18 research outputs found
Identification of altered genes associated with non-small cell lung cancer promotion and progression
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New Approaches With Natural Product Drugs for Overcoming Multidrug Resistance in Cancer
Resistance to chemotherapeautic drugs is one of the main obstacles to
effective cancer treatment. Multidrug resistance (MDR) is defined as
resistance to structurally and/or functionally unrelated drugs, and has
been extensively investigated for the last three decades. There are two
types of MDR: intrinsic and acquired. Tumor microenvironment selection
pressure leads to the development of intrinsic MDR, while acquired
resistance is a consequence of the administered chemotherapy. A central
issue in chemotherapy failure is the existence of heterogeneous
populations of cancer cells within one patient and patient-to-patient
variability within each type of cancer.
Numerous genes and pathways contribute to the development of MDR in
cancer. Point mutations, gene amplification or other genetic or
epigenetic changes all affect biological functions and may lead to the
occurrence of MDR phenotype. Similar to the characteristics of
cancerogenesis, the main features of MDR include abnormal tumor
vasculature, regions of hypoxia, aerobic glycolysis, and a lower
susceptibility to apoptosis. In order to achieve a lethal effect on
cancer cells, drugs need to reach their intracellular target molecules.
The overexpression of the efflux transporter P-glycoprotein (P-gp) in
MDR cancer cells leads to decreased uptake of the drug and intracellular
drug accumulation, minimising drug-target interactions.
New agents being or inspired by natural products that sucessfully target
these mechanisms are the main subject of this review. Two key approaches
in combating MDR in cancer are discussed (i) finding agents that
preserve citotoxicity toward MDR cancer cells; (ii) developing compounds
that restore the cytotoxic activity of classic anticancer drugs.Ministry of Education, Science and Technological Development of the
Republic of Serbia {[}III41031]; COST Actions {[}CM1106, CM1407
Identification of altered genes associated with non-small cell lung cancer promotion and progression
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Prolonged survival after neoadjuvant chemotherapy related with specific molecular alterations in the patients with nonsmall-cell lung carcinoma
Lung cancer is the most common cause of neoplasia-related death
worldwide. Accounting for approximately 80\% of all lung carcinomas, the
non-small cell lung carcinoma (NSCLC) is the most common clinical form
with its two predominant histological types, adenocarcinoma (ADC) and
squamous cell carcinoma (SCC). Although surgical resection is the most
favorable treatment for patients with NSCLC, relapse is still high, so
neoadjuvant chemotherapy (NAC) is an accepted treatment modality. In
this study we examined whether some of the key molecules associated with
the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways could have
predictive and prognostic value for the NAC application. To that end we
examined the expression status of PTEN, pAKT, pERK and loss of
heterozygosity (LOH) of PTEN in two groups of NSCLC patients, those who
received and those who did not receive NAG LOH PTEN and low pERK
expression is shown to be correlated with the longest survival of
patients with SCC and ADC, respectively, who received NAC. These results
point that the application of NAC is beneficial in the NSCLC patients
with specific molecular alterations which could further help to improve
constant search for the druggable molecular targets used in personalized
therapy. (C) 2014 Elsevier Inc. All rights reserved.Ministry of Education, Science and Technological Development of the
Republic of Serbia {[}III41031
Targeting RAS-MAPK-ERK and PI3K-AKT-mTOR signal transduction pathways to chemosensitize anaplastic thyroid carcinoma
Anaplastic thyroid carcinoma (ATC) is a rare, but aggressive and
chemoresistant tumor with dismal prognosis. Most ATCs harbor mutations
that activate RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. Therefore, we
investigated and correlated the expression of phosphatase and tensin
homolog, pERK, and pAKT proteins as well as mutations of BRAF, RAS, and
p53 genes in samples of patients with ATC. Furthermore, we evaluated the
potential of inhibition of these pathways on chemosensitization of ATC
using 2 thyroid carcinoma cell lines (FRO and SW1736). Our results
revealed a negative correlation between the activity of RAS-MAPK-ERK and
PI3K-AKT-mTOR pathways in samples of patients. To be specific, the
PI3K-AKT-mTOR pathway was suppressed in patients with activated NRAS or
high pERK expression. In vitro results suggest that the inhibition of
either RAS-MAPK-ERK or PI3K-AKT-mTOR components may confer sensitivity
of thyroid cancer cells to classic chemotherapeutics. This may form a
basis for the development of novel genetic-based therapeutic approach
for this cancer type.Ministry of Education, Science and Technological Development, Republic
of Serbia {[}III41031