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A concomitant ATP-depleting strategy markedly enhances anticancer agent activity
D S Martin1, D Spriggs, J A Koutcher
1Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Summary
Anticancer drugs can cause sublethal damage to cancer cells, creating a therapeutic window. Combining ATP-depleting agents with pyrimidine inhibitors enhances tumor regression and cures by severely reducing cancer cell energy levels.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Anticancer agents induce DNA damage, initiating cell death pathways like apoptosis and necrosis.
- Cancer cells with reduced sensitivity may only sustain sublethal injury and recover.
- Endogenous inhibitors and genetic factors can promote sublethal damage, hindering complete cell death.
Purpose of the Study:
- To review the interplay of cell death pathways and sublethal damage in cancer.
- To explore the therapeutic potential of further reducing ATP and pyrimidine levels in sublethally injured cancer cells.
- To present a novel therapeutic strategy combining ATP depletion and pyrimidine inhibition to enhance anticancer efficacy.
Main Methods:
- Review of existing data on ATP and pyrimidine metabolism in sublethally injured cancer cells.
- Analysis of in vivo data from tumor-bearing animals treated with combined ATP-depleting agents and a de novo pyrimidine inhibitor (PALA).
- Evaluation of specific agents targeting ATP synthesis (6-methylmercaptopurine riboside) and generation (6-aminonicotinamide) to achieve severe ATP depletion (>85%).
Main Results:
- Sublethal injury reduces ATP and pyrimidine levels but not sufficiently for cell death.
- Concomitant administration of ATP-depleting agents and PALA with various anticancer agents significantly enhanced tumor regression rates in animal models.
- Severe depletion of intracellular ATP to 15% or below was identified as critical for preventing cancer cell viability.
- In vivo data demonstrated the efficacy of this strategy, particularly with cisplatin.
Conclusions:
- Sublethal damage from anticancer agents presents a therapeutic opportunity to induce cell death.
- Combining agents that block both ATP synthesis and generation with pyrimidine inhibitors can synergistically enhance anticancer effects.
- This novel therapeutic strategy holds significant potential for improving cancer treatment outcomes by exploiting cancer cell energy metabolism.