What question did this study set out to answer?

To examine the synergistic effects of etoposide and resveratrol on breast cancer cell death via parthanatos activation.

April 10, 2026Open Access

Enhanced Antitumor Response in Breast Cancer via Parthanatos Activation Mediated by the Synergistic Effect of Etoposide and Resveratrol

Key Points

To examine the synergistic effects of etoposide and resveratrol on breast cancer cell death via parthanatos activation.
Assessed cell viability using MTT assays.
Evaluated parthanatos activation through AIF translocation and NAD+ depletion measurements.
Analyzed gene expression changes related to parthanatos.
Quantified synergy using the Chou–Talalay method.
Performed Olaparib PARP inhibitor experiments to confirm PARP-1 involvement.
The etoposide-resveratrol combination significantly increased cell death compared to single agents.
Combination index values indicated strong synergism for both MCF-7 and MDA-MB-231 cells.
Observations included increased PARP-1 expression and AIF nuclear translocation.
Significant NAD+ depletion was noted, linking it to increased cytotoxic effects.
Morphological features consistent with parthanatos were observed, confirming caspase-independent cell death.

Abstract

Breast cancer remains a major global health challenge, requiring novel therapeutic strategies that can overcome drug resistance and improve treatment efficacy. This study investigates the synergistic antitumor effects of etoposide, a conventional chemotherapeutic agent, and resveratrol, a natural polyphenol with anticancer properties, in human breast cancer cell lines, with particular focus on their ability to activate the parthanatos cell death pathway. Using MCF-7 (estrogen receptor-positive) and MDA-MB-231 (triple-negative) breast cancer cells, we assessed cell viability via MTT assays and evaluated parthanatos activation through multiple complementary approaches including AIF translocation determined by subcellular fractionation, NAD+ depletion measurement, and gene expression analysis. Synergy was quantified using the Chou–Talalay method across multiple effect levels (ED50, ED75, ED90). To establish causality, Olaparib PARP inhibitor experiments were performed to confirm that PARP-1 hyperactivation is essential for the observed cytotoxic effects. The results demonstrated that the etoposide–resveratrol combination significantly enhanced cell death and inhibited proliferation compared to single-agent treatments, with combination index (CI) values indicating strong synergism (CI = 0.62–0.75 for MCF-7; CI = 0.58–0.71 for MDA-MB-231). This synergy was associated with robust parthanatos activation, evidenced by increased PARP-1 expression, AIF nuclear translocation confirmed by subcellular fractionation, and significant NAD+ depletion. Critically, Olaparib pre-treatment (3 µM) significantly rescued cells from combination-induced death, restored NAD+ levels to near-control values, and prevented AIF translocation, establishing a causal link between PARP-1 hyperactivation and parthanatos-mediated cytotoxicity. The combination also induced significant DNA fragmentation, elevated oxidative stress, and cell death with morphological features consistent with parthanatos, while caspase activity remained low, confirming caspase-independent cell death. These findings suggest that targeting parthanatos with etoposide and resveratrol could offer a promising therapeutic strategy for breast cancer, potentially overcoming resistance and improving efficacy. Further in vivo studies and clinical investigations are needed to validate these results and explore translational applications.

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