Triple-negative breast cancer (TNBC) is a subtype of breast cancer that does not express the three hormonal receptors: estrogen (ER), progesterone (PR), and human epidermal growth factor receptor 2 (HER-2) (Zannetti, 2023). It is linked to a poor prognosis due to several aspects that include highly aggressive, invasive, and metastatic nature, as well as high recurrence rates. Altogether, it contributes to a 40 % mortality rate of 5-years overall survival after diagnosis in TNBC patients (Yin et al., 2020, Zaikova et al., 2024).
Biologically, tumor cells often produced substances that regulate cellular signaling and the tumor microenvironment, contributing to tumor progression. (Nakamura and Takada, 2021, Zhou et al., 2023). One of the most important factor involved in this scenario is the reactive oxygen species (ROS) balance (Zhou et al., 2023) that can be generated by multiple exogenous and endogenous sources, specially by mitochondrial respiration (Nakamura and Takada, 2021). Another important pathway in the production of ROS is NADPH oxidases (NOXs), a family of enzymatic complexes that produce ROS as their primary product (Brieger et al., 2012).
Helfinger and Schröder (2018) reported that ROS can also play distinct roles during carcinogenesis depending on their concentration, duration, and distribution. First, the slightly increased intracellular levels favoring growth, progression, and survival of tumor cells. In opposite, the excessive intracellular ROS levels after a cytotoxic threshold, promote oxidative stress, mainly inducing apoptosis, although senescence or autophagy and ferroptosis can also occur (Helfinger and Schröder, 2018).
To explore the mechanism of ROS, several innovative antitumor therapies have focused on their action forms: (1) using antioxidant substances to reduce and/or eliminate ROS (Wang et al., 2021) or (2) using pro-oxidant compounds capable of promoting an increase in ROS during carcinogenesis. Based on the second form, it occurs through cellular signaling pathways activation that control proliferation, migration, differentiation and induce irreversible intracellular lesions, leading to programmed cell death on tumor cells (Nakamura and Takada, 2021, Shah and Rogoff, 2021). Hence, the understanding of the second ROS form on TNBC progression could improve therapy modalities and as consequence impact on prognosis.
Outstanding, the use of compounds such as bromo-naphthoquinone (BrNQ) and tannic acid (TA) can modulate the oxidative stress of tumor cells, and also contribute as adjuncts to conventional treatments, reducing TNBC treatment resistance (Al-Ishaq et al., 2020, Mazurakova et al., 2022). BrNQ is a synthetic compound that contains a quinone group. Quinones generally exhibit biological activity related to their oxidant action and present antitumor, antibacterial, antifungal, and anti-inflammatory activities (Bozali et al., 2024, Sánchez-Calvo et al., 2016, Szeliga and Rola, 2022). The cytotoxicity of this compound has been extensively researched and utilized to comprehend its cellular mechanisms. It can modulate the redox balance of tumor cells by inducing oxidative stress through the generation of ROS, capable of causing damage to some essential cellular components, intervening at specific points of cell division, and consequently leading to tumor cell apoptosis (Graciani and Ximenes, 2012, Salunke-Gawali et al., 2014).
In line with these findings, TA, a polyphenol from the tannin family, has been studied for its antioxidant, anti-inflammatory, and antitumor activities (Jing et al., 2022, Sánchez-Carranza et al., 2023). TA can inhibit the growth of tumor cells and reduce resistance to chemotherapy, regulate the immunogenic profile of tumor cells, and act as a repressor of essential proteins in various oncological signaling pathways including the cell cycle and apoptosis (Youness et al., 2021).
Research that contributes to developing new therapies for TNBC, which are less invasive and aggressive, can lead to improved quality of life and increased survival rates for patients. This has significant implications for enhancing clinical outcomes and advancing tumor management. Therefore, we aimed to explore the synergistic effects of BrNQ and TA on ROS modulation in TNBC, focusing on their potential to reduce cell viability, induce apoptosis, and inhibit migration.
