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    Topic review

    Natural Product Treat Lung Diseases

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    Submitted by: Zhonglei Wang

    Definition

    As a traditional source for modern pharmaceutical discovery and potential drug leads, natural products have played an integral role in treating patients due to their unique structural, chemical, and biological diversity. A wide range of natural products can be considered promising anti-COVID-19 or anti-lung cancer agents have gained widespread attention, including natural products as monotherapy for the treatment of SARS-CoV-2 (ginkgolic acid, shiraiachrome A, resveratrol, and baicalein) or lung cancer (daurisoline, graveospene A, deguelin, and erianin) or in combination with FDA-approved anti-SARS-CoV-2 agents (cepharanthine plus nelfinavir, linoleic acid plus remdesivir) and anti-lung cancer agents (curcumin and cisplatin, celastrol and gefitinib).

    1. Natural Products as Monotherapy for the Treatment of SARS-CoV-2

    Natural products have demonstrated potential value, which supports this strategy as an indispensable research focus in the fight against the COVID-19 epidemic [1][2]. The chemical structures of the components described in this section are shown in Figure 1. The SARS-CoV-2 main protease (Mpro), also called the 3C-like protease (3CLpro), has a vital function in viral replication and is, therefore, a preferred drug target [3]. The papain-like protease (PLpro), another prime therapeutic target, plays an essential role in maturing viral RNA polyproteins and dysregulation of host inflammation [4]. Ginkgolic acid, a phenolic acid, is an essential component of the traditional herbal medicine Ginkgo biloba (EGb) [5]. A study has demonstrated that ginkgolic acid is characterized by half-maximal inhibitory concentration (IC50) values of 1.79 μM and 16.3 μM against SARS-CoV-2 Mpro and SARS-CoV-2 PLpro, respectively [6]. The study unambiguously showed that ginkgolic acid exerts good dual-inhibitory effects through its irreversible binding to SARS-CoV-2 cysteine proteases [6].

    Figure 1. Promising natural products for treating SARS-CoV-2.

    Angiotensin-converting enzyme 2 (ACE2), an essential ingredient of the renin–angiotensin–aldosterone system (RAAS), is a critical host cell surface receptor for viral infection [7]. The glycosylated spike protein (S protein) plays an essential role in mediating viral entry via interactions with the ACE2 cell surface receptor [8]. Hypocrellin A and shiraiachrome A, two-axial chiral perylenequinones, have been reported to exhibit potent effects on the infected monkey Vero E6 cell line by inhibiting the activity of the SARS-CoV-2 S protein at EC50 values of 0.22 μM and 0.21 μM, respectively, while at doses of up to 10 μM, these presented no observable cytotoxicity against these cells [9].

    Transmembrane protease serine 2 (TMPRSS2), a critical factor enabling SARS-CoV-2 infection, can interact with ACE2 [10]. It has been reported that platycodin D, a triterpenoid saponin isolated from Platycodon grandiflorum, prevents TMPRSS2-driven infection in vitro by impairing membrane fusion [11]. Platycodin D has IC50 values of 0.69 μM and 0.72 μM for SARS-CoV-2 pseudovirus (pSARS-CoV-2) overexpression of ACE2 (ACE2+) and ACE2/TMPRSS2+, respectively, and IC50 values of 1.19 μM and 4.76 μM for SARS-CoV-2 in TMPRSS2-negative Vero cells and TMPRSS2-positive Calu-3 cells, respectively [11]. Resveratrol, a remarkable phytoalexin, may effectively inhibit the replication of SARS-CoV-2 S protein in Vero E6 cells at an EC50 of 4.48 μM [12], and has an excellent safety tracking record, with no cytotoxicity even up to a concentration of 150 µM [13].

    The RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 is another promising target that regulates the replication of the viral genome [14]. Corilagin, a non-nucleoside inhibitor, is a gallotannin isolated from the medicinal plant Phmllanthi Fructus [15]. Corilagin has been reported to inhibit SARS-CoV-2 infection with an EC50 value of 0.13 μM in a concentration-dependent manner by preventing the conformational change of RdRp and inhibits SARS-CoV-2 replication [16]. Furthermore, corilagin, as identified via molecular dynamics simulation-guided studies, could also be used as an endogenous Mpro candidate, with an 88% anti-SARS-CoV-2 Mpro activity at concentrations of 20 μM in vitro [17].

    Bafilomycin B2, which can be isolated from Streptomyces sp. HTL16, indicates enhanced inhibitory potency against SARS-CoV-2 at IC50 values of 5.11 nM (in the full-time approach) and 8.32 nM (in the pretreatment-of-virus approach) in Vero E6 cells, respectively [18]. While bafilomycin B2 has demonstrated potential effectiveness in inhibiting the viral entry process, evidence of its utility as anti-SARS-CoV-2 agents in vivo is currently insufficient.

    The above evidence supports the potential value of the above natural products as therapeutic agents for the treatment of the novel SARS-CoV-2 infection, suggesting more validation studies (both in vitro and in animal models as well as on humans) could be encouraged to perform. Besides the above-mentioned molecules, several other natural products have also been shown to exhibit potent anti-SARS-CoV-2 activities in vitro. Table 1 summarizes a range of studies investigating the in vitro effects of anti-SARS-CoV-2 agents since 2020.

    Table 1. Other natural products with anti-SARS-CoV-2 activities in vitro.

    No. Name Structure EC50 or IC50 (μM) Strain Refs
    1 Acetoside Biomedicines 09 00689 i001 0.043 Vero E6 cells [19]
    2 Anacardic acid Biomedicines 09 00689 i002 2.07 USA-WA1/2020 [6]
    3 Andrographolide Biomedicines 09 00689 i003 0.034 Calu-3 cells [20][21]
    4 Apigenin-7-O-glucoside Biomedicines 09 00689 i004 0.074 Vero E6 cells [19]
    5 Artemisinin Biomedicines 09 00689 i005 64.45 Vero E6 cells [21][22]
    6 Azithromycin Biomedicines 09 00689 i006 2.12 Caco-2 cells [23]
    7 Baicalin Biomedicines 09 00689 i007 7.98 Vero E6 cells [24]
    8 Cannabidiol Biomedicines 09 00689 i008 7.91 Vero E6 cells [25][26]
    9 Catechin-3-O-gallate Biomedicines 09 00689 i009 2.98 Vero E6 cells [27]
    10 Chebulagic acid Biomedicines 09 00689 i010 9.76 Vero E6 cells [28]
    11 Daurisoline Biomedicines 09 00689 i011 3.66 Vero E6 cells [29]
    12 EGCG Biomedicines 09 00689 i012 0.874 Vero E6 cells [24][30]
    13 Emetine Biomedicines 09 00689 i013 0.46 Vero E6 cells [31][32]
    14 Epicatechin-3-O-gallate Biomedicines 09 00689 i014 5.21 Vero E6 cells [27]
    15 Gallinamide A Biomedicines 09 00689 i015 0.028 Vero E6 cells [33]
    16 Gallocatechin-3-O-gallate Biomedicines 09 00689 i016 6.38 Vero E6 cells [27]
    17 Hopeaphenol Biomedicines 09 00689 i017 2.3 B.1.351 [34]
    18 Ipomoeassin F Biomedicines 09 00689 i018   semi-permeabilized mammalian cells [35]
    19 Kobophenol A Biomedicines 09 00689 i019 1.81 Vero E6 cells [36]
    20 Myricetin Biomedicines 09 00689 i020 0.22 Vero E6 cells [37][38]
    21 Naringenin Biomedicines 09 00689 i021 0.092 Vero E6 cells [19][39]
    22 Osajin Biomedicines 09 00689 i022 3.87 Vero E6 cells [40]
    23 2,3′,4,5′,6-Pentahydroxybenzophenone Biomedicines 09 00689 i023 0.102 Vero E6 cells [19]
    24 Procyanidin B2 Biomedicines 09 00689 i024 75.3 Vero E6 cells [27]
    25 Punicalagin Biomedicines 09 00689 i025 7.20 Vero E6 cells [28]
    26 Sennoside B Biomedicines 09 00689 i026 0.104 Vero E6 cells [19]
    27 Shikonin Biomedicines 09 00689 i027 15.75 Vero E6 cells [41]
    28 Δ9-Tetrahydrocannabinol Biomedicines 09 00689 i028 10.25 Vero E6 cells [25]
    29 Tetrandrine Biomedicines 09 00689 i029 3.00 Vero E6 cells [40]
    30 Theaflavin Biomedicines 09 00689 i030 8.44 HEK293T human
    embryonic kidney cells
    [42]

    Traditional Chinese medicines have attracted considerable attention due to their ability to effectively inhibit SARS-CoV-2 [43][44][45]. For example, the Qingfei Paidu decoction (QFPD) has shown an ability to treat COVID-19 patients at all stages with excellent clinical efficacy (cure rate >90%) [46][47]. Shuanghuanglian oral liquid or injection (SHL), another well-known traditional Chinese medicine, dose-dependently inhibits SARS-CoV-2 Mpro replication [48]. In addition to the above-mentioned QFPD and SHL, several other traditional Chinese medicines (such as Kegan Liyan oral liquid and Toujie Quwen granule) listed in Table 2 contain Scutellaria baicalensis Georgi (Chinese name: Huangqin), whose major component is baicalein, exerts a marked anti-SARS-CoV-2 effect (IC50 of 0.94 μM, and SI > 212) [49]. Furthermore, it is crucial to investigate how herbal medicine affects SARS-CoV-2 infection by studying its active ingredients. To elucidate the underlying molecular mechanisms, a crystal structure of SARS-CoV-2 Mpro complexed with baicalein was constructed at a resolution of 2.2 Å (the Protein Data Bank (PDB) ID: 6M2N) [48]. Analysis of the core of the substrate-binding pocket revealed multiple interactions (such as hydrogen bonding with Leu141/Gly143 and Ser144/His163, π–π interactions with Cys145 and His4, and hydrophobic interactions with Met49 and His41), which effectively blocked SARS-CoV-2 replication via noncovalent incorporation [48]. The relevant studies [50][51][52] provided direct data for a better understanding of the molecular mechanisms of Chinese herbal medicine by studying its active ingredients.

    Table 2. Registered clinical trials relating to traditional Chinese medicine prescriptions containing baicalein (active ingredient of Huangqin) for treatment of COVID-19 patients (Chinese Clinical Trial Registry, www.chictr.org/cn/ (accessed on 31 January 2021).

    Baicalein (The Active Ingredient of Huangqin) Molecular Mechanisms of Baicalein Herbal Formula Containing Huangqin Registration Number Sample Size of the Control Group
    Biomedicines 09 00689 i031 RdRp inhibitor via noncovalent incorporation [53], potent antagonists against TMPRSS2 [50], improving respiratory function, decreasing IL-1β and TNF-α levels, and inhibiting cell infiltration [51][52]. Qingfei Paidu decoction ChiCTR2000029433 120
    ChiCTR2000030883 100
    ChiCTR2000032767 782
    Xinguan I decoction ChiCTR2000029637 50
    Tanreqing capsules ChiCTR2000029813 36
    Tanreqing injection ChiCTR2000029432 72
    Kegan Liyan oral liquid ChiCTR2000033720 240
    ChiCTR2000033745 240
    ChiCTR2000031982 240
    Shuanghuanglian oral liquid ChiCTR2000033133 30
    ChiCTR2000029605 100
    Toujie Quwen granule ChiCTR2000031888 150

    2. Natural Products as Monotherapy for the Treatment of Lung Cancer

    There is no doubt that natural products have always been recognized as promising anti-lung cancer agents. Daurisoline, an autophagy blocker, is a bisbenzylisoquinoline alkaloid extracted from the herbal medicine Nelumbo nucifera Gaertn [54]. The chemical structures of the molecules discussed in this section are shown in Figure 2. Daurisoline increases the degradation of β-catenin by targeting heat shock protein 90 (HSP90) directly and decreases the expression of MYC proto-oncogene (c-MYC) and cyclin D1, which resulted in cell cycle arrest at the G1 phase in human lung cancer A549 cells and Hop62 cells lines to exert its anti-lung cancer activity [55]. More importantly, in animals, daurisoline has been reported to be a promising anti-lung cancer agent (by inhibiting tumor growth in lung cancer xenografts) with no observable side effects, thus highlighting a potential role for daurisoline in the treatment of lung cancer [55]. Another recent study has shown that daurisoline can effectively inhibit SARS-CoV-2 replication at IC50 values of 3.664 μM and 0.875 μM in Vero E6 cells and in human pulmonary alveolar epithelial cells (HPAEpiC), respectively [29].

    Figure 2. Promising natural products for treating lung cancer.

    Graveospene A, isolated from the leaves of Casearia graveolens, is a new clerodane diterpenoid that has been reported to induce apoptosis in A549 cells with an IC50 value of 1.9 μM by inducing cell cycle arrest in phase G0/G1 [56]. Deguelin, a protein kinase B (AKT) kinase inhibitor, is isolated from the African plant Mundulea sericea (Leguminosae) and is commonly used to inhibit the growth of several types of human cancer cell lines [57]. Deguelin promoted the phosphorylation of myeloid cell leukemia sequence-1 (Mcl-1) protein and induced the inhibition of the wildtype and mutated epidermal growth factor receptor (EGFR)-Akt signaling pathway, which resulted in activation of downstream GSK3β/FBW7 and profound anti-NSCLC activity with no obvious side effects in vivo [58].

    Licochalcone A is a natural flavonoid derived from Xinjiang licorice and Glycyrrhiza inflata. Licochalcone A is known to possess a broad spectrum of activities with important pharmacological effects in various cancer cell lines [59]. Licochalcone A can significantly increase autophagic cytotoxicity (in both A549 and H460 cell lines) and downregulated the expression of c-IAP1, c-IAP2, XIAP, survivin, c-FLIPL, and RIP1, apoptosis-related proteins via inhibiting the activity of phosphorylated extracellular signal-regulated kinase (ERK) and autophagy [60]. In addition, licochalcone A has been reported to abolish the expression of programmed death ligand-1 (PD-L1) by increasing reactive oxygen species (ROS) levels in a time-dependent manner and interfering with protein translation in cancer cells [61]. Further, licochalcone A can inhibit PD-L1 translation likely through the inhibition of the phosphorylation of 4EBP1 and activation of the PERK-eIF2α signaling pathway [61]. Licochalcone A plays a vital role in reversing the ectopic expression of key microRNA (miR-144-3p, miR-20a-5p, miR-29c-3p, let-7d-3p, and miR-328-3p) to elicit lung cancer chemopreventive activities both in vivo and in vitro [62]. In addition, licochalcone A has been reported to inhibit EGFR signaling and reduced the expression of Survivin protein in a cap-dependent translation manner to exhibit profound activity in mutated NSCLC cells [63].

    Erianin, a novel dibenzyl compound, can be isolated from the traditional herbal medicine Dendrobium chrysotoxum Lindl and has been proposed as an apoptosis-inducing agent in human lung cancer cells [64]. The main mechanisms of its anti-lung cancer activity involve the induction of ferroptosis by activating Ca2+/calmodulin signaling, inhibition of cell proliferation and metastasis, and induction of cell cycle arrest in phase G2/M [65].

    Tutuilamide A, isolated from marine cyanobacteria Schizothrix sp., is a novel cyclic peptide reported to exhibit moderate cytotoxicity activity in the H-460 human lung cancer cell line with an IC50 value of 0.53 μM [66]. Tutuilamide A, with the help of the vinyl chloride side chain, showed enhanced inhibitory potency with high selectivity (IC50 0.73 nM) for human neutrophil elastase, which is associated mainly with the migration and metastasis of lung cancer cells [67]. Besides the above-mentioned molecules, Table 3 also exhibits other natural products (including their underlying molecular mechanisms) with notable anti-lung cancer activities reported since 2020.

    Table 3. The mechanism involved in anticancer activities of other natural products (reported since 2020).

    No. Name Structure Mechanism of Anti-Lung Cancer Refs
    1 Acovenoside A Biomedicines 09 00689 i032 Inhibit the adenosine triphosphate (ATP)-dependent Na+/K+ exchange through the Na+/K+-ATPase [68]
    2 Asiatic acid Biomedicines 09 00689 i033 Inhibited the ionizing radiation-induced migration and invasion [69]
    3 Baicalein Biomedicines 09 00689 i034 Restrained ezrin tension by decreasing inducible nitric oxide synthase expression levels, suppress invasion, reduced vasculogenic mimicry formation [70][71][72]
    4 Baicalin Biomedicines 09 00689 i035 Inhibited the invasion, migration, angiogenesis, and Akt/mTOR pathway [73][74]
    5 Casticin Biomedicines 09 00689 i036 Induced the expressions and nuclear translocation of phosphorylation of H2AX [75]
    6 Dioscin Biomedicines 09 00689 i037 Down-regulated signal transducer and activator of transcription 3 and c-Jun N-terminal kinase signaling pathways [76]
    7 EGCG Biomedicines 09 00689 i038 Regulated CTR1 expression through the ERK1/2/NEAT1 signaling pathway [77][78]
    8 Ellagic acid Biomedicines 09 00689 i039 Inhibited tumor growth, increased p-AMPK, and suppressed hypoxia-inducible factor 1α levels [79]
    9 Erianthridin Biomedicines 09 00689 i040 Attenuated extracellular signal-regulated kinase activity and mediated apoptosis, matrix-degrading metalloproteinases (MMPs) expression [80][81]
    10 Eugenol Biomedicines 09 00689 i041 Restriction of β-catenin nuclear transportation [82]
    11 Formononetin Biomedicines 09 00689 i042 Inhibited EGFR-Akt signaling, which in turn activates GSK3β and promotes Mcl-1 phosphorylation in NSCLC cells [83][84]
    12 Gallic Acid Biomedicines 09 00689 i043 Inhibited of EGFR activation and impairment, inhibition of phosphoinositide 3-kinase (PI3K) and AKT phosphorylation [85][86]
    13 Glochidiol Biomedicines 09 00689 i044 Inhibited tubulin polymerization [87]
    14 Gracillin Biomedicines 09 00689 i045 Inhibited both glycolysis and mitochondria-mediated bioenergetics, induced apoptosis through the mitochondrial pathway [88][89]
    15 Hispidulin Biomedicines 09 00689 i046 Promoted apoptosis by hispidulin via increased generation of ROS [90]
    16 Icaritin Biomedicines 09 00689 i047 Downregulated the immunosuppressive cytokine (TNF-α, IL10, IL6) and upregulated chemotaxis (CXCL9 and CXCL10) [91]
    17 Isoharringtonine Biomedicines 09 00689 i048 Induced death tumor spheroids by activating the intrinsic apoptosis pathway [92]
    18 Kaempferol Biomedicines 09 00689 i049 Inhibitor of nuclear factor erythroid 2-related factor 2 [93]
    19 Liriopesides B Biomedicines 09 00689 i050 Reduced proliferation, and induced apoptosis and cell cycle arrest, inhibited the progression of the cell cycle from the G1 to the S phase [94]
    20 Nagilactone E Biomedicines 09 00689 i051 Activated the c-Jun N-terminal kinases, increased the phosphorylation, and promoted the localization of c-Jun in the nucleus [95][96]
    21 8-Oxo-epiberberine Biomedicines 09 00689 i052 Inhibited TGF-β1-induced epithelial-mesenchymal transition (EMT) possibly by interfering with Smad3 [97]
    22 Parthenolide Biomedicines 09 00689 i053 Reduced the phosphorylation of EGFR and downstream signaling pathways mitogen-activated protein kinase (MAPK)/ERK, inhibited PI3K/Akt/FoxO3α signaling [98][99][100]
    23 PDB-1 Biomedicines 09 00689 i054 Suppressed lung cancer cell migration and invasion via FAK/Src and MAPK signaling pathways [101]
    24 Polyphyllin I Biomedicines 09 00689 i055 Induced autophagy by activating AMPK and then inhibited mTOR signaling, promoted apoptosis, modulated the PI3K/Akt signaling [102][103]
    25 Quercetin Biomedicines 09 00689 i056 Inhibited proliferation and induced apoptosis [104]
    26 Silibinin Biomedicines 09 00689 i057 Inhibited cell proliferation, migration, invasion, and EMT expression [105]
    27 Sinomenine Biomedicines 09 00689 i058 Downregulated expression of MMPs and miR-21, suppressed α7 nicotinic acetylcholine receptors expression [106][107][108]
    28 Toxicarioside O Biomedicines 09 00689 i059 Decreased the expression of trophoblast cell surface antigen 2, resulting in inhibition of the PI3K/Akt pathway and EMT program [109]
    29 Vincamine Biomedicines 09 00689 i060 Interaction with the apoptotic protein caspase-3 [110]
    30 Xanthohumol Biomedicines 09 00689 i061 Suppressed ERK1/2 signaling and reduced the protein levels of FOS-related antigen 1, decreased the mRNA level of cyclin D1 [111]

    The entry is from 10.3390/biomedicines9060689

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