Title : Aniline quinones produce mitochondrial dysfunction and migrastatic effect on triple-negative breast cancer line MDA-MB-231
Abstract:
Triple-negative breast cancer (TNBC), a subgroup that does not express estrogen, progesterone, and HER-2 receptors, is responsible for 20% of new cases. TNBC is characterized by a poor prognosis and absence of specific therapies, associated with a four-fold increased risk of metastasis. Current treatments act on the uncontrolled cancer cell proliferation of cancer cells but do not inhibit their migration and invasion. This represents an urgent need to obtain new drugs that selectively the metastatic cascade. Tumor cells have diverse metabolic phenotypes, exhibiting variable contributions of glycolysis and oxidative phosphorylation. In them, the mitochondrial electron transport chain has been identified as an essential component of bioenergetics, biosynthesis, and the redox control of cancer proliferation and metastasis, being a promising pharmacological target in metastasis. Many natural and synthetic naphthoquinones, such as juglone, plumbagin (a derivative of vitamin K3), 1,4-naphthoquinone, and menadione, have been studied for possessing pharmacological activities by interacting with traditionally validated therapeutic targets, such as altering kinase activity and activating or deactivating signaling pathways. Also, redox compounds increase the cellular oxidative stress, an important mechanism of their cytotoxicity. Plumbagin, with an effect on several types of cancer, including breast cancer, has been reported as a potent antitumor capable of inhibiting the process of epithelial-mesenchymal transition (EMT) that confers resistance to therapy endocrine against cancer.
In this study, we evaluated a series of amino quinone derivatives as potential antitumor compounds that affect the mitochondrial metabolism through the inhibition of complex I in TNBC, which reduces cell migration in vitro. The structure-activity relationship of amino quinone derivatives was evaluated. The results revealed that the RL-4 derivative selectively affected cell viability in cancer cells (1, 5, and 10 mM) and decreased their clonogenic capacity, which was reversed for pyruvate addition. It generated a decrease in OCR and an increase in ECAR. This shows a metabolic change towards glycolysis due to a possible inhibition of complex I. With the consequent increase in ROS, decrease in mitochondrial membrane potential, and inhibition of cell migration (5 and 10 mM) in addition to reversing the migration promoted by doxorubicin, a drug used as chemotherapy.
Audience Take-Away:
- The audience will be able to learn the basic structure of some naphthoquinone molecules that, due to their structure, can act as potential mitochondrial targets and intervene mainly in the mitochondrial function of tumor cells due to their impaired mitochondrial function.
- This research proposes the use of a potential target for cancer treatment aimed at preventing metastasis, such as mitochondria. Since current cancer treatments are directed at cell proliferation, this research opens a range of possibilities in the study of synthetic molecules based on scaffolds of molecules that occur in nature to avoid the formation of new tumor foci, which in most cases leads to the death of the tumor patient.
- Decreased cytotoxicity of conventional cancer treatments.
- Better prognosis and quality of life for patients with triple-negative breast cancer since they would avoid the terrible side effects caused by chemotherapy, their only treatment.
- It is an innovative approach that aims to avoid metastasis, which would decrease the mortality rate.
- It contributes to the knowledge of basic science since the mechanism of action can be studied, and the effects of molecules can be improved simply with minor changes in their structure.
