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Plant secondary metabolites have been seen as alternatives to seeking new medicines for treating various diseases. Phytochemical scientists remain hopeful that compounds isolated from natural sources could help alleviate the leading problem in oncology—the lung malignancy that kills an estimated two million people annually. In the present study, we characterized a medicinal compound benzophenanthridine alkaloid, called chelerythrine chloride for its anti-tumorigenic activities. Cell viability assays confirmed its cytotoxicity and anti-proliferative activity in non-small cell lung carcinoma (NSCLC) cell lines. Immunofluorescence staining of β-catenin revealed that there was a reduction of nuclear content as well as overall cellular content of β-catenin after treating NCI-H1703 with chelerythrine chloride. In functional characterizations, we observed favorable inhibitory activities of chelerythrine chloride in cancer stem cell (CSC) properties, which include soft agar colony-forming, migration, invasion, and spheroid forming abilities. Interesting observations in chelerythrine chloride treatment noted that its action abides to certain concentration-specific-targeting behavior in modulating β-catenin expression and apoptotic cell death. The downregulation of β-catenin implicates the downregulation of CSC transcription factors like SOX2 and MYC. In conclusion, chelerythrine chloride has the potential to mitigate cancer growth due to inhibitory actions toward the tumorigenic activity of CSC in lung cancer and it can be flexibly adjusted according to concentration to modulate specific targeting in different cell lines.

Lung cancer is still one of the deadliest cancers, with over two million incidences annually. Prevention is regarded as the most efficient way to reduce both the incidence and death figures. Nevertheless, treatment should still be improved, particularly in addressing therapeutic resistance due to cancer stem cells—the assumed drivers of tumor initiation and progression. Phytochemicals in plant-based diets are thought to contribute substantially to lung cancer prevention and may be efficacious for targeting lung cancer stem cells. In this review, we collect recent literature on lung homeostasis, carcinogenesis, and phytochemicals studied in lung cancers. We provide a comprehensive overview of how normal lung tissue operates and relate it with lung carcinogenesis to redefine better targets for lung cancer stem cells. Nine well-studied phytochemical compounds, namely curcumin, resveratrol, quercetin, epigallocatechin-3-gallate, luteolin, sulforaphane, berberine, genistein, and capsaicin, are discussed in terms of their chemopreventive and anticancer mechanisms in lung cancer and potential use in the clinic. How the use of phytochemicals can be improved by structural manipulations, targeted delivery, concentration adjustments, and combinatorial treatments is also highlighted. We propose that lung carcinomas should be treated differently based on their respective cellular origins. Targeting quiescence-inducing, inflammation-dampening, or reactive oxygen species-balancing pathways appears particularly interesting.

Decades of research has convinced us that phytochemical compounds contained within the plant products are the real deal, and they provide benefits such as health maintenance an d cure to illnesses. One of the deadliest noncommunicable diseases today is lung cancer, hence its disease management still deserves attention. Wnt/β-catenin pathway activation conferring cancer stem cell (CSC) activities to non-small cell lung carcinomas (NSCLCs) may explain why the disease is still difficult to cure. In the present study, we assessed several representatives of phytochemical categories consisting of alkaloids, chalcones and isothiocyanates for their inhibitory activity to nuclear localization of β-catenin—an important event for Wnt/β-catenin pathway activation, in lung cancer cell lines. Real-time cell analyzer confirmed that evodiamine (EVO), chelidonine (CHE), isoliquiritigenin (ISO), licochalcone-A (LICO), benzyl isothiocyanate (BI) and phenethylisothiocyanate (PI) exhibited anti-proliferative activities and cytotoxicities to adenocarcinoma cell line SK-LU-1 and human lung CSC primary cell line (HLCSC). Immunofluorescence assay identified that CHE, ISO, LICO, BI and PI were capable of reducing the number of cells harboring β-catenin within the nuclei of these cells. We extended the characterizations of BI and PI in Wnt-dependent squamous cell carcinoma cell line NCI-H1703 on several CSC functions and found that BI was better at inhibiting soft agar colony formation as an output of self-renewal ability, whereas PI was more effective in inhibiting the growth of multicellular tumor spheroid model mimicking micrometastases. Both however were not able to inhibit migration and invasion of NCI-H1703. In conclusion, BI could potentially be used as a safer alternative to target undifferentiated CSCs as adjuvant therapy, whereas PI could be used as chemotherapy to remove bulk tumor.

Cancer stem cells (CSCs) have been implicated in disease progression of aggressive cancers including small cell lung carcinoma (SCLC). Here, we have examined the possible contribution of CSCs to SCLC progression and aggressiveness. Materials and methods: GLC-14, GLC-16 and GLC-19 SCLC cell lines derived from one patient, representing increasing progressive stages of disease were used. CSC marker expressions was determined by RT-qPCR and western blotting analyses, and heterogeneity was studied by CSC marker expression by immunofluorescence microscopy and flow cytometry. Colony formation assays were used to assess stem cell properties and therapy sensitivity. Results: Increasing expression of stem cell markers MYC, SOX2 and particularly CD44 were found in association with advancing disease. Single and overlapping expression of these markers indicated the presence of different CSC populations. The accumulation of more homogeneous double-and triple-positive CSC populations evolved with disease progression. Functional characterization of CSC properties affirmed higher proficiency of colony forming ability and increased resistance to γ-irradiation in GLC-16 and GLC-19 compared to GLC-14. GLC-19 colony formation was significantly inhibited by a human anti-CD44 antibody. Conclusion: The progressive increase of MYC, SOX2 and particularly CD44 expression that was accompanied with enhanced colony forming capacity and resistance in the in vitro GLC disease progression model, supports the potential clinical relevance of CSC populations in malignancy and disease relapse of SCLC.

A brief history of lung cancer: from unknown to well-knownLung cancer is a collective term to describe malignancies comprising of tumors arising in the trachea, bronchi, bronchioles, and alveoli. The first clinical report in 1761 associating cancer with the use of tobacco products, highlighted the importance of chemical agents as carcinogens in the development of cancer 1 . This was recognized in lung cancer etiology after realizing sharp increases in incidence in parallel with increasing smoking activity 2 . Almost 200 years ago, lung cancer was not very common with only 1% of incidence recorded out of all cancer 2 . In the early 20th century, lung cancer was still so rare that it took 17 years to witness two successive cases 3 . However, the third case and subsequent seven cases were seen in only the next six months likely related to the increased prevalence of smoking activity. In the last decades, the disease has worsened to the extent that this disease recorded a nearly two million worldwide deaths annually 4 . Today, lung cancer is one of the most fearful diseases being one of the most common causes of death, together with cardiovascular, respiratory, and neurodegenerative diseases 5 . Risk factors of lung cancerAs mentioned above, the occurrence of lung cancer was presumed to be associated with carcinogens that were found in cigarettes 6 . Besides smoking behavior, Witschi discussed that lung cancer was also associated with miners and should be considered as an occupational disease due to the high incidence of the disease among the miners 2 . The mining cave was filled with a high concentration of radon gas, a known lung cancer risk factor today. Similarly, inadequate ventilation in uranium mines also led to lung cancer-related deaths. These occupational threats along with other industrial pollutants such as asbestos, chromium (VI), and silica that are released to the environment that lacks adequate ventilation constitute the environmental risk factors for lung cancer 7 . Behavioral patterns that prefer consumption of processed meat or red meat especially those being prepared fried, might increase the risk of lung cancer 8,9 . In addition, a family history of lung cancer and certain genetic polymorphisms were found to genetically predispose individuals to develop lung cancer 7 . These polymorphisms occur in coding genes including tumor protein p63 (TP63), telomerase reverse transcriptase (TERT), and DNA repair protein RAD52 among others 7 . Statistics and prevalence of lung cancerLung cancer's incidence and mortality are continuing on the rise as depicted in Figure 1. In 2008, the worldwide estimated numbers of incidence and death were 1.6 million and 1.4 million, respectively 10 . In 2012, the number rose to 1.8 million and 1.6 million, respectively 11 . The 2015's report estimated an annual figure of 2 million incidences and 1.7 million deaths 12 . The report in 2018 predicted a total of 2.1 million new cases and 1.8 million deaths in that year 13 . The most recent report estimated a figure of 2.2 mill...

Tumour-necrosis factor related apoptosis-inducing ligand (TRAIL) receptors (TRAIL-R1 and -R2) are appealing therapeutic targets to eradicate tumours specifically via caspase-dependent apoptosis. However, resistance is often observed and TRAIL-R activation can even activate pro-tumorigenic non-canonical signalling pathways. Previously, we found that TRAIL-induced RIPK1-Src-STAT3 signalling was mediating cell migration and invasion in resistant non-small cell lung cancer (NSCLC). Here, the contribution of Src in TRAIL signalling in NSCLC cell lines was further examined. TRAIL sensitive H460 and resistant A549 NSCLC cells showed distinct time-dependent rhTRAIL-induced Src phosphorylation patterns with early activation in A549 cells. Pharmacological Src inhibition as well as shRNA knockdown or CRISPR/CAS9-dependent knockout of Src expression did not alter sensitivity to rhTRAIL-induced apoptosis in both cell lines. Silencing of secondary complex proteins showed that TRADD, but not TRAF2, FADD nor caspase-8, was required for Src activation in A549 cells. Possible mediators of Src-dependent rhTRAIL signalling were identified by Src co-IP-LC-mass spectrometric analyses. In A549 cells the number of Src-interacting proteins increased after rhTRAIL treatment, whereas protein numbers decreased in H460 cells. In rhTRAIL treated A549 cells, Src biding proteins included components of the RAF-MEK1/2-ERK, Wnt and SMAD3 signalling pathways. Functional analyses showed that Src mediated phosphorylation of MEK1/2 and ERK, prevented phosphorylation of SMAD3 and was required for nuclear translocation of ERK and β-catenin in A549 cells. Clonogenic growth of both Src proficient and deficient A549 cells was not affected by rhTRAIL exposure, although Src depletion and MEK1/2 inhibition reduced colony size and numbers significantly. In conclusion, rhTRAIL-induced and Src dependent MEK/ERK, SMAD3 and β-catenin signalling may contribute to the known pro-tumorigenic effects of rhTRAIL in resistant NSCLC cells. However, this needs to be further examined, as well as the potential therapeutic implications of targeting these pathways when combined with TRAIL receptor agonists.