Gallic acid (GA) has demonstrated an antiproliferative effect on different tumor cells. This study was carried out to determine the apoptosis event, oxidative stress, and the related-antioxidant enzyme activity in HeLa cells treated with cisplatin, GA, and their combination. The morphology and percentage of apoptotic cells were evaluated using Hoechst staining and annexin V/PI assay. The intracellular reactive oxygen species (ROS) and activity of antioxidant enzymes were measured using 2′,7′-dichlorofluorescin diacetate assay and spectrophotometric method. Our findings showed that the percentages of early apoptotic cells in cells treated with cisplatin (CIS) (8.8 ± 1.75%), GA (9.6 ± 0.148%), and their combination (12.83 ± 1.44%) were significantly higher than the control group (4.67 ± 0.14%). Moreover, intracellular ROS in HeLa cells treated with CIS (122.7 ± 9.45%), GA (124.7 ± 4.94%), and the combination (137.1 ± 8.99%) were significantly increased compared to the control group. The combination treatment also decreased the activity of superoxide dismutase and catalase. Our findings suggest that in HeLa cells, GA is combined with cisplatininduced apoptosis by increasing ROS and reducing antioxidant enzyme levels. This result will support further research related to the combination of CIS and GA as a potential cervical cancer chemotherapeutic agent.

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Background: Most cervical cancer fatalities have been reported due to drug resistance, invasion, and metastasis. Combination therapy is a prominent technique for overcoming the toxicity of cancer chemotherapy to normal cells, which is mediated across numerous targeted pathways and requires a lower dose of each individual agent. Polyphenolic substances have the potential to improve chemotherapy efficacy while also reducing negative effects. Aims: This study aimed to review the research findings on the role of reactive oxygen species (ROS) in cervical cancer cell HeLa treated with combination therapy. Results: Hydroxyl radicals damage DNA, causing a cascade of structural changes in purine and pyrimidine bases that could lead to mutagenicity. ROS, such as hydroxyl radical (OH- ), superoxide anions (O2 - ), hydrogen peroxide (H2O2), and peroxyl radicals (ROO- ), are frequent products of aerobic metabolism that can be beneficial or detrimental to the biological system. To combat the harmful effects of ROS, cells have an antioxidative defense system that comprises superoxide dismutases, catalase, glutathione, and other defensive mechanisms. Excessive ROS accumulation causes DNA damage, which triggers the apoptotic machinery, resulting in cell death. Conclusion: Chemotherapeutic medications with phenolic compounds or polyphenol-rich extracts exhibit anticancer synergy. Combination treatment with polyphenols and anticancer drugs is one of the promising approaches in the treatment of cervical cancer.

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