Modern therapies of nonsmall cell lung cancer.

Lung cancer (LC), particularly nonsmall cell lung cancer (NSCLC), is one of the most prevalent types of neoplasia worldwide, regardless of gender, with the highest mortality rates in oncology. Over the years, treatment for NSCLC has evolved from conventional surgery, chemotherapy, and radiotherapy to more tailored and minimally invasive approaches. The use of personalised therapies has increased the expected efficacy of treatment while simultaneously reducing the frequency of severe adverse effects (AEs). In this review, we discuss established modern approaches, including immunotherapy and targeted therapy, as well as experimental molecular methods like clustered regularly interspaced short palindromic repeat (CRISPR) and nanoparticles. These emerging methods offer promising outcomes and shorten the recovery time for various patients. Recent advances in the diagnostic field, including imaging and genetic profiling, have enabled the implementation of these methods. The versatility of these modern therapies allows for multiple treatment options, such as single-agent use, combination with existing conventional treatments, or incorporation into new regimens. As a result, patients can survive even in the advanced stages of NSCLC, leading to increased survival indicators such as overall survival (OS) and progression-free survival (PFS).

The smoking estrogens - a potential synergy between estradiol and benzo(a)pyrene.

According to recent statistics, Lung Cancer (LC) is one of the most frequently diagnosed tumor types, representing nearly 12% of all global cancer cases. Moreover, in recent years, an increased mortality rate and incidence of this cancer were observed, especially among nonsmokers. Lung cancer patients are often characterized by poor prognosis and low survival rates, which encourages the scientific community to investigate the biochemical and molecular processes leading to the development of this malignancy. Furthermore, the mechanisms of LC formation and progression are not yet fully elucidated due to their high complexity, as well as a multitude of environmental, genetic, and molecular factors involved. Even though LC's association with exposure to cigarette smoke is indisputable, current research provides evidence that the development of this cancer can also be affected by the presence of estrogens and their interaction with several tobacco smoke components. Hence, the main goal of this brief review was to investigate reports of a possible synergy between 17ß estradiol (E2), the most biologically active estrogen, and benzo(a)pyrene (BaP), a strongly carcinogenic compound produced as a result of incomplete tobacco combustion. The literature sources demonstrate a possible carcinogenic synergy between estrogens, especially E2, and BaP, a toxic tobacco smoke component. Therefeore, the combined effect of disturbed estrogen production in cancer cells, as well as the molecular influence exerted by BaP, could explain the increased aggressiveness and rate of LC development. Summarizing, the synergistic effect of these risk factors is an interesting area of further research.

The influence of conjugated linoleic acid on the expression of peroxisome proliferator-activated receptor-γ and selected apoptotic genes in non-small cell lung cancer.

In recent years, peroxisome proliferator-activated receptor-γ (PPARγ) has been intensively studied. Because its activation is often associated with changes in the expression level of various apoptotic genes, many studies have emphasized the role of PPARγ as an important anticancer agent. However, in different types of cancer, different genes are influenced by PPARγ action. Previous studies showed that conjugated linoleic acid (CLA) was able to induce apoptosis, upregulate PPARG gene expression and activate PPARγ protein in certain human cancer cell lines. Moreover, some PPARγ agonists inhibited the growth of human lung cancer cells through the induction of apoptosis. Nevertheless, the impact of CLA on PPARγ mRNA and protein levels in non-small cell lung cancer (NSCLC) cell lines has not been investigated thus far. Therefore, in our study, we analysed the influence of the c9,t11 linoleic acid isomer on the expression of PPARG and other genes involved in the apoptotic response (BCL-2, BAX, and CDKN1A) in two NSCLC cell lines of different histological origin (A549 and Calu-1) and in normal human bronchial epithelial Beas-2B cells. Cells were treated with several doses of c9,t11 CLA, followed by RNA and protein isolation, cDNA synthesis, real-time quantitative PCR (RT-qPCR) and Western blot analysis. We showed that the investigated CLA isomer was able to enhance the expression of PPARγ in the examined cell lines and alter the mRNA and protein levels of genes involved in apoptosis. Fluorescent staining and MMT assay revealed the antiproliferative potential of CLA as well as its ability to activate pathways that lead to cell death.

Decreased expression of cytochrome p450 1B1 in non-small cell lung cancer.

Recent studies have associated oestrogen metabolism and cigarette smoking with their carcinogenic impact on the lungs. Compounds commonly found in tobacco smoke induce the activity of CYP1B1, the enzyme responsible for the synthesis of catecholic derivatives of oestrogens. During their redox transformations, these structures can release large amounts of reactive oxygen species or can form DNA adducts, which lead to the decomposition of genetic material. This process may illustrate the synergistic effect of oestrogenic activity and tobacco combustion on oestrogen-dependant lung cancer development. There is considerable evidence suggesting that the level of oestrogen in lung tumours is elevated. Therefore, by using reverse transcription, real-time PCR and Western Blot analysis, we evaluated the CYP1B1 status in tissues from 76 patients diagnosed with non-small cell lung cancer (NSCLC) to confirm whether potential overexpression of CYP1B1 may impact lung cancerogenesis induced by oestrogens. We found significantly lower levels of CYP1B1 transcripts (p=0.00001) and proteins (p=0.000085) in lung tumour material compared to corresponding, histopathologically unchanged tissues. We also analysed the association of CYP1B1 expression with gender, age and clinicopathological data of NSCLC patients. We observed lower amounts of CYP1B1 occurring in the middle stages of LC, regardless of gender, age or histological type of lung cancer.

Exploring estrogenic activity in lung cancer.

It is well known that a connection between xenobiotics inhalation, especially tobacco combustion and Lung Cancer development is strongly significant and indisputable. However, recent studies provide evidence indicating that another factors such as, estrogens are also involved in lung carcinoma biology and metabolism. Although the status of estrogen receptors (ER), in both cancerous and healthy lung tissue has been well documented, there is still inconclusive data with respect of which isoform of the receptor is present in the lungs. However according to several studies, ERß appears to be predominant form. Apart from ERs, estrogens can work through a recently discovered G-coupled estrogen receptor. Binding with both types of the receptors causes a signal, which leads to i.e. enhanced cell proliferation. There are many published reports which suggest that estrogen can be synthesized in situ in lung cancer. Some disturbances in the activity and expression levels of enzymes involved in estrogen synthesis were proved. This suggests that increased amounts of sex-steroid hormones can affect cells biology and be the reason of the accelerated development and pathogenesis of lung cancer. There also exist phenomena which associate estrogenic metabolism and tobacco combustion and its carcinogenic influence on the lungs. Compounds present in cigarette smoke induce the activity of CYP1B1, the enzyme responsible for estrogenic metabolism and synthesis of their cateholic derivatives. These structures during their redox cycle are able to release reactive oxygen species or form DNA adduct, which generally leads to destruction of genetic material. This process may explain the synergistic effect of smoking and estrogens on estrogen-dependent lung cancer development.

Increased expression of proline-, glutamic acid- and leucine-rich protein PELP1 in non-small cell lung cancer.

It has been demonstrated that estrogens are able to enhance lung tumorigenesis by estrogen receptor (ER) pathway. ER signaling is a highly complex process that requires a number of different coactivators, including proline-, glutamic acid- and leucine-rich protein-1 (PELP1). We studied PELP1 transcript and protein levels in cancerous and histopathologically unchanged lung tissues obtained from 73 patients diagnosed with non-small cell lung cancer (NSCLC). We observed increased levels of PELP1 transcript (P=0.00001) and protein (P=0.00001) in tumor tissues compared to adjacent histopathologically unchanged tissues. Significant increase of PELP1 transcript/protein level was found in all patients, regardless of gender (males: P=0.0003/P=0.000003; females: P=0.0005/P=0.02), age (≤ 60 patients: P=0.042/P=0.016; >60 patients: P=0.00001/P=0.00001) or histopathological type of tumor (adenocarcinoma [ADC]: P=0.004/P=0.0006; squamous cell carcinoma [SSC]: P=0.0009/P=0.0008). Increased PELP1 transcript/protein levels were also correlated with some lung cancer stage (1a: P=0.07/P=0.02; 1b: P=0.001/P=0.03; 2a: P=0.012/P=0.001), tumor size (T2a: P=0.0006/P=0.001) and lymph node metastasis (N0: P=0.0003/P=0.0006; N1: P=0.017/P=0.003). Moreover, significant increase in PELP1 transcript level in cancer stage 1a (P=0.02) was observed. PELP1 protein content was higher in tumor tissues of patients with cancer stage 3a (P=0.04) and in T1a tumor size (P=0.03). Our studies demonstrate significantly higher amounts of PELP1 transcript and protein in tumor tissues in patients with NSCLC. Moreover, we also determined the association of PELP1 transcript and protein level with some clinicopathological features of NSCLC.