INHIBITION OF METABOLISM AND INDUCTION OF APOPTOSIS IN TRIPLE NEGATIVE BREAST CANCER CELLS BY LIPPIA ORIGANOIDES PLANT EXTRACTS.
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According to the Global Cancer Incidence, Mortality, and Prevention (GLOBOCAN) study for 2018, 2,089,000 women will have been diagnosed with breast cancer worldwide, with 627,000 breast cancer-related mortalities. It is estimated that between 15 – 20 % of breast cancer diagnoses are of the triple-negative subtype. Triple-negative breast cancers (TNBCs) do not express the receptors for estrogen, progesterone, and human epidermal growth factor 2, and hence cannot be treated using hormone receptor-targeted therapy.
TNBCs are commonly of the basal-like phenotype, with high expression levels of proteins involved in epithelial-mesenchymal transition, extracellular-matrix (ECM) remodeling, cell cycle progression, survival and drug resistance, invasion, and metastasis. 5-year survival rates are significantly lower for TNBC patients, and the disease is characterized by poorer grade at the time of diagnosis as well as higher 5-year distant relapse rates, with a greater chance of lung and CNS metastases. Current treatments for TNBC take the form of aggressive cytotoxic chemotherapy regimens with multiple adverse side-effects. An important goal of on-going studies is to identify new compounds with significant TNBC-specificity, in order to improve patient survival outcomes while preserving a high quality of life during treatment.
For several decades, compounds originally isolated from bioactive natural extracts, such as the taxanes and vinca alkaloids, have been at the forefront of chemotherapy. However, due to their non -specific mechanisms of action, treatment with these compounds eventually leads to significant toxicity to normal cells and tissues. Modern transcriptomics, metabolomics, and proteomics tools have greatly improved our understanding of the mechanisms governing cancer initiation and progression, and revealed the considerable heterogeneity of tumor cells. This has allowed for the identification of potential vulnerabilities in multiple cancers, including TNBCs. By leveraging these new technologies and insights with the tremendous diversity of bioactive compounds from organisms that remain unstudied, new classes of onco-drugs targeting pathways specific to TNBC cells could be identified in the near future.
Here, we describe the cytotoxic effects of extracts from Lippia origanoides - a species of medicinal shrub native to Central and South America - on TNBC cells. We report that these extracts induce rapid, sustained, and irreversible apoptosis in TNBC cells in vitro, with significantly reduced cytotoxicity against normal mammary epithelial cells. The L. origanoides extracts LOE and L42 exploited two TNBC-specific characteristics to induce apoptosis in these cells: i) inhibiting the constitutively active survival and inflammatory NF-kB signaling pathway, and ii) significantly dysregulating the expression levels of mitochondrial enzymes required to maintain the TCA cycle and oxidative phosphorylation; metabolic pathways that are required for the maintenance of TNBC cell growth and proliferation.
Finally, to lay the foundations for future studies on the abilities of these extracts to prevent tumor initiation and inhibit tumor growth in vivo, we also show that the L. origanoides extract, L42, is non-toxic to immunocompetent C57BL/6 mice, and have developed an in vivo model of human TNBC in athymic nu/nu mice.
Collectively, our studies are the first to identify the anti-TNBC-specific properties of bioactive extracts from the Lippia species, and reveal that targeting NF-kB signaling and mitochondrial metabolism are potential avenues to new therapeutics against this subtype of breast cancer. Future work in our lab will focus on identifying the bioactive components (BACs) of the extract mediating its apoptotic effects, and shedding light on their protein binding partners within the cell.