Synergistic Antitumor Activity of Curcumin and the PARP1 Inhibitor PJ34 in Platinum-Sensitive and Resistant Ovarian Cancer Cells

TL;DR

Combining curcumin and a PARP1 inhibitor shows strong antitumor effects in ovarian cancer cells, even those resistant to platinum-based treatments.

Contribution

The study demonstrates a synergistic effect of curcumin and PARP1 inhibitor PJ34 in platinum-resistant ovarian cancer models.

Findings

The combination treatment significantly suppresses tumor cell proliferation and migration.

The combination promotes programmed cell death through an ROS-associated but not strictly ROS-dependent process.

The synergy is preserved in 3D tumor spheroid models and is effective in platinum-resistant cells.

Abstract

Ovarian cancer remains one of the most lethal gynecological malignancies, largely due to the development of resistance to platinum-based chemotherapy and limited responsiveness to subsequent treatment options. Although poly(ADP-ribose) polymerase-1 (PARP1) inhibitors are clinically effective in selected patient populations, their therapeutic efficacy is often reduced in treatment-resistant disease contexts. Curcumin, a natural polyphenolic compound, has been shown to modulate multiple cancer-related signaling pathways and may enhance the activity of anticancer agents. In this study, we investigated the combined effects of the PARP1 inhibitor PJ34 and curcumin and found that this combination exhibits synergistic antitumor activity in ovarian cancer cell models, including cells with experimentally validated reduced responsiveness to platinum treatment. In addition to conventional two-dimensional assays, we employed three-dimensional tumor spheroid models and ROS-rescue experiments to better reflect tumor architecture and to functionally explore potential contributing mechanisms. Our findings show that the combination treatment markedly suppresses tumor cell proliferation and migration while promoting programmed cell death through an ROS-associated but not strictly ROS-dependent process, without inducing excessive oxidative stress. Together, these results provide preclinical, mechanistically informative proof-of-concept evidence supporting PARP inhibitor–curcumin combinations as a complementary strategy for future experimental validation in treatment-resistant ovarian cancer.

Background/Objectives: Ovarian cancer remains a highly lethal malignancy, largely due to the development of therapeutic resistance, particularly in advanced disease. Combination strategies targeting complementary molecular pathways may enhance antitumor efficacy and help overcome resistance. The present study aimed to systematically evaluate the anticancer effects of the PARP1 inhibitor PJ34 and the natural polyphenol curcumin, administered alone and in combination, in platinum-sensitive and relatively platinum-resistant ovarian cancer models, with an emphasis on quantitative synergy assessment and functionally supported, hypothesis-generating mechanistic insight. Materials and Methods: Cell viability was evaluated using the MTT assay, and IC50 values were derived from dose–response curves. Drug interactions were quantitatively analyzed using the Chou–Talalay method, including combination index (CI) and dose reduction index (DRI) calculations. Intracellular reactive oxygen species (ROS) levels were measured using DCFH-DA-based assays. Cell migration was assessed using scratch-wound assays. Apoptosis was evaluated using Annexin V/PI flow cytometry, caspase-3 activity assays, and quantitative real-time PCR (RT-qPCR) analysis of apoptosis-related genes (Bax, Bcl-2, Caspase-3, Caspase-9, and p53). To further validate the findings under physiologically relevant conditions, three-dimensional (3D) tumor spheroid models were employed, and ROS involvement was functionally interrogated using N-acetyl-L-cysteine (NAC) rescue experiments to assess ROS-associated contributions rather than direct causality. Results: PJ34 and curcumin each reduced cell viability in a dose-dependent manner, whereas their combination produced a synergistic antiproliferative effect with reduced IC50 values. Synergism was particularly pronounced in relatively platinum-resistant SKOV-3 cells. Combination treatment significantly enhanced regulated apoptotic cell death, as demonstrated by increased apoptotic fractions, elevated caspase-3 activity, and an increased Bax/Bcl-2 ratio, with minimal necrosis. While PJ34 moderately increased intracellular ROS levels and curcumin reduced oxidative stress, the combination was associated with the normalization of ROS levels to near-control values. In 3D tumor spheroid models, combined treatment induced marked spheroid shrinkage, loss of structural integrity, and reduced viability, indicating a preservation of synergistic cytotoxic effects beyond two-dimensional (2D) conditions. NAC pretreatment partially attenuated, but did not fully rescue, the cytotoxic effects of the combination, indicating a ROS-associated, but not exclusively ROS-dependent, mechanism of action. In addition, the combination markedly inhibited cell migration in both ovarian cancer cell lines. Conclusions: This preclinical provides evidence that combined PARP1 inhibition and curcumin treatment can exert synergistic antitumor effects in ovarian cancer models, including relatively platinum-resistant disease, through the coordinated suppression of proliferation, induction of regulated apoptosis, and inhibition of migration. The integration of quantitative synergy analysis, 3D spheroid validation, and ROS-rescue experiments provides functionally supported, hypothesis-generating mechanistic insight and supports further evaluation of PARP inhibitor–curcumin combinations as a mechanistic proof-of-concept in advanced preclinical models.

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