COMBINATION OF PACLITAXEL AND A COPPER (II) COMPLEX AS A SYNERGISTIC STRATEGY FOR THE TREATMENT OF TRIPLE-NEGATIVE BREAST CANCER

Abstract

Encompassing a group of more than 100 diseases, cancer is considered a major public health problem and one of the leading causes of mortality worldwide. Among the different types, breast cancer (BC) stands out as the most incident among women, excluding non-melanoma skin cancer, accounting for approximately 2.3 million new cases and 670,000 deaths in 2022. Characterized as a heterogeneous disease, BC can be classified into four molecular subtypes based on the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor type 2 (HER2). The Luminal A, Luminal B, and HER2-enriched subtypes express these receptors at different levels and generally show good responses to hormonal and targeted therapies. In contrast, triple-negative breast cancer (TNBC) does not express these markers and is associated with higher aggressiveness, poorer prognosis, and limited therapeutic options. Chemotherapy remains the main therapeutic strategy for TNBC, however, it presents significant limitations, such as pronounced side effects and the development of tumor resistance. In this context, the identification of new antitumor agents and the development of combination strategies become relevant to increase therapeutic efficacy and reduce systemic toxicity. Therapeutic regimens are often performed in combination using drugs with distinct mechanisms of action, promoting synergistic effects and allowing dose reduction. Thus, the present study aimed to evaluate the synergistic effect of paclitaxel, a mitosis-inhibiting chemotherapeutic agent widely used in the treatment of breast neoplasms, in combination with a novel copper (II) metal complex. Copper-based compounds have been investigated for their ability to increase the generation of reactive oxygen species (ROS), inducing cell death through multiple mechanisms. Considering that breast neoplastic cells frequently exhibit elevated ROS levels and overexpression of copper transporters, these cells become more susceptible to the effects of such compounds. As an essential element for the organism, copper-based complexes tend to present lower systemic toxicity, resulting in potential therapeutic selectivity, especially when compared to agents based on non-essential metals, such as cisplatin. The effects of the copper complex and paclitaxel were initially evaluated individually in the TNBC MDA-MB-231 cell line using the MTT cell viability assay after 24 and 48 hours of treatment, aiming to determine IC50 values. Based on these data, assays comprising 49 binary combinations were conducted, and pharmacological interactions were analyzed using the Chou-Talalay method, with calculation of the combination index. After 24 hours, 16 synergistic combinations were identified at different levels, including five interactions classified as very strong synergism. Similarly, after 48 hours, 11 combinations exhibited distinct degrees of synergism. Taken together, the results indicate that the association between the copper complex and paclitaxel promotes relevant synergistic effects in TNBC cells, highlighting the potential of this combination as a promising therapeutic strategy to optimize antitumor responses compared to individual treatments.