One of the most common cancer incidences worldwide is lung cancer which exhibits the highest mortality rate among cancers (Tao 2019). Non-small cell lung cancer (NSCLC), which accounts for 80–85% of lung cancer cases, is the most common type of this cancer (Hatami et al. 2020). Approximately 15 to 20% of other lung cancer cases are small cell lung cancer (SCLC) that showed an aggressive metastatic phenotype rendering a poor prognosis (Hutchinson et al. 2019). Despite substantial progressions in therapeutic strategies, only a few patients with NSCLC met a 5-year survival rate (Samarghandian et al. 2019). Nowadays, NSCL cell lines are widely used in primary research to discover drugs. Among the widely used cell lines, the A549 lung cancer cell line can be mentioned as a suitable model for investigating human lung epithelial cancer (Shen et al. 2018). This cell line has the biochemical characteristics of type II alveolar pulmonary cells (Zhang et al. 2018).
Currently, the main therapeutic strategy for lung cancer is surgery, radiotherapy, and chemotherapeutic regimens (Bulbul and Husain 2018). On the one hand, the prognosis of advanced lung cancer is poor, and on the other hand, common treatments for this type of cancer do not have a strong therapeutic effect, which leads to further progress of the disease (Gajra et al. 2014). Some drugs such as cisplatin, docetaxel, gemcitabine (Gem), irinotecan, and paclitaxel are one of the most effective chemotherapy methods for NSCLC (Hatami et al. 2020). However, chemotherapeutic agents have nonspecific mechanisms of action causing key components or metabolic pathways of both malignant and normal cells to be targeted. Therefore, many negative side effects are observed after chemotherapy (Hatami et al. 2020; Sardeli et al. 2019). Hence, a major challenge is the development of novel molecular mechanisms for lung cancer treatment to improve agents with a greater cytotoxic effect on cancer cells but safer for normal cells (Namwan et al. 2022). In NSCLC patients, designing new drugs based on natural bioactive compounds can target biological compounds interacting with cell surface receptors or their downstream critical adaptors leading to cancer development (Mohan et al. 2020). Therefore, natural compounds may provide promising and durable broad-range responses with fewer side effects in patients with NSCLC.
Genetics and cell signaling pathways that cause tumorigenesis in NSCLC have been partially investigated. The extracellular-signal-regulated kinase (ERK)–MAPK signaling cascade is the most critical of these pathways. Activating mutations in epidermal growth factor receptor (EGFR), a human gene that encodes a protein called B-Raf (BRAF) and an oncogenic pathway (RAS), have been identified in this cascade to result in altered gene expression and lung malignant transformation (Roberts and Der 2007). The aberrant activation of signaling pathways originating from proto-oncogenes, such as AKT (also named PKB, protein kinase B) and ERK lead to uncontrolled cell proliferation and apoptosis resistance in the majority of patients with NSCLC (Papadimitrakopoulou and Adjei 2006; Yip et al. 2015). Therefore, targeting these oncogenic signaling pathways are interest research topic to develop novel efficient therapeutic agents for patients with NSCLC (Harada et al. 2014; Stinchcombe and Johnson 2014).
Cancer research efforts in the last decade have been focused on identifying chemopreventive and chemotherapeutic agents and investigating their antiproliferative effects. Natural compounds have been considered cancer therapeutic agents due to their ingestible nature and excellent toxicity profile (Wattanathamsan et al. 2019). Grandivittin (GRA) is a dihydrofuranocoumarin that is extracted from Fenzl (Ferulago trifida Boiss.) with established medicinal, phytochemical, and pharmacological properties (Ahmadi et al. 2016; Basile et al. 2009). Fenzle is a perennial herb that grows in the west of Iran. This plant, called Chavile-Roshanball in Persian, has its essential oil displaying larvicidal activity (Basile et al. 2009; HAJI et al. 2002). Previously, studies demonstrated that the GRA has antibacterial and cytotoxic effects on cancer cells such as lung cancer (Basile et al. 2009; Rosselli et al. 2009). Therefore, the GRA may be suggested as a potential chemopreventive drug against tumorigenesis. However, the precise underlying mechanisms of the GRA anticancer actions are not well discovered. Chemoprotective agents in the human alveolar basal epithelial carcinoma cells were shown to activate several pathways, including apoptosis. During the apoptosis process, instigators may trigger releasing of mitochondrial proteins, such as cytochrome c (cyt c) into the cytosol. This event destroys the mitochondrial membrane (Sgarra et al. 2018).
The proteins belonging to the Bcl-2 family, such as proapoptotic (e.g., Bax) and antiapoptotic (e.g., Bcl‐2) highly regulate the release of cyt c from mitochondria. The permeability of the mitochondrial membrane and cyt c releasing is increased by BAX, whereas Bcl‐2 inhibits cyt c transportation by stabilizing the permeability of the mitochondrial membrane (Roy et al. 2019). The proteins of the Bcl‐2 family can control the mitochondrial release of apoptogenic agents known as caspases. These apoptogenic agents are the main contributors to the caspase–apoptotic cascade, involving successive proteolytic cleavage events (Wong 2011). The p53 as an adapter molecule that regulates the cell cycle, acts as the main contributor to the apoptosis of the destructive cell. Therefore, cancer development has been strongly connected with mutations of the p53 gene (Wong 2011). Considering that inducing apoptosis in cancer cells can bypass the death signaling pathways, discovering new apoptosis‐inducing agents heralds an excellent and promising strategy for cancer prevention and treatment (Liu et al. 2011). Therefore, this study aimed to evaluate the antitumor effects of GRA and their underlying mechanisms in the A549 lung cancer cell line as a model of carcinomic human alveolar basal epithelial cells.