Methioninase cell-cycle trap cancer chemotherapy

Robert M. Hoffman, Shuuya Yano, Kentaro Igarashi

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Cancer cells are methionine (MET) dependent compared to normal cells as they have an elevated requirement for MET in order to proliferate. MET restriction selectively traps cancer cells in the S/G 2 phase of the cell cycle. The cell cycle phase can be visualized by color coding with the fluorescence ubiquitination-based cell cycle indicator (FUCCI). Recombinant methioninase (rMETase) is an enzyme that effectively degrades MET. rMETase induces S/G 2 -phase blockage of cancer cells which is identified by the cancer cells’ green fluorescence with FUCCI imaging. Cancer cells in G 1 /G 0 are the majority of the cells in solid tumors and are resistant to the chemotherapy. Treatment of cancer cells with standard chemotherapy drugs only led to the majority of the cancer cell population being arrested in G 0 /G 1 phase, identified by the cancer cells’ red fluorescence in the FUCCI system. The G 0 /G 1 -phase cancer cells are chemo-resistant. Tumor targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) was used to decoy quiescent G 0 /G 1 stomach cancer cells growing in nude mice to cycle, with subsequent rMETase treatment to selectively trap the decoyed cancer cells in S/G 2 phase, which made them highly sensitive to chemotherapy. Subsequent cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy was then administered to kill the decoyed and trapped cancer cells, which completely prevented or regressed tumor growth. In a subsequent experiment, a patient-derived orthotopic xenograft (PDOX) model of recurrent CDDP-resistant metastatic osteosarcoma was eradicated by the combination of Salmonella typhimurium A1-R decoy, rMETase S/G 2 -phase cell cycle trap, and CDDP cell kill. Salmonella typhimurium A1-R and rMETase pre-treatment thereby overcame CDDP resistance. These results demonstrate the effectiveness of the new chemotherapy paradigm of “decoy, trap, and kill” chemotherapy.

Original languageEnglish
Title of host publicationMethods in Molecular Biology
PublisherHumana Press Inc.
Pages133-148
Number of pages16
DOIs
Publication statusPublished - Jan 1 2019
Externally publishedYes

Publication series

NameMethods in Molecular Biology
Volume1866
ISSN (Print)1064-3745

Keywords

  • Cell cycle
  • Cisplatinum
  • Decoy
  • Decoy-trap-kill chemotherapy
  • FUCCI
  • Imaging
  • Methionine dependence
  • Paclitaxel
  • Recombinant methioninase
  • rMETase
  • S/G
  • Salmonella typhimurium A1-R
  • Trap
  • Tumor-targeting

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics

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  • Cite this

    Hoffman, R. M., Yano, S., & Igarashi, K. (2019). Methioninase cell-cycle trap cancer chemotherapy. In Methods in Molecular Biology (pp. 133-148). (Methods in Molecular Biology; Vol. 1866). Humana Press Inc.. https://doi.org/10.1007/978-1-4939-8796-2_11