<p>With 2.1 million new
cases, breast cancer is the most common cancer in women. Triple negative breast cancer (TNBC), which is
15-20% of these breast cancer cases is clinically negative for expression of
estrogen and progesterone receptors (ER/PR) and human epidermal growth factor
receptor 2 (HER2) receptors<a>.</a> It is characterized by its unique molecular
profile, aggressive behavior, distinct patterns of metastasis, and lack of
targeted therapies. TNBCs utilize
glycolysis for growth, proliferation, invasiveness, chemotherapeutic resistance
and hence has poor therapeutic response.
There is an urgent need for novel/alternate therapeutic strategies
beyond current standard of treatment for this subset of high-risk
patients. Electrical pulse-based
chemotherapy, known as electrochemotherapy (ECT) could be a viable option for
TNBC therapy. ECT involves the local
application of precisely controlled electrical pulses to reversibly
permeabilize the cell membrane for enhanced uptake. ECT can increase the cytotoxicity of the
chemotherapeutics up-to 1000 times, facilitating a potent local cytotoxic
effect. </p>
<p>The high cost and
severe side-effects of conventional chemotherapeutics motivate the application
of effective natural compounds.
Combining electrical pulses with natural compounds will enhance the
treatment efficacy. This dissertation
focuses on curcumin, the yellow pigment of natural herb turmeric, that has been
used for over 5000 years for its excellent anticancer properties. Previous studies have demonstrated the
effectiveness of curcumin for treating multiple cancers, including TNBC, with
limited side effects. The potency of
curcumin can be enhanced further by combining it with ECT to provide an
attractive and cost-effective alternative for TNBC treatment. </p>
<p>Towards this we
studied the effect of ECT with curcumin on MDA-MB-231 cell line, a human
adenocarcinoma epithelial TNBC cell line.
We performed various assays, including cell viability, colony forming,
cell cycle, apoptosis, H<sub>2</sub>O<sub>2</sub> reactive oxygen species (ROS),
immunoblotting, real time quantitative PCR (qPCR), and cellular metabolites
detection to study the impact of ECT with curcumin on MDA-MB-231 cells. In addition, to better understand the
underlying mechanisms, we used high throughput, label-free quantitative
proteomics. While several studies have
attempted to define the mechanism of action of curcumin on cancer cells, little
is known on the action mechanism of the curcumin delivered with electrical
pulses. This work unravels the molecular
mechanism behind the enhanced effects observed under the ECT-based curcumin
therapy in TNBC cells, employing a high-throughput, quantitative, label-free
mass spectroscopy-based proteomics approach.
The proteomics approach provides information on the thousands of cellular
proteins involved in the cellular process, allowing a comprehensive
understanding of the electro-curcumin-therapy mechanism. Similar studies were also performed for ECT
with cisplatin to compare the efficacy of the electro-curcumin-therapy to the
standard stand-alone cisplatin-based therapy.</p>
<p>Our results revealed
a switch in the metabolism from glycolysis to mitochondrial metabolic
pathways. This metabolic switch caused
an excessive production of H<sub>2</sub>O<sub>2</sub> ROS to inflict apoptotic
cell death in MDA-MB-231 cells, demonstrating the potency of this ECT based
curcumin therapy. These results encourage
further studies to extend the application of ECT for clinical practice.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/13100357 |
| Date | 16 December 2020 |
| Creators | Lakshya Mittal (9520208) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/EFFICIENT_AND_ECONOMICAL_ELECTROCHEMOTHERAPY_TREATMENTS_FOR_TRIPLE_NEGATIVE_BREAST_CANCER_AN_IN_VITRO_MODEL_STUDY/13100357 |
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