Lung cancer (LC) is a global issue that undoubtedly requires pay attention in order to find complete treatment for the disease [1]. Lung cancer is classified historically as small-cell lung carcinoma (SCLC), non-small cell lung cancer (NSCLC), and neuroendocrine tumors (NET) [2].
Non-small cell lung cancer is the most encountered type among the three categories of lung cancers. Patients with advanced lung cancer exhibit a high death rate. So, it is considered as one of the most dangerous types of cancer. Unfortunately, there is no definite treatment. Some symptoms are included in patients with lung cancers. They are commonly breathlessness, sleep disorder, tiredness, depression, and anxiety [3]. These symptoms revealed the fact not the only limitation of the physical activity of individuals with lung cancer but also the worsening of the sanity of the patients occurs [1]. Detection of lung cancer in the early stage is critical. Although, general lung cancer cases are recognized in the advanced stage of cancer. The primary reason for the late diagnosis is an asymptomatic character of early-stage lung cancer [4]. Low-dose computed tomography (LDCT) has been designed to screen lung cancer[5,6]. Lung cancer screening supplies a reduction of fatality [5]. Hence, scanning for lung cancer is especially advised for regular smokers [1].
On the other hand, many factors are thought to cause lung cancer. Smoking is the most known reason for lung cancer. Pollution, increasing population, industrialization, etc. can be given as inducement agents of lung cancer. Besides physical factors, genetic modifications also result in cancer. For example, research showed that epigenetic changes have the potential to cause tumorigenesis. In detail, the research revealed that the ALKBH1 demethylase enzyme that participates in the RNA m6A demethylation process is upregulated in abnormal proliferating lung cells which results in carcinogenesis [7,8]. In addition to this, recent studies discovered that lung cancer disease may originate from connective tissue disease that leads to interstitial lung disease [9].

Moreover, SH3-domain GRB2-like 3 (SH3GL3) is known as the SH3 domain-containing GRB2- like protein 3 or Endophilin-3. Some recent studies detected its role in lung cancer progression [10].SH3GL3 expression inversely correlated with lung cancer progression. The overexpression of SH3GL3 supplies blockage lung cancer cell migration. SH3GL3 rises p21 expression so as to hold lung cancer cell cycle at G0/G1 phase [10].
Migration ratio (% of Ctrl) Up-regulation of p21 promotes cellular apoptosis. p21- tumor suppressor gene expression is low in non-small cell lung cancer11. However, no appropriate drug is available to target p21 for lung cancer treatment [10]. Instead of targeting p21, activation of SH3GL3 is targeted by new therapies [10].

Besides, distinct therapies such as surgery, chemotherapy, radiotherapy, and targeted therapies are designed and used to treat lung cancer. And also, immunotherapies have been developed to reduce the fatality rate of lung cancer [12]. However, the predicament of treatment of cancer is still unsolvable12. Surgery is the most frequently applied therapy for patients with lung cancer. This therapy is efficient in stage I and stage II Lung Cancer and decrease the rate of fatality [13].
Moreover, Xihuang Pill (XHW) which is one of the Chinese medicine is utilized for the treatment of lung cancer as well as breast cancer and colorectal cancer. Investigations on XHW treatment showed that XHW treatment blocks G1 to S phase progression so as to obstruct the development of lung cancer stem cells*2. Interestingly, XHW application supplies to reduce phenylalanine and tryptophan levels to their normal level in plasma14. Levels of the proteins in the plasma of patients are important because hepatic gluconeogenesis and protein catabolism highly occur in patients with lung cancer12. Cells catabolize their proteins by the way of autophagy and produce amino acids that are utilized by cancer cells [15]. The blockage of autophagy means that the preclusion of amino acid utilization of cancer cells happens, so the growth of cancer cells can be hindered [15]. Recently, the development of cancer nanotechnology research is highly accelerated. Inhalation treatment involving pulmonary delivery of chemotherapeutic agents to tumor tissue was studied in this area16. Inhalable biodegradable polymeric nanocarriers have the ability to trap chemotherapeutic drugs. Polymeric Nanoparticles (NPs) are utilized for the delivery of genes or their combinations for lung cancer therapy. Particularly, Lipid–polymer hybrid Nano Particles (LPHNs) have been investigated for the delivery of anti-cancer drugs [16]. Since they possess several characteristics such as having a biodegradable polymer core and liposome shell, structure integrity and physical stability, high cell affinity & cell uptake, and high loading capacity for hydrophilic and hydrophobic drugs [17,18]. Actively-targeted inhalable nanoparticles occur via receptor-mediated endocytosis and target cancer cells or tumor vascular endothelium such as targeting luteinizing hormone-releasing hormone receptors (LHRHR) that are overexpressed on the plasma membrane of lung cancerous cells or Transferrin receptors which are also overexpressed on several pulmonary cells [16].
In contrast to systemic chemotherapy, inhalable chemotherapy of lung cancer provides delivery of the chemotherapeutic agents to tumor tissues bypassing First Pass Metabolism, enhancing drug efficacy, and reducing systemic side-effects that are mostly encountered in systemic chemotherapy [16]. However, safety issues for the inhalable NPs for pulmonary drug delivery still exist and they are under examination16. Biodegradability, particle size, surface charge, shape, and structure of nano- and micro-particulates were detected to affect toxic behaviors of the particles16. Greater lung deposition of NPs may result in the induction of the release of inflammatory mediators that rise preexisting inflammation in the lung [19]. Accumulation of insoluble nano- or micro-carriers causes locally increased macrophages, oxidative stress, and inflammation [20,21]. Despite bypassing First Pass Metabolism, inhaled therapeutics are still subjected to enzymatic degradation that occurs by several isoforms of cytochrome P450 expressed in the lungs [16]. The natural defense mechanism of the respiratory system against xenobiotics may lead to disruption of the inhaled therapeutics which causes inhibition of the interaction between the therapeutics and their target in the lung and eventually result in ineffective therapy [16].
Overall, the essay explained some characteristics of lung cancer and potential therapies for it. However, it is still so hard to say the exact reason for lung cancer or therapy for patients with lung cancer. There are many other implementations of the prevention and detection of lung cancer at the earliest stage. Many scientists put in the effort to reduce the fatality rate due to lung cancer by using different therapeutics and applying distinct methods. According to Cancer Statistics of the American Cancer Society, the relative survival rate of patients with lung cancer in 2015 increased two-fold in comparison to data on the relative survival rate of patients with lung cancer in 1975.
References:
- Yang M, Liu L, Gan C e., et al. Effects of home-based exercise on exercise capacity, symptoms, and quality of life in patients with lung cancer: A meta-analysis. Eur J Oncol Nurs. Published online 2020. doi:10.1016/j.ejon.2020.101836
- Brennan P, Hainaut P, Boffetta P. Genetics of lung-cancer susceptibility. Lancet Oncol. Published online 2011. doi:10.1016/S1470-2045(10)70126-1
- Mosher CE, Secinti E, Hirsh AT, et al. Acceptance and Commitment Therapy for Symptom Interference in Advanced Lung Cancer and Caregiver Distress: A Pilot Randomized Trial. J Pain Symptom Manage. Published online 2019. doi:10.1016/j.jpainsymman.2019.06.021
- Toumazis I, Bastani M, Han SS, Plevritis SK. Risk-Based lung cancer screening: A systematic review. Lung Cancer. Published online 2020. doi:10.1016/j.lungcan.2020.07.007
- Aberle DR, Adams AM BC, Black WC, Clapp JD, Fagerstrom RM, Gareen IF, Gatsonis C, Marcus PM SJ. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening – The National Lung Screening Trial Research Team. N Engl J Med. Published online 2011. de Koning HJ, van der Aalst CM, de Jong PA, et al. Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial. N Engl J Med. Published online 2020. doi:10.1056/nejmoa1911793
- Liu Z-X, Li L-M, Sun H-L, Liu S-M. Link Between m6A Modification and Cancers. Front Bioeng Biotechnol. Published online 2018. doi:10.3389/fbioe.2018.00089
- Pilžys T, Marcinkowski M, Kukwa W, et al. ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy. Sci Rep. Published online 2019. doi:10.1038/s41598-019-49550-x
- Enomoto Y, Inui N, Yoshimura K, et al. Lung cancer development in patients with connective tissue disease-related interstitial lung disease: A retrospective observational study. Med (United States). Published online 2016. doi:10.1097/MD.0000000000005716
- Lin Z, Liu Z, Tan X, Li C. SH3GL3 functions as a potent tumor suppressor in lung cancer in a SH3 domain dependent manner. Biochem Biophys Res Commun. Published online 2020. doi:10.1016/j.bbrc.2020.10.107
- Vonlanthen S, Heighway J, Kappeler A, Altermatt HJ, Borner MM, Betticher DC. p21 is associated with cyclin D1, p16INK4a and pRb expression in resectable non-small cell lung cancer. Int J Oncol. Published online 2000. doi:10.3892/ijo.16.5.951
- Li C, Chen W, Zhang M, et al. Modulatory effects of Xihuang Pill on lung cancer treatment by an integrative approach. Biomed Pharmacother. Published online 2020. doi:10.1016/j.biopha.2020.110533
- Le Chevalier T. Adjuvant chemotherapy for resectable non-small-cell lung cancer: Where is it going? In: Annals of Oncology. ; 2010. doi:10.1093/annonc/mdq376 Wiggins T, Kumar S, Markar SR, Antonowicz S, Hanna GB. Tyrosine, phenylalanine, and tryptophan in gastroesophageal malignancy: A systematic review. Cancer Epidemiol Biomarkers Prev. Published online 2015. doi:10.1158/1055-9965.EPI-14- 0980
- Katheder NS, Khezri R, O’Farrell F, et al. Microenvironmental autophagy promotes tumour growth. Nature. Published online 2017. doi:10.1038/nature20815
- Abdelaziz HM, Gaber M, Abd-Elwakil MM, et al. Inhalable particulate drug delivery systems for lung cancer therapy: Nanoparticles, microparticles, nanocomposites and nanoaggregates. J Control Release. Published online 2018. doi:10.1016/j.jconrel.2017.11.036
- Garbuzenko OB, Mainelis G, Taratula O, Minko T. Inhalation treatment of lung cancer: the influence of composition, size and shape of nanocarriers on their lung accumulation and retention. Cancer Biol Med. Published online 2014. doi:10.7497/j.issn.2095-3941.2014.01.004
- Elzoghby AO, Mostafa SK, Helmy MW, ElDemellawy MA, Sheweita SA. MultiReservoir Phospholipid Shell Encapsulating Protamine Nanocapsules for Co-Delivery of Letrozole and Celecoxib in Breast Cancer Therapy. Pharm Res. Published online 2017. doi:10.1007/s11095-017-2207-2
- Inoue KI, Takano H, Yanagisawa R, et al. Effects of airway exposure to nanoparticles on lung inflammation induced by bacterial endotoxin in mice. Environ Health Perspect. Published online 2006. doi:10.1289/ehp.8903
- Bermudez E, Mangum JB, Wong BA, et al. Pulmonary responses of mice, rats, and hamsters to subchronic inhalation of ultrafine titanium dioxide particles. Toxicol Sci. Published online 2004. doi:10.1093/toxsci/kfh019
- Warheit DB, Webb TR, Sayes CM, Colvin VL, Reed KL. Pulmonary instillation studies with nanoscale TiO2 rods and dots in rats: Toxicity is not dependent upon particle size and surface area. Toxicol Sci. Published online 2006. doi:10.1093/toxsci/kfj140
Figure References:
- Pilžys T, Marcinkowski M, Kukwa W, et al. ALKBH overexpression in head and neck cancer: potential target for novel anticancer therapy. Sci Rep. Published online 2019. doi:10.1038/s41598-019-49550-x
- Z. Lin, Z. Liu, X. Tan, C. Li, SH3GL3 functions as a potent tumor suppressor in lung cancer in a SH3 domain dependent manner, 2020
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