Traditional Herbal Medicine: A Potential Therapeutic Approach for
Adjuvant Treatment of Non-small Cell Lung Cancer in the Future
Lung cancer is the primary cancer-associated cause of mortality and constitutes a major public health concern around the globe. , Non-small cell lung cancer (NSCLC) comprises ~85% of lung cancer cases, and the 5-year survival rate for patients with advanced NSCLC is only 15%. , In the last 20 years, conventional therapies for NSCLC have included surgical resection, radio-chemotherapy, and immunotherapy. Surgical removal is the primary medical intervention for patients with early-stage NSCLC; however, >81% of clinically diagnosed patients with NSCLC are not candidates for surgery. For advanced NSCLC, platinum-based chemotherapy is the first-line choice of medication, but the prognosis remains unsatisfactory. , Radio-chemotherapy often causes adverse effects in clinical practice, and drug resistance is prone to develop. These side effects may exacerbate the condition in certain patients with lung cancer and have unintended consequences. Immunotherapy is not yet commonly used in clinical practice and is expensive. , With the remarkable improvement of disease screening and diagnosis technology, targeted therapy and immunotherapy have gradually emerged in recent years. Many targeted drugs and immune checkpoint inhibitors have been approved by FDA and used in the clinic, - but with many toxic side effects including rash, diarrhea, nausea, and even nervous/cardiac system disorders . Therefore, finding effective therapies remains a serious challenge. , Traditional Chinese herbal medicine dates back thousands of years and is a subset of traditional Chinese medicine. Recently, Chinese herbal medicine has become a widespread topic, and researchers are currently using scientific approaches to elucidate its mechanism, safety, and effectiveness. During the COVID-19 epidemic, about 90% of COVID-19 patients in China have received TCM treatment. The clinical efficiency is as high as 80% and it has nearly no toxic side effects. Researchers have summarized numerous herbs or their derivatives with potential preventive and therapeutic effects on anti-COVID-19, such as Jinhua Qinggan granules, Xuebijing, Pudilan Xiaoyan Oral Liquid, and so on. As an auxiliary and complementary medicine in China, traditional herbal medicine is prevalently used in clinical practice. , Traditional herbal medicine has the advantages of alleviating clinical symptoms, enhancing autoimmunity and helping to manage the quality of life of patients. - Previous studies have reported that herbal extracts and prescriptions through multi-targeting inhibit tumor proliferation, induce tumor apoptosis, and alleviate drug resistance. - The present review focuses on recent developments in using herbal medicine to treat NSCLC and may offer a potential adjuvant treatment option.   The identification of novel drugs against neoplasms is important for cancer treatment. Numerous observations indicate that herbal medicine may exert anticancer effects via various mechanisms, including modulating cancer-related signaling pathways, suppressing cell proliferation, and causing apoptosis and autophagy. Herbal medicine extracts help to treat various malignancies. , The following herbal extracts are examples of their effects against NSCLC . Thevebioside, Sesamin, and Jervine Act Against NSCLC by Inhibiting AKT Signaling Thevebioside (THB ) , a monomer from Thevetia peruviana (Pers.) K. Schum. (TPKS), may have pharmacological effects. THB has shown anti-inflammatory effects on skin diseases. Researchers have found that THB exerts the most cytotoxic activity in p53 wild-type A549 and H460 cell lines in a dose and time-dependent manner. THB has been shown to hinder the proliferation of NSCLC by triggering apoptosis, as indicated by increasing the Bad, cleaved caspase-3 and cleaved PARP expression, and reducing the expression of Bcl-xl. In addition, animal and cell studies have demonstrated that THB promotes apoptosis by inhibiting the steroid receptor coactivator-3 (SRC-3)-induced insulin like growth factor 1 receptor (IGF1R)−P13K-AKT signaling pathway. SRC1, SRC2 and SRC-3 are members of a transcription coactivator family. Elevated SRC-3 expression is frequently associated with tumor progression. , THB has also exhibited promising pharmacological safety, with low inhibition of normal lung epithelial cells, as well as no observable harm to the organs of A549-bearing mice. THB is a low-toxicity natural product extract that may be employed as an adjuvant medication in lung cancer. Sesamin is a lignan abundant in Sesamum indicum . Sesamin has antihypertension, antithrombosis, and antitumor pharmacodynamic activities. - Sesamin modulates the AKT/P53 signaling pathway, mainly inhibits AKT activity, and downregulates cyclin D1 and CDK2 in A549 and H1792 lung cancer cells. In a previous study, sesamin suppressed AKT/PI3K signaling by downregulating cyclooxygenase 2, leading to G 1 phase cell arrest, and down-regulating Bcl-2, Bax and cyclin E1 gene expression. Yang et al showed that sesamin causes an increase in the production of ROS in A549 cells and loss of the mitochondrial membrane potential. Sesamin-treated A549 cells promote the expression of apoptosis-related proteins (cleaved caspase-3, caspase-9, cytochrome c and Bax/Bcl-2). Sesamin stimulated mitophagy in A549 cells via the ROS-mediated PTEN-induced kinase 1 (PINK1)/Parkin signaling pathway, increased Parkin levels in mitochondria and whole cells, and reduced Parkin levels in the cytoplasm. Cyclosporine A, a mitotic inhibitor, abolishes sesamin’s inhibitory effect on A549. Sesamin may therefore be a suitable NSCLC adjuvant. Jervine is a steroid alkaloid from Veratrum rhizome . Jervine exhibited a dose and time-dependent inhibition of proliferation and colony formation. Jervine promotes the expression of LC3 to induce autophagy and activates caspase-3 to promote apoptosis. Bafilmycina1, an autophagy inhibitor, can abolish the jervine-mediated suppression of human lung cancer cell proliferation. Transformation of cytosolic LC3 (LC3-I) into autophagy, the vesicle-associated form (LC3-II) bound by phosphatidylethanolamine, is essential for inducing autophagy. The AKT/mTOR and hedgehog signaling pathways are usually strongly suppressed in multiple cancer cells. , Jervine acts against NSCLC by suppressing hedgehog and AKT signaling. Treatment with jervine effectively suppressed the AKT/mTOR and hedgehog signaling pathways by decreasing the expression of AKT, patched 1, sonic hedgehog, GLI family zinc finger 1 and smoothened, frizzled class receptor. Notably, jervine inhibited tumor growth in A549 tumor-bearing mice. Therefore, jervine may become a potential drug for lung cancer treatment. Thymol Acts Against NSCLC by Arresting the Cell Cycle Thymol can be found in various plants, including Ocimum gratissimum L. and Satureja thymbra L. Thymol is a naturally occurring monoterpene phenol. A previous study has demonstrated that thymol has important pharmacodynamic effects in antibacterial, antioxidant and analgesic applications. In addition, researchers have found that thymol exerts cytotoxic effects in multiple types of cancer. - Balan et al demonstrated that thymol’s antiproliferative activity on A549 cells was dose and time-dependent, showing IC 50 values of 745 μM after 24 hours. Thymol induced cell death by arresting the cell cycle. In the G 0 /G 1 phase, the number of cells increased considerably. Moreover, Bax overexpression, Bcl-2 downregulation and apoptotic fragmented DNA were observed, which accelerated cell death. It is worth mentioning that thymol upregulates reactive oxygen species (ROS) levels and changes the mitochondrial membrane potential. Elbe et al reported the antitumor activity of thymol on NSCLC KLN205 cells. In the KLN205 cell line, thymol suppressed cell proliferation and promoted cell death. Notably, at 72 hours and 400 μM concentration, apoptosis increased at a higher rate than control in the cells. Koparal and Zeytinoğlu found that A549 lung cancer cells treated with 500 and 1000 μM thymol exhibited certain apoptotic features and morphological changes after 24 hours. To summarize, thymol, as a natural chemical, could be used against NSCLC. Ginseng Inhibits Angiogenesis and Relieves Drug Resistance Ginseng is a herb that has been used for millennia in China and East Asia. The steroid ginsenoside, an extract of ginseng, is the main active component responsible for its anticancer properties. , Zhang et al used a multi-center, prospective, randomized, double-blind trial to assess the effectiveness of Rg3 ginsenoside in patients with advanced NSCLC. A total of 414 patients diagnosed with stage III-IV NSCLC were randomized to combined group (ginsenoside Rg3 + chemotherapy) and chemotherapy group (placebo + chemotherapy). The results showed that the combined treatment alleviated adverse side effects. The combined group had a median survival time of 12.03 months, which was longer than the chemotherapy group’s median survival time (8.46 months) ( P < .05). The Karnofsky Performance Scale scores for patients in the combined and chemotherapy groups were 78.95 ± 9.14 and 76.77 ± 9.15, respectively ( P < .05). Previous research has demonstrated that the ginsenoside Rg3 in conjunction with chemotherapy may increase overall survival, improve symptoms and alleviate the bone marrow suppression. Previous studies have demonstrated that ginsenoside Rg3 exerts antitumor effects by controlling exogenous DNA damage. , Proto-oncogenes and cancer suppressor genes play vital roles in DNA damage repair. The stress response of cells to DNA damage is critical for preserving genetic material integrity, avoiding gene mutations and sustaining cell function. , Liu et al showed that ginsenoside Rg3 prevents the destruction of DNA integrity by stimulating the vaccinia-related kinase 1 (VRK1)/P53 binding protein 1 (bp1) signaling pathway. VRK1 is a serine-threonine kinase present in the nucleus, which is involved in DNA repair and cell death following DNA damage. P53 bp1 is a downstream protein associated with the VRK1-mediated DNA damage and repair mechanism. VRK1 can recognize the local distortion of chromatin by phosphorylating specific proteins such as P53 bp1, which triggers downstream cascade signaling. , Ginsenoside Rg3 has been shown to increase chemotherapeutic sensitivity. For instance, combined treatment with ginsenoside Rg3 and osimertinib reduces drug resistance in NSCLC cells ; ginsenoside Rg3 downregulates programed death-ligand 1 to reduce A549/DDP cisplatin resistance ; and ginsenoside Rg3 has the ability to specifically and effectively reverse icotinib resistance in HCC827 and PC-9 cells. These findings suggest that ginsenoside Rg3 may be an effective anti-NSCLC agent. Cinnamaldehyde (CA) Acts Against NSCLC by Inhibiting the Wnt/β-catenin Signaling Pathway CA, an anticancer component found in Cinnamomum cassia , is effective against a diversity of cancer types, including human oral squamous cell carcinoma and colon cancer. , Wu et al reported that CA exerts cytotoxicity in NSCLC cells, particularly in the A549, YTMLC-90 and NCI-H1299 cell lines, in which the IC 50 was 41.02, 32.30, and 10.50 g/ml, respectively. CA increased Bax gene and protein expression but decreased Bcl-2 and Bcl-xl expression. CA increases E-cadherin and inhibits N-cadherin to block cell motility via reversing the epithelial-mesenchymal transition (EMT). Animal and cell studies demonstrated that CA promote apoptosis by inhibiting the Wnt/β-catenin signaling pathway, as evidenced by reduced expression of β-catenin. Tumor volume and weight decreased in A549-bearing mice following CA treatment. A recent study showed that CA regulated the Wnt/β-catenin signaling pathway via circular RNA Homo sapiens circ 0043256, which induced NCI-H460 and A549 cell death. Hong et al reported that CA inhibits invasive by downregulating MMP-2 and MMP-9. Park and Baek demonstrated that CA and hyperthermia arrest the cell cycle, increase ROS and up-regulate pro-apoptotic protein levels to generate significant cytotoxicity in A549. In addition, the Food and Drug Administration has approved CA as a food ingredient. Eupatolide and Piperlongumine Act Against NSCLC by Suppressing STAT3 Signaling Eupatolide is a new type of terpenoid extracted from the Chinese medicinal plant Inula helenium . Research has reported that eupatolide may have inflammatory, analgesic, and antimicrobial activity. The action of eupatolide against neoplasms has gained the interest of researchers. Cisplatin and 5-fluorouracil are 2 drugs commonly used for NSCLC treatment. Previous studies reported that eupatolide markedly increases NSCLC cell chemosensitivity to cisplatin and 5-fluorouracil. Eupatolide may promote A549 and H1975 cell death by downregulating Bcl-2 and myeloid leukemia 1. In nude mice injected with A549 and H1975 cells, oral eupatolide therapy reduce tumor volume for 3 weeks. In addition, eupatolide suppresses STAT3 signaling to promote apoptosis in NSCLC cells. Persistent stimulation of STAT3 signaling may cause cancer cells aberrant proliferation and malignant transformation. Additionally, eupatolide was not toxic. Thus, it is likely to be a potential drug for adjuvant antitumor therapy. Piperlongumine, which is isolated from Piper longum L., exhibits anticancer activity in numerous carcinomas. - Piperlongumine inhibits the phosphorylation and degradation of IκBα, reducing NF-κB p50 and p65 subunit phosphorylation in NSCLC cells. In addition, piperlongumine (15 μM) downregulates Bcl-2 and upregulates Bax, cleaved caspase-3 and cleaved caspase-8 in A549/NCI-H460. In A549 xenografts it was shown that cleaved caspase-3, cleaved caspase-8 and Bax levels increased, while Bcl-2 levels decreased. Profilin-1 (PFN1) belongs to the actin-binding protein family. PFN1 has been demonstrated to affect cell migration and apoptosis. Using a wound-healing assay, Gagat et al demonstrated that piperlongumine suppresses PFN1 to inhibit migration in A549. Piperlongumine dose-dependently inhibited proliferation and induced cell death. The concentration of piperlongumine at which IC50 was observed was 10.64 μM. Lewis et al reported that piperlongumine lowered phosphorylated STAT3 levels and decreased anti-apoptotic protein targets (Bcl-2, Bcl-xl, and cyclin D1). In addition, piperlongumine reduced STAT3 downstream transcriptional targets and suppressed tumor volume. These studies suggest that piperlongumine may become an active anticancer compound. In addition to these herbal extracts, Ophiopogon saponin C1, kaempferol, and cordycepin are effective against NSCLC. Ophiopogon saponin C1 exerts antitumor effects by modulating kinase activity and blocking the cell cycle to alter the tumor microenvironment. Kaempferol, a natural flavonoid, is mainly found in tea, grapes, berries, and cruciferous vegetables. This compound plays an antitumor role primarily by modulating the level of Bcl-2 family proteins that trigger apoptosis. Cordycepin acts as an antitumor agent by blocking the cell cycle at G 0 /G 1 and by affecting protein expression in the H1975 and PC9 cell lines.   Thevebioside (THB ) , a monomer from Thevetia peruviana (Pers.) K. Schum. (TPKS), may have pharmacological effects. THB has shown anti-inflammatory effects on skin diseases. Researchers have found that THB exerts the most cytotoxic activity in p53 wild-type A549 and H460 cell lines in a dose and time-dependent manner. THB has been shown to hinder the proliferation of NSCLC by triggering apoptosis, as indicated by increasing the Bad, cleaved caspase-3 and cleaved PARP expression, and reducing the expression of Bcl-xl. In addition, animal and cell studies have demonstrated that THB promotes apoptosis by inhibiting the steroid receptor coactivator-3 (SRC-3)-induced insulin like growth factor 1 receptor (IGF1R)−P13K-AKT signaling pathway. SRC1, SRC2 and SRC-3 are members of a transcription coactivator family. Elevated SRC-3 expression is frequently associated with tumor progression. , THB has also exhibited promising pharmacological safety, with low inhibition of normal lung epithelial cells, as well as no observable harm to the organs of A549-bearing mice. THB is a low-toxicity natural product extract that may be employed as an adjuvant medication in lung cancer. Sesamin is a lignan abundant in Sesamum indicum . Sesamin has antihypertension, antithrombosis, and antitumor pharmacodynamic activities. - Sesamin modulates the AKT/P53 signaling pathway, mainly inhibits AKT activity, and downregulates cyclin D1 and CDK2 in A549 and H1792 lung cancer cells. In a previous study, sesamin suppressed AKT/PI3K signaling by downregulating cyclooxygenase 2, leading to G 1 phase cell arrest, and down-regulating Bcl-2, Bax and cyclin E1 gene expression. Yang et al showed that sesamin causes an increase in the production of ROS in A549 cells and loss of the mitochondrial membrane potential. Sesamin-treated A549 cells promote the expression of apoptosis-related proteins (cleaved caspase-3, caspase-9, cytochrome c and Bax/Bcl-2). Sesamin stimulated mitophagy in A549 cells via the ROS-mediated PTEN-induced kinase 1 (PINK1)/Parkin signaling pathway, increased Parkin levels in mitochondria and whole cells, and reduced Parkin levels in the cytoplasm. Cyclosporine A, a mitotic inhibitor, abolishes sesamin’s inhibitory effect on A549. Sesamin may therefore be a suitable NSCLC adjuvant. Jervine is a steroid alkaloid from Veratrum rhizome . Jervine exhibited a dose and time-dependent inhibition of proliferation and colony formation. Jervine promotes the expression of LC3 to induce autophagy and activates caspase-3 to promote apoptosis. Bafilmycina1, an autophagy inhibitor, can abolish the jervine-mediated suppression of human lung cancer cell proliferation. Transformation of cytosolic LC3 (LC3-I) into autophagy, the vesicle-associated form (LC3-II) bound by phosphatidylethanolamine, is essential for inducing autophagy. The AKT/mTOR and hedgehog signaling pathways are usually strongly suppressed in multiple cancer cells. , Jervine acts against NSCLC by suppressing hedgehog and AKT signaling. Treatment with jervine effectively suppressed the AKT/mTOR and hedgehog signaling pathways by decreasing the expression of AKT, patched 1, sonic hedgehog, GLI family zinc finger 1 and smoothened, frizzled class receptor. Notably, jervine inhibited tumor growth in A549 tumor-bearing mice. Therefore, jervine may become a potential drug for lung cancer treatment.   Thymol can be found in various plants, including Ocimum gratissimum L. and Satureja thymbra L. Thymol is a naturally occurring monoterpene phenol. A previous study has demonstrated that thymol has important pharmacodynamic effects in antibacterial, antioxidant and analgesic applications. In addition, researchers have found that thymol exerts cytotoxic effects in multiple types of cancer. - Balan et al demonstrated that thymol’s antiproliferative activity on A549 cells was dose and time-dependent, showing IC 50 values of 745 μM after 24 hours. Thymol induced cell death by arresting the cell cycle. In the G 0 /G 1 phase, the number of cells increased considerably. Moreover, Bax overexpression, Bcl-2 downregulation and apoptotic fragmented DNA were observed, which accelerated cell death. It is worth mentioning that thymol upregulates reactive oxygen species (ROS) levels and changes the mitochondrial membrane potential. Elbe et al reported the antitumor activity of thymol on NSCLC KLN205 cells. In the KLN205 cell line, thymol suppressed cell proliferation and promoted cell death. Notably, at 72 hours and 400 μM concentration, apoptosis increased at a higher rate than control in the cells. Koparal and Zeytinoğlu found that A549 lung cancer cells treated with 500 and 1000 μM thymol exhibited certain apoptotic features and morphological changes after 24 hours. To summarize, thymol, as a natural chemical, could be used against NSCLC.   Ginseng is a herb that has been used for millennia in China and East Asia. The steroid ginsenoside, an extract of ginseng, is the main active component responsible for its anticancer properties. , Zhang et al used a multi-center, prospective, randomized, double-blind trial to assess the effectiveness of Rg3 ginsenoside in patients with advanced NSCLC. A total of 414 patients diagnosed with stage III-IV NSCLC were randomized to combined group (ginsenoside Rg3 + chemotherapy) and chemotherapy group (placebo + chemotherapy). The results showed that the combined treatment alleviated adverse side effects. The combined group had a median survival time of 12.03 months, which was longer than the chemotherapy group’s median survival time (8.46 months) ( P < .05). The Karnofsky Performance Scale scores for patients in the combined and chemotherapy groups were 78.95 ± 9.14 and 76.77 ± 9.15, respectively ( P < .05). Previous research has demonstrated that the ginsenoside Rg3 in conjunction with chemotherapy may increase overall survival, improve symptoms and alleviate the bone marrow suppression. Previous studies have demonstrated that ginsenoside Rg3 exerts antitumor effects by controlling exogenous DNA damage. , Proto-oncogenes and cancer suppressor genes play vital roles in DNA damage repair. The stress response of cells to DNA damage is critical for preserving genetic material integrity, avoiding gene mutations and sustaining cell function. , Liu et al showed that ginsenoside Rg3 prevents the destruction of DNA integrity by stimulating the vaccinia-related kinase 1 (VRK1)/P53 binding protein 1 (bp1) signaling pathway. VRK1 is a serine-threonine kinase present in the nucleus, which is involved in DNA repair and cell death following DNA damage. P53 bp1 is a downstream protein associated with the VRK1-mediated DNA damage and repair mechanism. VRK1 can recognize the local distortion of chromatin by phosphorylating specific proteins such as P53 bp1, which triggers downstream cascade signaling. , Ginsenoside Rg3 has been shown to increase chemotherapeutic sensitivity. For instance, combined treatment with ginsenoside Rg3 and osimertinib reduces drug resistance in NSCLC cells ; ginsenoside Rg3 downregulates programed death-ligand 1 to reduce A549/DDP cisplatin resistance ; and ginsenoside Rg3 has the ability to specifically and effectively reverse icotinib resistance in HCC827 and PC-9 cells. These findings suggest that ginsenoside Rg3 may be an effective anti-NSCLC agent.   CA, an anticancer component found in Cinnamomum cassia , is effective against a diversity of cancer types, including human oral squamous cell carcinoma and colon cancer. , Wu et al reported that CA exerts cytotoxicity in NSCLC cells, particularly in the A549, YTMLC-90 and NCI-H1299 cell lines, in which the IC 50 was 41.02, 32.30, and 10.50 g/ml, respectively. CA increased Bax gene and protein expression but decreased Bcl-2 and Bcl-xl expression. CA increases E-cadherin and inhibits N-cadherin to block cell motility via reversing the epithelial-mesenchymal transition (EMT). Animal and cell studies demonstrated that CA promote apoptosis by inhibiting the Wnt/β-catenin signaling pathway, as evidenced by reduced expression of β-catenin. Tumor volume and weight decreased in A549-bearing mice following CA treatment. A recent study showed that CA regulated the Wnt/β-catenin signaling pathway via circular RNA Homo sapiens circ 0043256, which induced NCI-H460 and A549 cell death. Hong et al reported that CA inhibits invasive by downregulating MMP-2 and MMP-9. Park and Baek demonstrated that CA and hyperthermia arrest the cell cycle, increase ROS and up-regulate pro-apoptotic protein levels to generate significant cytotoxicity in A549. In addition, the Food and Drug Administration has approved CA as a food ingredient.   Eupatolide is a new type of terpenoid extracted from the Chinese medicinal plant Inula helenium . Research has reported that eupatolide may have inflammatory, analgesic, and antimicrobial activity. The action of eupatolide against neoplasms has gained the interest of researchers. Cisplatin and 5-fluorouracil are 2 drugs commonly used for NSCLC treatment. Previous studies reported that eupatolide markedly increases NSCLC cell chemosensitivity to cisplatin and 5-fluorouracil. Eupatolide may promote A549 and H1975 cell death by downregulating Bcl-2 and myeloid leukemia 1. In nude mice injected with A549 and H1975 cells, oral eupatolide therapy reduce tumor volume for 3 weeks. In addition, eupatolide suppresses STAT3 signaling to promote apoptosis in NSCLC cells. Persistent stimulation of STAT3 signaling may cause cancer cells aberrant proliferation and malignant transformation. Additionally, eupatolide was not toxic. Thus, it is likely to be a potential drug for adjuvant antitumor therapy. Piperlongumine, which is isolated from Piper longum L., exhibits anticancer activity in numerous carcinomas. - Piperlongumine inhibits the phosphorylation and degradation of IκBα, reducing NF-κB p50 and p65 subunit phosphorylation in NSCLC cells. In addition, piperlongumine (15 μM) downregulates Bcl-2 and upregulates Bax, cleaved caspase-3 and cleaved caspase-8 in A549/NCI-H460. In A549 xenografts it was shown that cleaved caspase-3, cleaved caspase-8 and Bax levels increased, while Bcl-2 levels decreased. Profilin-1 (PFN1) belongs to the actin-binding protein family. PFN1 has been demonstrated to affect cell migration and apoptosis. Using a wound-healing assay, Gagat et al demonstrated that piperlongumine suppresses PFN1 to inhibit migration in A549. Piperlongumine dose-dependently inhibited proliferation and induced cell death. The concentration of piperlongumine at which IC50 was observed was 10.64 μM. Lewis et al reported that piperlongumine lowered phosphorylated STAT3 levels and decreased anti-apoptotic protein targets (Bcl-2, Bcl-xl, and cyclin D1). In addition, piperlongumine reduced STAT3 downstream transcriptional targets and suppressed tumor volume. These studies suggest that piperlongumine may become an active anticancer compound. In addition to these herbal extracts, Ophiopogon saponin C1, kaempferol, and cordycepin are effective against NSCLC. Ophiopogon saponin C1 exerts antitumor effects by modulating kinase activity and blocking the cell cycle to alter the tumor microenvironment. Kaempferol, a natural flavonoid, is mainly found in tea, grapes, berries, and cruciferous vegetables. This compound plays an antitumor role primarily by modulating the level of Bcl-2 family proteins that trigger apoptosis. Cordycepin acts as an antitumor agent by blocking the cell cycle at G 0 /G 1 and by affecting protein expression in the H1975 and PC9 cell lines.   Traditional herbal prescriptions are usually composed of >2 types of herbal medicine. The ingredients of herbal remedies are complex, but their rich active ingredients exert immunomodulatory and antitumor effects. Herbal prescriptions have been shown to act on different signaling pathways in vivo and in vitro to exert anti-NSCLC effects . Maimendong and Qianjin Weijing decoction are oriental prescriptions for treating “pulmonary carbuncles,” as recorded in traditional Chinese medicine classic books over 1000 year ago. Maimendong and Qianjin Weijing decoction are composed of 8 Chinese medicinal herbs: Ophiopogonis Radix, Ginseng Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma, Pinelliae Rhizoma, Phragmites Rhizoma, Coicis Semen, Benincasa hispida , and Persicae Semen . In modern pharmacological trials, Maimendong and Qianjin Weijing decoction was able to suppress cell proliferation and induce NSCLC cell death. , Jiang et al showed that Maimendong and Qianjinweijing decoction acted on the Wnt signaling pathway to induce the expression of microRNA (miR)-149-3p and inhibit the expression of may-associated zinc-finger protein (MAZ), c-Myc and cyclin D1, thus inhibiting NSCLC cell metastasis. A study reported a significant inhibitory effect of Maimendong and Qianjin Weijing decoction combined with cisplatin on A549 xenografts in nude mice, mainly through inhibition of p-AKT and p-PTEN expression and down-regulated Bcl-2. A clinical study revealed that Maimendong decoction combined with cisplatin was more effective than cisplatin alone in 19 patients with NSCLC. Jinfukang (JFK) decoction (JFKD) is an herbal prescription approved by the Food and Drug Adiministration for NSCLC therapy. JFK is composed of 12 herbs, including Radix astragali, Radix glehniae, Radix asparagi, Fructus ligustrum Lucidi, Herba selaginella, Rhizoma paradise yunnanensis, Folium epimedii, Herbal gynostemmatis, Fructus corni, Herba salviae chinensis, Radix Ophiopogon , and Semen trigonella . Lu et al stated that JFKD prescriptions may be associated with Fas and DR4 activation to cause apoptosis. Research has shown that JFK prescriptions act as tumor inhibitors in human lung cancer cells by blocking cancer cells due to its inhibitory effect on DNA. In addition, clinical reports have shown that JFKD combined with cisplatin chemotherapy prolongs survival in patients with stage II/III NSCLC, improves immune parameters and reduces cisplatin-related side effects. - Buzhong Yiqi (BZYQ) decoction (BZYQD) first appeared in the book “Spleen and Stomach Theory” by Li Dongyuan >700 years ago, which focused on prescriptions for treating visceral ptosis, chronic gastrointestinal diarrhea, and other spleen and stomach diseases. Previous studies reported that high concentrations of BZYQ can cause gastric cancer and ovarian neoplasm tumor cell death by regulating apoptosis. BZYQ contains 8 herbs: Astragali Radix, Glycyrrhizae Radix, Codonopsis Radix, Angelicae Sinensis Radix, Citri Reticulatae Pericarpium, Cimicifugae Rhizoma, Bupleuri Radix , and Atractylodis Macrocephalae Rhizoma . Gou et al confirmed that BZYQD could reduce gastrointestinal damage by inhibiting the expression of inflammatory cytokines. Moreover, BZYQD reduces kidney damage in mice through antioxidant mechanisms. Yu et al demonstrated that BZYQ could reduce the resistance of the A549/DDP cell line to cisplatin, making the A549/DDP cell line more sensitive to chemotherapy. Previous clinical studies showed that BZYQ combined with conventional chemotherapy drug effectively improved patient symptoms and systemic inflammation. Additionally, BZYQ prescriptions can alleviate fatigue caused by the chemotherapeutic drug paclitaxel and improve lung cancer survival. - WenXiaChangFu (WXC), a commercial herbal prescription, comprises Aconiti Lateralis Radix Praeparata, Ginseng, Angelicae Sinensis Radix , and Rhei Radix et Rhizoma . Ji et al reported that WXC mitigated cisplatin resistance by inducing cell death. Previous studies have indicated that WCF acts on the A549 cell line, and in a nude mouse model, it can inhibit the integrin β/PI3K/AKT signaling pathway to reverse drug resistance. Previous studies revealed that WXC prescriptions with cisplatin may effectively suppress tumors by block the cell cycle and induce apoptosis. , Lianjia Sanjie decoction (LJSJD) is a composition of 14 herbs mainly used as a lung cancer adjuvant therapy, including Scutellariae Radix, Trionycis Carapax, Sarcandrae Herba, Ranunculus terminates Thunb, Adenophorae Radix, Glehniae Radix, Pseudostellariae Radix, Ophiopogonis Radix, Asparagi Radix, Rubia cordifolia, Pinelliae Rhizoma, Hedyotidis Herba, Bombyx Batryticatus , and Inula japonica . Wang et al showed that LJSJD prescriptions had a pronounced cytotoxic effect on A549, H460, H1650 and H1975 cells. Additionally, LJSJD prescriptions could inhibit EGFR mutations and stimulate the expression of P53. LJSJD prescriptions have been shown to mitigate gefitinib drug resistance in lung cancer cell lines. BuFei decoction (BFD) is a conventional Chinese medicine prescription formulated to treat lung cancer. The medicinal ingredients of BFD include Codonopsis pilosula, Schisandra chinensis, Rehmannia glutinosa, Astragalus, Aster , and Cortex Mori . Previous studies showed that BFD inhibits IL-10 and PD-L1 expression to interrupt the association between TAMs and NSCLC cells (A549, H1975). He et al showed that BFD blocks cancer cell metastasis by the Smad signaling pathway, thus inhibiting the TGF-β1-induced EMT process, thereby exerting an antitumor effect. In the clinic, BFD as an adjuvant therapy could mitigate tumor recurrence rates, modulate human immunological functions, and extend the disease-free survival of patients with stage II-IIIA NSCLC. , , In summary, the multicomponent and multitarget effects of traditional herbal prescriptions effectively prevent cancer and overcome drug resistance. The above studies have shown that herbal prescriptions have a potential as adjuvant cancer therapy. Clinical studies should be conducted to explore their mechanism of action.   As NSCLC gradually progresses, the applications of traditional herbal medicine attract increasing attention. Whether in combination with chemotherapy drugs or by alleviating chemotherapy-related adverse side effects in patients with cancer, herbal medicine provides an optional adjuvant treatment for clinicians. Apoptosis is a form of cell death vital for the human body to maintain its proper function and is frequently a major factor in herbal anticancer treatment. Apoptosis occurs via nuclear fragmentation, cell contraction, cell membrane blistering, chromosome DNA breakage and chromatin concentration. , Internal pathways (also known as mitochondrial pathways) and exterior pathways (also called death receptor pathways) participate in the apoptotic process. The mitochondrial pathway primarily involves the Bcl-2 family. The pro-apoptotic Bcl-2 family of proteins can be transported to the mitochondrial outer membrane to secrete pro-apoptotic factors and activate caspase-9, which triggers caspase-3 activation and finally induces apoptosis. Conversely, anti-apoptotic proteins in the Bcl-2 family often act as inhibitors of apoptosis. The exogenous apoptosis pathway activates caspase-8 by enhancing death receptor expression, which directly cleaves or activates downstream caspases to transmit apoptotic signals. Autophagy involves autophagosomes phagocytizing proteins and organelles, and then transporting them to lysosomes. Autophagy can promote tumor proliferation while also causing tumor cell death. Previously, it was reported that puerarin may regulate LC3II/LC3I and autophagy related 5 expression by PI3K/AKT signaling pathways, ultimately inducing the cancer cells autophagic death. Thus, apoptosis and autophagy may be beneficial in preventing and treating NSCLC. Cell proliferation and metastasis are linked to cancer-related mortality and poor prognosis. Tumor metastasis is the product of cell biological processes involving numerous aspects, such as cell adhesion, extracellular matrix degradation, tumor cell migration and invasion. It has been shown that, in NSCLC, brain and liver are common tumor metastatic organs. Herbal extracts have been reported to exhibit potential efficacy in inhibiting neoplasm metastasis. Marine-mediated inhibition neoplasm metastasis is generally associated with the migration-related gene paired box 2 (PAX2). Patients with cancer often have high expression levels of the PAX2 gene. Overexpression of the PAX2 gene may contribute to tumorigenesis, but it may be a useful tumor marker. The cell cycle is divided into 4 phases: G 1 , S, G 2 , and M. Inhibiting the cell cycle can block tumor progression. Herbal extracts such as praeruptorin C block the cell cycle and induce cell death by controlling cyclin D1 and p21 proteins. Polyphyllin D induces G0/G1 cell cycle arrest and downregulates cyclin D1 expressions by upregulating the level of sex-determining region Y-box 7 (SOX7) transcription factor. Garg et al reported that SOX7 acts as a tumor suppressor in lung tissue, especially in NSCLC cell lines (H23 and H1299). It was found that stimulating the high expression of SOX7 could significantly induce apoptosis and inhibit cell proliferation. Aberrant activation of signaling pathways is critical in tumor progression. Herbal medicine may selectively interfere with cancer cells at different stages by regulating different signaling pathways, thereby playing an auxiliary antitumor effect. The Wnt signaling pathway is one of the classical signaling pathways, and its mis-regulation is common in NSCLC. The Wnt signaling pathway is responsible for regulating various behaviors associated with tumor cells, including proliferation, invasion, metabolic activity, apoptosis, and inflammation. In orthotopic xenografts, Jiang et al observed that Maimendong and Qianjinweijing prescriptions reduced Wnt target gene expression, particularly miR-149-3p, and thus had an anti-NSCLC effect. CA, the most cytotoxic component in Cinnamomum cassia , blocks NSCLC proliferation by regulating the Wnt signaling pathway. AKT signaling pathway activation is often positively correlated with neoplasm occurrence. AKT signaling pathway is frequently aberrantly activated in lung cancer, leukemia, gastric cancer, and other cancer types, so inhibiting AKT signaling pathway could effectively prevent tumor proliferation and migration. Therefore, targeting the AKT signaling pathway may provide potential anti-NSCLC effects. The NF-κB signaling pathway is crucial in anti-cancer activity, inducing apoptosis, blocking the cell cycle and suppressing the inflammatory response. The formula YangYinWenYang regulates inflammatory cytokine levels and inhibits NF-κB signaling pathway. Zheng et al found that piperlongumine, a potential anti-tumor herbal extracts, blocks NF-κB and DNA binding activity. In conclusion, the common pathways involved in anti-NSCLC are P13K/AKT, Wnt, and NF-κB signaling pathways, which can be inhibited by acting on different targets. Also, herbal medicine inhibits anti-apoptotic protein levels while inducing pro-apoptotic protein expression, leading to cancer cell apoptosis. In addition to the main signaling pathways mentioned above, some herbal extracts or prescriptions use different anti-tumor mechanisms. The herbal extracts also act on the STAT3 signaling pathway and Hedgehog signaling pathway to inhibit NSCLC by regulating these pathways’ upstream and downstream related proteins. STAT3 plays a vital role in human malignancies. It regulates cell apoptosis, cell proliferation, and angiogenesis. On the other hand, STAT3 signaling overexpression promotes drug resistance and induces cell metastasis. Garg et al summarized that several potential natural product-derived small molecules inhibit STAT3 signaling, such as formononetin, zerumbone, garcinol, and others, providing a reference for new drug discovery in the future. The herbal prescriptions inactivate the classical Smad signaling pathway by regulating the expression of TGF-β1. summarizes the study of herbal medicine treatment for NSCLC .   To summarize, herbal medicine has the potential to be used as adjunctive therapy for NSCLC. With the advancement in systems biology, a more profound and systematic knowledge of herbal treatment has been obtained. The practice of herbal medicine has progressively evolved into a medical system based on evidence rather than the practitioner’s own experiences. Herbal medicines inhibit tumor progression and improve chemoradiotherapy sensitivity mainly through the P13K/AKT signaling pathway, Wnt signaling pathway, NF-κB signaling pathway. Additionally, some herbal extracts and prescriptions exert multi-target, pleiotropic effects by regulating related apoptosis proteins (Bad, Bax, Bcl-xl, Bcl-2), ROS levels, and upstream and downstream proteins affecting related pathways. They act to achieve network regulation and ultimately produce tumor-inhibiting effects. In NSCLC treatment, Chinese herbal medicine combined with radio-chemotherapy can improve efficacy, alleviate the toxicity and adverse side effect caused by radio-chemotherapy, and prolong progression-free survival. By reviewing and summarizing these drugs, it is helpful to discover that herbal medicine may be applied as a potential adjunct treatment to NSCLC in the future and provide useful information for the development of effective new drugs. However, there are limitations in the published studies. Research on herbal medicines is still mainly based on cell and animal experiments. Clinical trials are rare in the literature; thus, further studies should be conducted to confirm their safety and efficacy. In conclusion, Chinese herbal medicine inhibits tumor growth through induces apoptosis of tumor cells, inhibits metastasis of cancer cells, reverses the resistance of conventional chemotherapeutic drugs and so on. Clinically, Chinese herbal medicine combined with traditional chemotherapeutic drugs may increase effectiveness and reduce toxicity.   