Lung
cancer is now the leading cause of cancer-related death worldwide, with 1.7
million fatalities in 2018. The most common kind of lung cancer is non-small
cell carcinoma (NSCLC), which accounts for about 80% of all occurrences. In
most countries, chemotherapy is still the first-line treatment for NSCLC
patients. Chemotherapy is expected to be utilised for at least another two
decades, despite the development of novel medicines (targeted chemicals,
immunotherapy). Chemotherapy resistance is one of the key variables
contributing to lung cancer mortality, and it has been well established in
preclinical investigations and clinical trials to date. Currently, there are
only a few biomarkers for predicting chemotherapy efficacy, most of which are
clinical. Furthermore, clinically, sensitization of cancer cells to such
chemicals is largely useless. This research looks into new ways for lung cancer
cells to become sensitive to four standard chemotherapeutics (cisplatin,
carboplatin, gemcitabine, and vinorelbine), with a focus on epigenetics and the
involvement of extracellular vesicles. Cloning, inducible transgene expression,
shRNA-based silencing, proliferation and apoptosis assays, the neutral comet
assay, RT-qPCR, pyrosequencing-based DNA methylation analysis, and other
molecular and cell biology methods (cloning, inducible transgene expression,
shRNA-based silencing, proliferation and apoptosis assays, the neutral comet
assay, RT-qPCR I examined a wide range of factors in connection to drug
resistance in NSCLC cell lines (e.g., western blots, EV isolation and
characterization). Resistant cell lines were chosen for sensitization with
epigenetic medicines (VPA and DAC), aminomethylphosphonic acid (AMPA), and
fendiline after the IC50 of each of the four medications was determined in
eight NSCLC cell lines.
VPA showed strong chemotherapeutic sensitization potential for all four
chemotherapeutics, which is a first for lung cancer cells. In cells treated
with cisplatin or carboplatin, both VPA and DAC caused a considerable increase
in apoptotic activity. Gemcitabine produced double strand DNA breaks in the
NSCLC cell lines A549, CALU-6, and COR-L23, and pre-treatment with VPA
amplified this impact, which was also a novel discovery in this investigation.
I also looked at the role of LANCL1-AS1, a long-noncoding RNA that was shown to
be reduced in NSCLC tissues by our research team. Following the establishment
of an inducible expression model in the SK-MES-1 cell line, it was discovered
that LANCL1-AS1 induced an increase in proliferation rate, migration invasion,
sensitivity to gemcitabine and vinorelbine, increased resistance to platin
compounds, and, most notably, expression of its coding counterpart gene,
LANCL1. The LANCL1 shRNA-based silencing resulted in a reduction in
proliferation, migration, and oxidative stress sensitivity. However,
sensitivity to all four medications followed the same pattern as overexpression
of LANCL1-AS1, raising doubts about whether these two activities are connected
or separate, with no way to rule out the possibility of off-target effects from
the shRNA method at this time.
The function of extracellular vesicles (EVs) in cancer development and
medication resistance has just lately been studied. As a result, I decided to
see if the LANCL1-AS1-dependent gemcitabine sensitivity could be transferred to
EVs. Increased LANCL1-AS1 expression resulted in a dose-dependent increase in
EV release. Unfortunately, due to a variety of technical concerns with the EV
isolation reagent's toxicity, knowledge of how LANCL1-AS1 produced EVs affect
gemcitabine resistance when transmitted to a recipient cell line was not
possible. Finally, this research has revealed some new insights towards
sensitising NSCLC cells in a preclinical setting. More research is needed to
determine whether these findings are clinically useful and how they might alter
lung cancer treatment.
Author(s) Details
Ghaliah Obaid F. Alnefaie
Medical Genetic Department, Taif University, Taif, Saudi Arabia.
View Book:- https://stm.bookpi.org/ESCCNSCLC/article/view/1837
