Methioninase Cell-Cycle Trap Cancer Chemotherapy

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Cancer cells exhibit heightened dependence on methionine (MET) for proliferation compared to normal cells.
• MET restriction selectively arrests cancer cells in the S/G2 phase of the cell cycle.
• Quiescent G0/G1-phase cancer cells are typically resistant to conventional chemotherapy.

Purpose of the Study:

• To investigate a novel "decoy, trap, and kill" chemotherapy strategy.
• To evaluate the efficacy of combining Salmonella typhimurium A1-R, recombinant methioninase (rMETase), and chemotherapy against cancer cells.
• To overcome chemotherapy resistance in cancer models.

Main Methods:

• Utilizing fluorescence ubiquitination-based cell cycle indicator (FUCCI) to visualize cell cycle phases.
• Employing recombinant methioninase (rMETase) to degrade MET and induce S/G2-phase arrest.
• Using tumor-targeting Salmonella typhimurium A1-R to stimulate quiescent G0/G1 cancer cells into the cell cycle.
• Administering chemotherapy (cisplatin or paclitaxel) to eliminate trapped cancer cells.

Main Results:

• rMETase treatment induced S/G2-phase blockage in cancer cells, visualized by green FUCCI fluorescence.
• Salmonella typhimurium A1-R decoyed quiescent G0/G1 cancer cells (red FUCCI fluorescence) into cell cycle progression.
• The combination therapy completely prevented or regressed tumor growth in mouse models.
• A patient-derived orthotopic xenograft (PDOX) model of cisplatin-resistant osteosarcoma was eradicated.

Conclusions:

• The "decoy, trap, and kill" strategy effectively targets methionine-dependent cancer cells.
• This approach overcomes chemoresistance by synchronizing resistant cells and enhancing drug sensitivity.
• The combination of Salmonella typhimurium A1-R, rMETase, and chemotherapy represents a promising new paradigm for cancer treatment.