Mechanistic basis for overcoming platinum resistance using copper chelating agents

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Platinum-based chemotherapy is a cornerstone of ovarian cancer treatment.
• Acquired resistance to platinum drugs limits treatment efficacy, necessitating novel therapeutic strategies.
• The high-affinity copper transporter (hCtr1) is crucial for cellular uptake of cisplatin (cDDP) and platinum drug resistance.

Purpose of the Study:

• To investigate the potential of copper-lowering agents to overcome cDDP resistance in ovarian cancer.
• To elucidate the role of hCtr1 expression in cDDP resistance and resensitization.
• To explore the clinical relevance of hCtr1 levels in patient outcomes.

Main Methods:

• Utilized cisplatin-resistant and sensitive ovarian cancer cell lines and patient-derived xenografts.
• Assessed the effect of copper chelation on hCtr1 expression and cDDP sensitivity.
• Analyzed public gene expression datasets to correlate hCtr1 levels with patient prognosis.

Main Results:

• Copper-lowering agents preferentially resensitized cDDP-resistant cells by enhancing hCtr1 expression.
• This effect is linked to mammalian copper homeostasis regulatory mechanisms.
• Copper chelation demonstrated enhanced cell-killing efficacy in preclinical models.
• Elevated tumor hCtr1 levels, but not ATP7A/ATP7B, correlated with favorable outcomes in ovarian cancer patients treated with platinum drugs.

Conclusions:

• Copper chelation represents a viable strategy to overcome platinum drug resistance in ovarian cancer.
• Targeting hCtr1 expression via copper modulation offers a mechanistic basis for improving chemotherapy efficacy.
• hCtr1 levels can serve as a predictive biomarker for platinum-based treatment response in ovarian cancer.