Natural Compounds Targeting Inflammation in NSCLC

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1		Ali Azhar	--	2235	2023-03-22 03:06:07	\|
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This entry is adapted from the peer-reviewed paper 10.3390/ph16030451

Lung cancer is the most common cause of cancer-related deaths and can be classified as small-cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Approximately 84% of all cases are NSCLC and the remaining 16% belong to SCLC. In recent years, there has been several breakthroughs in NSCLC management through screening, diagnosis and treatment improvements. However, most lung cancer patients will eventually develop resistance to existing treatments. Therefore, there is clearly a need to identify new targets for therapeutic intervention in NSCLC.

non-small cell lung cancer inflammation drug-repurposing

1. NSCLC and therapy limitation

According to GLOBOCAN 2020, lung cancer tops the cancer list, with highest fatality rate and accounts for 18% of all cancer deaths worldwide ^[1]. About 84% of lung cancer cases belong to non-small cell lung carcinoma (NSCLC) and the remaining 15% are classified as small cell lung carcinoma (SCLC) ^[2]. NSCLC is categorized into three sub-types: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Adenocarcinoma is the major subtype with about 45% of all NSCLC followed by squamous cell carcinoma with 25–30% and the remaining 5–10% is large cell carcinoma subtype ^[3]. Late diagnosis of disease (at stage III and IV) is the major factor for the poor survival rate in lung cancer patients as the disease has progressed to the metastatic stage. About 92% of patients diagnosed at stage IA1 could survived for 5 years or more compared to 10% of patients diagnosed at stage IV. Furthermore, slight enlargement in tumor size from <1 cm (stage IA1) to >2 cm (stage IA3) could reduce the 5-year survival rate of patients from 92% to 77% ^[4].

Current NCSLC therapies, including surgery, chemotherapy, and radiotherapy, are insufficient to reduce the high mortality rates. These approaches lack precision and are usually limited by low drug bioavailability due to high first pass metabolism. Further, serious adverse effects occur due to non-specificity where the chemotherapeutics adversely affect healthy cells ^[5]. To improve the survival of NSCLC patients, personalized medicine is preferred. Recent molecular targeted therapies, such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), could restrict growth and proliferation of lung tumors with EGFR mutations. On the other hand, targeting ROS could inhibit signaling pathways, such as MAPK/ERK, JAK/STAT, and P13K/AKT/mTOR. Then, targeting BRAF can interfere in cell proliferation and growth ^[6]. However, this treatment is only effective for a short duration due to subsequent development of acquired drug resistance ^[7]. Anaplastic lymphoma kinase (ALK) mutation is another example of a successful targeted therapy approach. Crizotinib is an FDA-approved agent that targets tyrosine kinases, such as ALK, c-mesenchymal-epithelial transition (c-MET), and c-ros oncogene 1 (ROS). Crizotinib has shown promising improvement in progression-free survival, and was the first ALK-tyrosine kinase inhibitor approved in the treatment of ALK-rearranged NSCLC ^[8]. However, treatment with Lorlatinib have indicated a survival rate of only 12 out 37 patients who were ALK positive, while 8 out of 14 patients who were positive for ROS survived ^[9].

2. Natural Compounds To Target Inflammation in NSCLC

Natural products remain a potential source for new and innovative drug discovery, given that many have shown to possess anti-inflammatory properties. They are rich with secondary metabolites, such as flavonoids, terpenes, and alkaloids. Several herbal medicinal plants have been actively studied for their anti-inflammatory properties. In recent years, many natural products have been reported to exert effects against lung TME. Most are recognized with potential to be developed as new plant-derived chemotherapy agents due to their ability to modulate angiogenesis, the extracellular matrix, MDSC, TAMs, and immune checkpoint ^[10].

Cinnamon contains secondary metabolites, such as cinnamaldehyde, cinnamic acid, 2-hydroxycinnamaldehyde, 2-methoxycinnamaldehyde, and eugenol, and possesses potent anti-inflammatory effect by reducing pro-inflammatory IL6, IL-1β, and TNF-α and suppressing NF-ĸB-mediated COX-2 and iNOS pathways ^[11]. With regards to NSCLC, cinnamon extract was found to suppress invasion of A549 and H1299 cells by regulating the expression of FAK and ERK pathways ^[12]. Combination therapy with cinnamaldehyde and hyperthermia was also found to induce apoptosis of A549 cells by regulation of reactive oxygen species and the MAPK pathway ^[13].

Hochuekkito (TJ-41) is a Japanese traditional herbal kampo medicine comprising 10 natural herbs. TJ-41 was shown effective in attenuating lung inflammation in the COPD mouse model and LPS-induced macrophage cell line through TNF-α ablation ^[14]. Secondary plant metabolites found to possess potent anti-inflammatory properties include Andrographolide, baicalein, curcumin, Pterostilbene, Dihydroisotanshinone I, Ginsenoside Rh2, vitamin D, and zerumbone.

Immune cell regulation is a crucial event in lung inflammation, and manipulating these immune cells can prevent inflammation and impede cancer progression, particularly in the early stages. Andrographolide, the primary active component found in Andrographis paniculata, is a labdane diterpene known for its potent anti-inflammatory properties ^[15]. It has been reported to inhibit the production of several pro-inflammatory cytokines and chemokines, such as TNF-α, IL-6, and IL-8, and suppress the activation of the NF-κB and MAPK signaling pathways, which are crucial regulators of inflammation ^[16]^[17]. Additionally, andrographolide has been found to exhibit anticancer effects in various cancers.

Andrographolide has been reported to suppress migration of macrophages towards chemo-attractants, such as complement 5a (C5a), through the inhibition of phosphorylation of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) and downstream p42/p44 MAPK (aka extracellular signal-related kinase 1/2, ERK1/2) and Akt signaling pathways ^[18]. Furthermore, andrographolide acts on other cellular pathways regulation, including mTOR, Wnt/β-catenin, TRAIL-mediated apoptosis, as well as VEGF-mediated intracellular signaling, and adversely affects tumor development ^[19]. Interestingly, andrographolide can also inhibit human NSCLC cellular proliferation and induces apoptosis by reprogramming host glucose metabolism ^[20]. In addition to growth inhibition, andrographolide could suppress aggressive metastatic cancer, including luminal-like breast cancer through NF-ĸB pathway inhibition ^[21]. Data from high-throughput metabolomics analysis revealed that this compound exerted its anticancer properties by enhancing immune system activity, reduces inflammation, tumor cell metastasis, and balancing visceral metabolism in a Lewis lung cancer model ^[22]. Resistance to cisplatin in NSCLC, achieved through autophagy, is a hindrance and andrographolide is found capable of inhibiting autophagy in cisplatin-resistant NSCLC by activating the Akt/mTOR pathway, and re-sensitizes tumor cells towards cisplatin ^[23].

Pterostilbene, Dihydroisotanshinone I, and Ginsenoside Rh2 are natural compounds capable of inhibiting TAMs activity ^[10]. Pterostilbene is a natural analogue of resveratrol, which has metabolic stability and superior pharmacological activities. Pterostilbene was initially extracted from red sandalwood (Pterocarpus santalinus) and can primarily be found in a few natural sources, such as grapes, blueberries, and Pterocarpus marsupium ^[24]. Pterostilbene treatment led to reduced expressions of NF-ĸB, CD133, MUC1, β-catenin, and Sox2 in inflammatory lung TAMs. This also led to a significant loss of stemness by TAMs with decreased side-population cells and suppression of self-renewal ability in TAM-co-cultured lung cancer cells ^[25]. In another study, female Balb/C mice were treated with varying doses of pterostilbene to examine its impact on cell proliferation, cell death, and the p53 pathway. The study observed a reduction in Ki-67 expression and an increase in caspase-3 expression, leading to a decrease in cyclin D1 and cyclin E2 protein expression, causing cell cycle arrest. Furthermore, pterostilbene increased p53, p21, and p27 protein expression ^[24].

Dihydroisotanshinone I is a pure compound extracted from danshen, which is a Chinese medicinal herb. Dihydroisotanshinone I could inhibit tumor migration and cell motility, block macrophage recruitment by lung cancer cells, reduce CCL2 secretion, and suppress p-STAT3 signaling in NSCLC A549 and H460 cells ^[26].

Ginsenoside Rh2, found in ginseng, possessed the ability to convert TAMs from M2 to M1 subtype and prevented cancer cell migration by curbing TAMs activity in TME ^[27]. Ginsenoside Rh2 was also found to inhibit hypoxia-induced cell migration by increasing the expression of mir-491, which subsequently downregulated the expression of MMP-9. In this study, the effects of ginsenoside Rh2 on hypoxia-induced migration in lung adenocarcinoma was studied. Rh2 was found to inhibit hypoxia-induced cell migration in A549 and H1299 cell lines through the upregulation of mir-491 expression. Additionally, mir-491 antisense oligonucleotide suppressed hypoxia-induced migration and the expression of matrix metalloproteinase (MMP)-9 expression in Rh2-treated A549 cells ^[28].

Vitamin D, found in sea fish and animal liver, was reported to reduce hyperinflammation in both macrophages and MDSCs in COVID-19 patients. A complication, commonly seen in the lungs of COVID-19 patients, is hyperinflammation-induced acute respiratory distress syndrome. In patients who suffered from acute respiratory distress syndrome and lacked vitamin D, symptoms were reduced after vitamin D supplementation ^[29]. Vitamin D was also found to improve the survival of patients with cancer found by a meta-analysis of randomized clinical trials performed ^[30]. Additionally, in a randomized controlled trial with 155 patients NSCLC, vitamin D supplementation show a significant difference in relapse-free survival (RFS) or overall survival (OS) compared to placebo among the subgroup of patients with early-stage adenocarcinoma and low levels of 25(OH)D ^[31].

Resveratrol is a naturally occurring non-flavone polyphenol compound that is derived from various plants, such as Polygonum cuspidatum, Cassia tora Linn, and Vitis vinifera. It belongs to the stilbene family. Resveratol was found to activate autophagy and apoptosis in A549 cell by regulating the NGFR-AMPK-mTOR signaling pathway ^[32]. Resveratrol, found in grape skin and seeds, and silymarin, from Silybum marianum, were shown to modulate MDSCs in lung cancer in vivo model ^[10].

Baicalein is a major bioactive compound found in the root of Scutellaria baicalensis, a traditional Chinese herb. Baicalein was reported to effectively inhibit NSCLC cell invasion and metastasis without any toxicity. This flavonoid significantly reduces ezrin tension by reducing cellular ezrin S-nitrosylation (SNO) levels and iNOS expression in the inflammatory microenvironment of NSCLC ^[33]. Baicalein has been proven to exert anti-airway inflammation in cigarette smoke-induced chronic obstructive pulmonary rat model by regulating pro- and anti-inflammatory balance ^[34], and in an OVA-induced allergic airway inflammation model through iNOS and NF-ĸB signaling inhibition ^[35]. Dimethyl fumarate is a promising fumaric acid ester and possesses strong anti-oxidative, anti-inflammatory, and immunomodulation properties ^[36]. Given to mice with chronic exposure to diesel exhaust particles, peroxynitrite, total reactive oxygen species, and nitric oxide levels in the lung were significantly reduced, whereas expression of products such as nitrotyrosine, glutathione peroxidase-1/2, and catalase were significantly elevated ^[37]. The observed changes were possibly due to downregulation of NF-ĸB pathway. Dimethyl fumarate has been reported to inhibit metastasis in cutaneous T cell lymphoma and melanoma through NF-ĸB pathway inhibition as well ^[36].

Curcumin is a natural compound found in Curcuma longa, possessing a variety of pharmacological properties, including antidiabetic, neuroprotective, anticancer, and anti-inflammation ^[38]. In NSCLC, migratory and invasive ability of A549 cells is reduced by curcumin through inhibition of adiponectin, an acid peptide hormone, via the NF-ĸB pathway ^[39]. Zerumbone, a monocyclic sesquiterpene compound, found in Zingiber zerumbet rhizomes has a broad range of pharmacological activities and anti-inflammatory effects. Recently, zerumbone was shown to suppress LPS-Induced inflammation in macrophages through inhibition of NLRP3 inflammasome. Furthermore, NF-ĸB activity and production of inflammatory cytokines, such as IL-1β and IL-6, were also significantly reduced ^[40]. The same inhibitory effect could also be seen in TNF-α-activated fibroblasts treated with zerumbone, in which tumor-promoting cytokines TNF-α, TGF-β, IL-33, SDF-1, and MCP-1 were significantly reduced in comparison to TNF-α-activated fibroblasts ^[41]. Astaxanthin, a naturally occurring xanthophyll carotenoid is found in marine organisms, such as algae, shrimp, and salmon ^[42]. Asthaxanthin possesses both anti-inflammatory and anti-oxidant properties and is shown to be capable of protecting the lung against inflammatory-based diseases. This compound exerts these effects by regulating nuclear factor erythroid 2-related factor/heme oxygenase-1, NF-ĸB, MAPK, JAK-STAT3, PI3-kinase/Akt pathways, and modulating immune response ^[42]^[43]^[44].

Farnesoid X receptor, known to regulate immune responses and inflammation in immune-mediated diseases, can promote tumor cell proliferation in NSCLC. Overexpression of this receptor in a Lewis lung carcinoma (LLC) syngeneic mouse model resulted in downregulation of PD-L1 ^[45]. The immunosuppressive role of farnesoid X receptor suggests it is a candidate for drug development. Additionally, it offers the opportunity for existing anti-PD-1 therapy to be fully utilized in treatment of NSCLC patients with high PD-1 expression. Bile acid and non-bile antagonists, such as Tauro-β-muricholic acid (T-β-MCA), taurochenodeoxycholic acid, glycoursodeoxycholic acid, guggulsterone, epiallopregnanolone sulfate, 3,5-disubstituted oxadiazole core, stigmasterol, tuberatolides, and andrographolide, are known to inhibit farnesoid X receptor ^[46]. These versatile natural compounds offer an alternative approach to curb cancer progression. Table 1 below provides a list of natural compounds possessing anti-inflammation properties for NSCLC treatment.

Table 1. List of natural compounds to target inflammation in NSCLC.

Compound	Mechanism of Action	Initial Purpose	Performance Remarks	Reference
Andrographolide	Inhibition of NF-ĸB	Treatment of upper airway disorders		^[19]^[21]^[22]
Asthaxanthin	Regulating the nuclear factor erythroid 2-related factor/heme oxygenase-1 pathway, NF-ĸB signaling, MAPK signaling, JAK-STAT 3 signaling, Pi3-kinase/Akt pathway, and modulating immune response	Dietary supplement		^[42]^[43]^[44]
Curcumin	Inhibition of NF-ĸB	Dietary supplement		^[47]^[48]
Fumaric Acid Esters	Alters leukocyte, keratinocyte, and/or endothelial functions	To treat psoriasis and multiple sclerosis		^[36]
Baicalein	Inhibits metastasis (exact mechanism of action yet to be confirmed)			^[33]
Kampo medicine, Hochuekkito, TJ-41	Inhibited influenza A virus replication by IFN-α upregulation	To treat infectious disease, possesses virological activity	In vivo and in vitro study shows positive results	^[14]
Cinnamon (cinnamaldehyde, cinnamic acid, 2-hydroxycinnamaldehyde, 2-methoxycinnamaldehyde, and eugenol)	Suppressed nitric oxide (NO), IL-6, TNF-α, and IL-1β production. Production and blocking of nuclear factor-ĸB (NF-ĸB) and mitogen-activated protein kinase (MAPK)	Has immunomodulator, antiseptic and antiviral properties		^[11]
β-carbolines	Inhibits NF-κB/p65 and EMT transition	To treat altitude sickness and possess anti-inflammatory properties		^[49]
Magnesium isoglycyrrhizinate (MgIG)	Inhibits fibroblast differentiation via the p38MAPK/Nox4/Akt pathway	Respiratory disorders, hyperdipsia, epilepsy, fever		^[49]
Polydatin (PD)	NLRP3 inflammasome and NF-κB pathway	Used to reduce symptoms of menopause, digestive system		^[49]
Zingerone (vanillylacetone)	Inhibiting NF-κB and MAPKs	To treat infections, nausea, bronchitis, dysentery, heartburn, cough, flatulence, diarrhea, loss of appetite		^[49]
Zerumbone	Inhibits TNF-α or LPS-induced production inflammatory cytokines via inhibition of NF-ĸB	To treat fever, sprains, asthma, torment, severe sprains, toothache, allergies, wounds, and stomachache		^[40]

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Thiviyadarshini Rajasegaran

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1. NSCLC and therapy limitation

2. Natural Compounds To Target Inflammation in NSCLC

References