Ali Rafieian
1 
, Mohammad Maroufi
2,3 , Manal Sami Abduridha
4, Mohammad Kordkatouli
5,6* 1 Student Research Center, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Biological Science, Faculty of Science, University of Kurdistan, Sanandaj, Iran
3 Biotechnology Research Center, Ur.C, Islamic Azad University, Urmia, Iran
4 Department of Pharmaceutical Chemistry, College of Pharmacy, Al-Zahraa University for Women, Karbala, Iraq
5 Department of Genetics, Faculty of Advanced Sciences and Technology, TeMS.C, Islamic Azad University, Tehran, Iran
6 Medicinal Plants Research Center, Go.C, Islamic Azad University, Gorgan, Iran
Abstract
Oxidative stress and antioxidant systems are complex components of human physiology and pathology. Reactive oxygen species (ROS), previously viewed as undesirable byproducts of cellular metabolism, have now been identified as critical signaling agents that participate in cell proliferation, differentiation, and immune responses. Both endogenous and exogenous antioxidants play a critical role in redox homeostasis by countering surplus ROS and preventing oxidative injury. Nevertheless, growing evidence points to the paradoxical dual nature of antioxidants, casting doubt on their universally positive effects. This paradox is particularly pronounced in cancer. Although high levels of ROS promote tumor development and progression by causing genomic instability and activating oncogenic signaling, high levels of ROS can also cause cancer cell death and represent a major mechanism of action of anticancer therapies. Tumor cells respond by increasing their antioxidant capacity, which enables them to maintain ROS at levels that promote survival without causing cytotoxicity. Exogenous antioxidant supplementation can therefore disrupt this balance, potentially stimulating tumor growth, enabling metastasis, and diminishing the efficacy of ROS-dependent therapies like chemotherapy and radiotherapy. Moreover, plant-derived antioxidants, such as polyphenols and flavonoids, exhibit both antioxidant and pro-oxidant effects, highlighting the context-specificity of redox modulation in cancer. Although these compounds may have chemopreventive advantages, their impact on established malignancies is complex and requires additional research. This review provides a broad description of the duality of oxidative stress and antioxidants, specifically regarding their implications in cancer treatment and resistance. A better comprehension of redox biology is needed to develop more effective and personalized therapeutic interventions based on the specific regulation of oxidative stress.
Implication for health policy/practice/research/medical education:
The double edged nature of antioxidants suggests that routine supplementation during cancer therapy might warrant caution. Context dependent effects imply that clinical recommendations should remain tentative, and further investigation into redox modulation appears advisable before revising health policies.
Please cite this paper as: Rafieian A, Maroufi M, Abduridha MS, Kordkatouli M. Double-edged role of antioxidants and oxidative stress: Focusing on cancer therapy and resistance. J Herbmed Pharmacol. 2026;15(3):303-310. doi: 10.34172/jhp.53694.