • Female
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Male
  • Mice
  • Myeloid Cell Leukemia Sequence 1 Protein / genetics
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism*

Substances

  • Antineoplastic Agents
  • Mcl1 protein, mouse
  • Myeloid Cell Leukemia Sequence 1 Protein