Methioninase Cell-Cycle Trap Cancer Chemotherapy.

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/G2 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/G2-phase blockage of cancer cells which is identified by the cancer cells' green fluorescence with FUCCI imaging. Cancer cells in G1/G0 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 G0/G1 phase, identified by the cancer cells' red fluorescence in the FUCCI system. The G0/G1-phase cancer cells are chemo-resistant. Tumor targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) was used to decoy quiescent G0/G1 stomach cancer cells growing in nude mice to cycle, with subsequent rMETase treatment to selectively trap the decoyed cancer cells in S/G2 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/G2-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.