<p>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. </p>
<p>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.</p>
<p> For several
decades, compounds originally isolated from bioactive natural extracts, such as
the taxanes and vinca<i> </i>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.</p>
<p>Here, we describe the cytotoxic
effects of extracts from <i>Lippia
origanoides </i>- 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 <i>in vitro</i>, with significantly reduced
cytotoxicity against normal mammary epithelial cells. The <i>L. origanoides </i>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.</p>
<p>Finally, to lay the foundations
for future studies on the abilities of these extracts to prevent tumor
initiation and inhibit tumor growth <i>in
vivo</i>, we also show that the <i>L.
origanoides </i>extract, L42, is non-toxic<i>
</i>to immunocompetent C57BL/6 mice, and have developed an <i>in vivo </i>model of human TNBC in athymic <i>nu/nu</i> mice. </p>
<p>Collectively, our studies are the
first to identify the anti-TNBC-specific properties of bioactive extracts from
the <i>Lippia </i>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.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/7868354 |
| Date | 15 May 2019 |
| Creators | Vishak Raman (5930177) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/INHIBITION_OF_METABOLISM_AND_INDUCTION_OF_APOPTOSIS_IN_TRIPLE_NEGATIVE_BREAST_CANCER_CELLS_BY_LIPPIA_ORIGANOIDES_PLANT_EXTRACTS_/7868354 |
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