Clinical Application and Mechanism of Traditional Chinese Medicine in Treatment of Lung Cancer
Lung cancer is one of the most aggressive and life-threatening malignancies worldwide, characterized by rapid proliferation, high metastatic potential, and poor prognosis. It is broadly classified into two major types: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Despite advancements in conventional treatments such as surgery, chemotherapy, and radiation therapy, the overall survival rate for lung cancer patients remains low, with significant side effects often worsening the quality of life (QOL). In recent years, traditional Chinese medicine (TCM) has emerged as a promising adjuvant therapy, offering synergistic effects with conventional treatments, reducing toxicity, and improving patient outcomes. This article explores the clinical applications and mechanisms of TCM in the treatment of lung cancer, based on recent research.
Clinical Applications of TCM in Lung Cancer
TCM in Combination with Chemotherapy
TCM has been widely used as an adjuvant therapy alongside chemotherapy, particularly platinum-based regimens, which are the standard treatment for NSCLC. Studies have shown that TCM can enhance the efficacy of chemotherapy while reducing its side effects. For instance, a study involving 314 NSCLC patients demonstrated that TCM formulas combined with platinum-based chemotherapy significantly alleviated symptoms such as vomiting, fatigue, and pain, while reducing chemotherapy-induced toxicity. Similarly, the Aidi injection, a TCM preparation, was found to improve the disease control rate, objective response rate, and survival rates in NSCLC patients when used alongside platinum-based chemotherapy. Additionally, elemene injection, another TCM preparation, enhanced the clinical efficacy of platinum drugs and improved immune function in patients with advanced NSCLC.
TCM in Combination with Radiation Therapy
Radiation therapy, while effective in killing cancer cells, often damages healthy tissues, leading to adverse effects such as radiation-induced pneumonia and esophagitis. TCM has been shown to mitigate these side effects when used in combination with radiotherapy. For example, the Kushen injection and Zhuye Shigao Granule, when administered alongside radiation therapy, improved the effective rate, QOL, and Karnofsky Performance Status scores in NSCLC patients. These TCM preparations also reduced the incidence of acute radiation pneumonia and bone marrow suppression.
TCM in Combination with EGFR-TKIs
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are a first-line treatment for NSCLC patients with EGFR mutations. However, long-term use of EGFR-TKIs can lead to side effects such as diarrhea and hepatotoxicity. TCM has been shown to enhance the therapeutic effects of EGFR-TKIs while reducing their toxicity. A meta-analysis of 1,159 NSCLC patients revealed that TCM combined with EGFR-TKIs significantly improved the total response rate, QOL, and one-year survival rate compared to EGFR-TKI treatment alone. For instance, the TCM formula Er Chen Tang prolonged progression-free survival in NSCLC patients with EGFR mutations.
TCM as Maintenance Therapy
Maintenance therapy is crucial for preventing relapse in lung cancer patients after first-line treatment. TCM has been increasingly used as a maintenance therapy for advanced NSCLC patients. In a study involving 106 NSCLC patients, TCM maintenance therapy significantly improved the three-month progression-free survival index and QOL compared to the control group. Another study demonstrated that TCM maintenance therapy reduced the serum concentration of soluble cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4), which is associated with tumor progression.
Mechanisms of TCM in Lung Cancer Treatment
Induction of Apoptosis
Apoptosis, or programmed cell death, is a critical mechanism by which TCM exerts its anti-cancer effects. Several TCM monomers and compounds have been shown to induce apoptosis in lung cancer cells through various pathways. For example, cantharidin (CTD), a TCM monomer, induced apoptosis in H460 lung cancer cells by activating caspase-3 and caspase-8, increasing reactive oxygen species (ROS) production, and upregulating pro-apoptotic proteins such as Bax and cytochrome c. Similarly, bufalin, derived from toad venom, induced apoptosis in NCI-H460 lung cancer cells by reducing mitochondrial membrane potential and increasing ROS levels. Cryptotanshinone, isolated from Salvia miltiorrhiza Bunge, promoted apoptosis in A549 lung cancer cells by upregulating p53 and Bax while downregulating Bcl-2.
Induction of Autophagy
Autophagy is another mechanism by which TCM inhibits tumor growth. Autophagy can either suppress or promote cancer cell survival, depending on the context. TCM has been shown to induce protective autophagy in lung cancer cells. For instance, isodeoxyelephantopin (ESI) induced autophagy in lung cancer cells by upregulating autophagy-related proteins such as ATG3, LC3-II, and Beclin1. Glycyrrhetinic acid (GA), derived from licorice, activated the c-Jun N-terminal kinase (JNK) pathway, leading to autophagy in NSCLC cells. Ginkgo biloba exocarp extracts (GBEE) induced autophagy in Lewis lung cancer cells by inhibiting the AMPK/mTOR/p70S6k signaling pathway.
Dual Induction of Apoptosis and Autophagy
Some TCM preparations induce both apoptosis and autophagy in lung cancer cells. For example, Polygonatum odoratum lectin (POL) triggered apoptosis by inhibiting the Akt-NF-κB pathway while inducing autophagy through the suppression of the Akt-mTOR pathway in A549 cells. Marsdenia tenacissima (MTE) induced apoptosis and suppressed autophagy simultaneously in lung cancer cells via extracellular signal-regulated kinase (ERK) activation. Bu-Zhong-Yi-Qi Decoction (BZYQD) induced both apoptosis and autophagy through ROS accumulation and oxidative stress.
Cell Cycle Arrest
TCM can inhibit lung cancer cell proliferation by inducing cell cycle arrest. Ailanthone, a natural compound extracted from Ailanthus altissima, arrested NSCLC cells in the G2/M phase by downregulating RPA1, a protein involved in DNA replication. Matrine, an alkaloid from Sophora flavescens, arrested A549 NSCLC cells in the S and G2/M phases by restoring the expression of miR-126. Xanthatin, derived from Xanthium strumarium L, induced G2/M phase arrest in lung cancer cells by disrupting the NF-κB pathway.
Inhibition of Metastasis
Metastasis is a major cause of mortality in lung cancer patients. TCM has been shown to inhibit lung cancer metastasis by targeting the epithelial-mesenchymal transition (EMT) and related signaling pathways. For instance, Huaier granules suppressed the expression of EMT-related proteins such as N-cadherin and vimentin in lung cancer cells. The Fuzheng Kang-Ai (FZKA) decoction inhibited lung cancer metastasis by downregulating STAT3 and MMP9, proteins involved in tumor invasion and metastasis. The Jin-Fu-An decoction inhibited lung cancer cell migration by downregulating p120-catenin, a protein involved in cell adhesion.
Modulation of Immune Response
TCM can enhance the immune response against lung cancer by modulating immune cell activity. For example, rocaglamide (Roc), derived from the TCM plant Aglaia, improved natural killer (NK) cell-mediated killing of NSCLC cells by inhibiting autophagy. The Feiji Recipe, a classical TCM formula, reduced the percentage of CD4(+) CD25(+) regulatory T cells, enhancing the anti-tumor immune response. The Feiyanning decoction also regulated T cell activity in mice with Lewis lung cancer, reducing tumor growth and improving survival.
Enhancement of Chemotherapeutic Efficacy
TCM can enhance the efficacy of chemotherapy drugs, particularly platinum-based regimens, through multiple mechanisms. Crocin, a compound from saffron, improved the chemosensitivity of lung adenocarcinoma cells to cisplatin by upregulating pro-apoptotic proteins such as p53 and Bax. The Yangyin Fuzheng Decoction enhanced the anti-tumor efficacy of cisplatin in a Lewis lung cancer mouse model by upregulating p53 and Bax while downregulating Bcl-2. The Yu Ping Feng San (YPFS) formula reversed cisplatin-induced multidrug resistance in NSCLC cells by regulating drug transporters via the p62/TRAF6 signaling pathway.
Reduction of Chemotherapy Toxicity
TCM can reduce the toxicity of chemotherapy drugs, improving patient QOL. Dendrobine, derived from Dendrobium nobile, attenuated cisplatin-induced cardiotoxicity in a lung cancer mouse model by inducing pro-apoptotic proteins such as Bim and Bax. The combination of TCM with chemotherapy has been shown to reduce side effects such as weight loss, bone marrow suppression, and gastrointestinal toxicity.
Conclusion
TCM has demonstrated significant potential as an adjuvant therapy in the treatment of lung cancer. Its clinical applications range from enhancing the efficacy of chemotherapy and radiation therapy to serving as a maintenance therapy for advanced NSCLC patients. The mechanisms by which TCM exerts its anti-cancer effects are multifaceted, including the induction of apoptosis and autophagy, cell cycle arrest, inhibition of metastasis, modulation of the immune response, and enhancement of chemotherapeutic efficacy. While TCM primarily plays a supportive role in lung cancer treatment, its ability to reduce toxicity and improve QOL makes it a valuable addition to conventional therapies. Further research is needed to fully elucidate the mechanisms of TCM and to develop standardized treatment protocols for lung cancer patients.
doi.org/10.1097/CM9.0000000000001141
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