Research progress on natural products targeting tumor angiogenesis
Traditional cancer treatment mainly inhibits or kills tumor cells by acting on different stages of their growth. Although significant results have been achieved, it is prone to drug resistance and serious adverse reactions. In 1971, Folkman et al. reported in detail the important role of angiogenesis in tumor growth and metastasis, and proposed the hypothesis of controlling tumor cell growth by inhibiting angiogenesis, which provided new ideas for tumor treatment. Angiogenesis is a complex process of growing or splitting new blood vessels from existing ones, which is related to many pathological processes and is one of the top ten characteristics of solid tumors. It is also a therapeutic target for various cancers such as lung cancer, liver cancer, kidney cancer, rectal cancer, and ovarian cancer. Recent studies have shown that tumor growth and metastasis rely on the oxygen and nutrients provided by neovascularization. If tumor angiogenesis is inhibited, the tumor will enter a “dormant state”, and the proliferation rate and mortality rate of tumor cells will reach a balance. Therefore, inhibiting angiogenesis can suppress tumor growth and metastasis by cutting off the nutrient source and oxygen delivery to tumor cells.

The process of tumor angiogenesis is regulated by multiple angiogenic factors and inhibitory factors. Once the balance between the two is disrupted, the “angiogenesis switch” is activated, and the tumor begins to generate new blood vessels. Among them, vascular endothelial growth factor (VEGF) is currently found to be the most effective specific promoter of angiogenesis, which can be secreted by various cells such as tumor cells, endothelial cells, and stromal cells. VEGF and vascular endothelial growth factor receptor (VEGFR) play a key role in tumor angiogenesis. When VEGF binds to VEGFR, it can activate downstream pathways such as PI3K/Akt, PTEN/Akt, Akt/mTOR, NF – κ B, and MAPK/ERK, causing proliferation, differentiation, and migration of endothelial cells and promoting tumor angiogenesis. In addition, there are many other angiogenic factors, such as platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hypoxia inducible factor-1 (HIF-1), angiopoietin (ANG), insulin-like growth factor (IGF), matrix metalloproteinases (MMP), and tumor necrosis factor (TNF). Among them, PDGF family ligands bind to platelet-derived growth factor receptor (PDGFR) and activate downstream Ras/MAPK, JAK/STAT, NF – κ B signaling pathways, triggering ERK1/2 phosphorylation, promoting the secretion of angiogenic factors such as ANG and VEGF, stimulating endothelial cell proliferation, and participating in regulating vascular maturation and tumor cell migration. FGF and fibroblast growth factor receptor (FGFR) can not only regulate the growth and differentiation of normal cells, but also promote tumor vascular density and permeability, and work together with VEGF to induce angiogenesis. Previous studies have reported that expressing FGF can activate downstream signaling pathways such as Ras/MAPK, PI3K/Akt, and PKC to promote tumor cell proliferation, differentiation, and angiogenesis. The synergy between PDGF, FGF, and VEGF is considered an important process in angiogenesis and metastasis. In addition, the activity level of HIF-1 in tumor cells is closely related to its invasion, metastasis, angiogenesis, and treatment resistance. Under hypoxic conditions, the PI3K/Akt and Ras/Raf/MAPK pathways are activated in tumor cells, inducing the synthesis of HIF-1 α protein. At the same time, HIF-1 α and HIF-1 β can bind to form HIF-1 heterodimers, which bind to HRE elements in the promoter/enhancer regions of target genes, thereby participating in the transcription of angiogenesis related genes such as VEGF and promoting tumor angiogenesis. With the in-depth study of the regulatory mechanism of tumor angiogenesis by scientists, it has been found that blocking the binding of angiogenic factors to their specific receptors, inhibiting their signaling pathway activation in endothelial cells, and thereby inhibiting the invasion, migration, and reduction of vascular permeability of endothelial cells are the main mechanisms of inhibiting tumor angiogenesis. Therefore, by blocking the generation of tumor blood vessels, the nutritional supply to tumor cells can be cut off, thereby inhibiting the occurrence and development of tumors. At present, targeted angiogenesis therapy has become an important strategy for tumor treatment and has broad clinical application prospects.

In recent years, with the increasing cost and longer development cycle of chemically synthesized drugs, the success rate has significantly decreased, especially the emergence of drug resistance issues, which greatly limits the clinical application and efficacy of anti-tumor drugs. Natural products (NPs) have become the main source of new drug development due to their novel and diverse structures, low toxicity and side effects, strong biological activity, unique mechanisms of action, and wide range of targets, and have received widespread attention from scientists. In 1804, Friedrich isolated pure morphine from poppies, pioneering the study of NPs. NPs refer to low molecular weight organic compounds produced by organisms in nature with special biological functions. NPs have always been a source of lead compounds in drug development, especially in anti-cancer and antibacterial drugs. Most prescription drugs approved by the US Food and Drug Administration (FDA) or the European Medical Agency (EMA) are developed based on natural products or their derivatives, such as the anti-cancer natural product paclitaxel, which was approved by the FDA in December 1992 for second-line treatment of ovarian cancer, and its derivative docetaxel, which was also approved by the FDA in May 1996, for the treatment of breast cancer, local late stage after platinum treatment failure, or metastatic non-small cell lung cancer, metastatic gastric cancer, and head and neck squamous cell cancer; Vincris, which was approved by FDA for marketing in July 1988, is used to treat bladder cancer and other blood and solid cancers, including Hodgkin’s Lymph; Camptothecin derivatives have also been approved for market by the FDA, such as Topotecan (Hycamtin), which was approved by the FDA in 1996 for first-line treatment of small cell lung cancer (SCLC) on February 25, 2011, and Irinotecan (Camptosar, Onifyde), which was approved by the FDA for first-line treatment of metastatic colorectal cancer on June 14, 1996; The domestically developed anti-tumor new drug ginsenoside Rg3 obtained the CFDA new drug certificate in 2000. In addition, new camptothecin derivatives such as DX-8951f, GG211, CKD-602, ST1481, BNP-1350, BN80915, etc. are still under further research and development, and some have been approved for clinical trials.

This article will focus on the research progress of natural products with anti-tumor angiogenesis activity, and classify their targeted angiogenesis factors (see Table 1). I hope to provide theoretical basis for the discovery and development of anti-tumor drugs targeting angiogenesis, as well as research on combination targeted therapy.

With the in-depth study of the important physiological functions played by angiogenesis in the development of tumors in recent years, as well as the molecular mechanisms underlying the inhibition of tumor angiogenesis by targeted angiogenic factors. It has been reported that after using targeted angiogenic factor drugs for a period of time, some subjects may develop treatment resistance and develop drug resistance. The currently discovered mechanisms of resistance to anti angiogenic therapy include inducing EMT, promoting cancer cell spread and metastasis, and inhibiting angiogenesis in normal tissues. In addition, activation of other angiogenesis related factors such as MMP-9, HIF-1, etc. during anti VEGF therapy may also lead to drug resistance. The existence of these issues greatly limits the clinical efficacy of anti-tumor angiogenesis drugs.

Compared to chemically synthesized drugs, natural products have unique advantages such as diverse structures, multiple components, and multiple targets, making them more effective than drugs that only target certain angiogenic factors. Meanwhile, natural products have minimal toxic side effects and good tolerance, making them an important direction for the development of new drugs. In recent years, an increasing number of natural products with anti angiogenic activity have been discovered and developed as potential targeted anti-tumor drugs. However, there are still many problems such as difficulties in extraction and processing due to the complexity of active ingredients in natural products, and unclear mechanisms of action. Therefore, by (1) modifying the structure, utilizing computer-aided design technology and novel drug delivery techniques to optimize the defects of natural products, and providing reference and assistance for the development of targeted angiogenesis drugs based on natural products; (2) Utilizing high-throughput screening, genomic analysis, and other methods to discover more natural products targeting angiogenesis, and conducting in-depth research on their active ingredients and mechanisms of action; (3) In clinical practice, the efficacy can be improved by combining natural products with radiotherapy and chemotherapy. Nowadays, the natural world has abundant natural product resources. How to develop and utilize these resources more reasonably to maximize their effectiveness still requires the joint efforts of researchers in future research.