Disulfiram Depletes PARPi-Resistant Dormant Cells in Ovarian Cancer

High-grade serous ovarian cancer (HGSOC) is the most common and aggressive form of ovarian cancer. Poly(ADP-ribose) polymerase inhibitors (PARPi) — drugs such as olaparib, rucaparib, and niraparib — have transformed treatment for patients with homologous recombination deficiency (HRD), particularly those with BRCA1/2 mutations. Yet acquired resistance to PARPi remains a major clinical obstacle, and a growing body of evidence suggests that non-genetic, drug-tolerant dormant cell populations may seed relapse.

In a study published in Biomedicine & Pharmacotherapy in September 2026, researchers at Mahidol University (Thailand) identified a conserved redox-dependent vulnerability in PARPi-induced dormant HGSOC cells and showed that disulfiram — an FDA-approved drug originally developed to treat alcohol use disorder — could exploit it. The findings suggest a mechanistically grounded combination strategy to delay resistance. For readers exploring repurposed-drug protocols, our protocol calculator can help estimate weight-based dosing parameters for combination regimens.

Table of Contents

• How PARPi Resistance Arises: Beyond Genetics
• Study Design and Key Findings
• Why Disulfiram? The ALDH-Redox Connection
• Caveats and Limitations
• Frequently Asked Questions

How PARPi Resistance Arises: Beyond Genetics

PARP inhibitors work by trapping PARP enzymes on DNA, preventing single-strand break repair and causing lethal double-strand breaks in cells that lack effective homologous recombination (HR) repair — typically those with BRCA1/2 mutations or other HRD signatures. The clinical benefit is substantial: maintenance PARPi therapy after platinum-sensitive recurrence has extended progression-free survival in HGSOC.

However, resistance mechanisms are multifactorial. While reversion mutations that restore HR function are well documented, a parallel and increasingly recognized driver is the emergence of drug-tolerant dormant cells — slow-cycling or quiescent cells that survive PARPi exposure and later reconstitute the tumor. These dormant reservoirs are often enriched in polyploid giant cancer cells (PGCCs), which can generate mononuclear progeny after drug withdrawal and reinitiate proliferation. Because dormancy is a reversible, non-genetic state, it may explain why some patients relapse even in the absence of new resistance mutations.

Understanding what sustains dormant HGSOC cells during PARPi treatment is therefore critical to designing adjuvant strategies that prevent relapse rather than merely treating it.

Study Design and Key Findings

The Mahidol team established a longitudinal model of PARPi-induced dormancy using authenticated HGSOC cell lines representing low, intermediate, and high HRD backgrounds. After prolonged olaparib exposure, cells entered a dormant state characterized by enlarged morphology, polyploidy, and reduced proliferation. Critically, these dormant cells retained the ability to recover proliferative capacity after drug withdrawal — confirming their role as a relapse-competent reservoir.

Integrated transcriptomic and proteomic analyses across all three HRD contexts revealed a conserved dependence on redox homeostasis during dormancy. Despite heterogeneous adaptive remodeling in metabolism, mesenchymal transition, and stress signaling, every dormant population converged on maintaining redox balance to survive. This shared vulnerability became the therapeutic target.

Through transcriptomics-guided functional screening, disulfiram emerged as the top candidate. The study then tested the disulfiram-PARPi combination and found:

Live-cell time-lapse imaging provided direct visual evidence: a subset of PGCCs generated mononuclear progeny after PARPi withdrawal, confirming their contribution to repopulation. The disulfiram-PARPi combination prevented this recovery. Antioxidant rescue experiments further supported oxidative stress as the key mediator — when antioxidants were added, the disulfiram effect was partially reversed, strengthening the mechanistic link.

Why Disulfiram? The ALDH-Redox Connection

Disulfiram (tetraethylthiuram disulfide) has been used for decades to treat alcohol use disorder by irreversibly inhibiting aldehyde dehydrogenase (ALDH), the enzyme that metabolizes acetaldehyde. In oncology, disulfiram has attracted preclinical interest because ALDH is also highly expressed in cancer stem cells and drug-tolerant dormant populations, where it buffers oxidative stress by detoxifying reactive aldehydes and maintaining redox homeostasis.

In this HGSOC study, the dormant reservoir generated by PARPi was enriched in ALDH activity. By inhibiting ALDH with disulfiram, the researchers disrupted the redox buffer, causing ROS accumulation, DNA damage accumulation, and ultimately cell death — but only when combined with PARPi, which independently creates DNA repair stress. The synergy is mechanistically logical: PARPi creates DNA damage that dormant cells normally survive by maintaining redox balance; disulfiram removes that survival mechanism.

This convergence on a conserved redox vulnerability — despite heterogeneous HRD backgrounds — is noteworthy. It suggests the strategy may be broadly applicable across different genetic subtypes of HGSOC, not only BRCA-mutant tumors.

Caveats and Limitations

• In-vitro only: The study used authenticated human HGSOC cell lines in culture. No animal model (mouse xenograft, patient-derived xenograft) or human clinical data were included.
• No pharmacokinetic data: Disulfiram is rapidly metabolized in vivo to its active metabolite diethyldithiocarbamate (DTC), and oral bioavailability is poor. Cell-culture concentrations may not translate to achievable plasma or intratumoral levels in patients.
• Cell-line limitations: Only a limited panel of HGSOC lines was tested. Heterogeneity across the full spectrum of patient tumors may alter the dormant phenotype and disulfiram sensitivity.
• Mechanism partially inferred: While ALDH inhibition and ROS increase were demonstrated, the precise molecular chain linking ALDH blockade to DNA damage accumulation in PARPi-treated dormant cells was not fully resolved.
• Clinical translation hurdles: Disulfiram's narrow therapeutic window, rapid metabolism, and need for concurrent copper chelation (in some repurposing protocols) complicate clinical application. This study did not address formulation, dosing, or safety in a human context.

Frequently Asked Questions

Shop Sanare Lab

Lab-tested products referenced in the research above. Links are provided for convenience — always review the label and consult a professional before use.

Disclaimer: Links are informational and for convenience. This site does not provide medical advice and does not endorse any specific vendor. Always verify product quality, labeling, and consult a licensed professional for health decisions. Disulfiram is not sold by Sanare Lab.

References

1. Suriya S, Jamnongsong S, Jamyuang C, Therasakvichya S, Sampattavanich S. PARP inhibition induces a redox-dependent dormant reservoir vulnerable to disulfiram in high-grade serous ovarian cancer. Biomed Pharmacother. 2026;202:119821. doi:10.1016/j.biopha.2026.119821. PubMed: 42546410.
2. Mahidol University, Siriraj Center of Research Excellence for Systems Pharmacology, Bangkok, Thailand — study institution.

Medical Disclaimer

The content on this site is for informational and educational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the guidance of a qualified healthcare provider with any questions you may have regarding a medical condition or treatment. Never disregard professional medical advice because of something you have read on this website.