Cancer, with the continuously increasing morbidity and mortality, is the second most deadly disease in the world, which seriously threaten people’s life and health. (Fidler et al., 2017). At present, continuous proliferation, invasion and metastasis, angiogenesis and apoptosis resistance have been founded to be closely related to the occurrence and development of cancer (Hisano and Hla, 2019; Wimmer et al., 2020). For example, tumor metastasis is a common process in the development of malignant tumors, in which cancer cells undergo the invasion–metastasis cascade, including five main steps: leaving the primary lesion, passing through blood vessels, spreading through blood circulation and lymphatic circulation, or directly spreading through body cavity, continuing to proliferate and grow in other parts, and eventually forming colonization at a remote site of the body (Mittal, 2018). In this process, occurred autophagy and apoptosis inhibition may equip cancer cells with enhanced ability to divide and proliferate (Dower et al., 2018). In addition, abnormal metabolic and immune escape, as well as changes in the tumor microenvironment, are also considered to be crucial hallmarks of cancer (McGranahan et al., 2017; Counihan et al., 2018; Hinshaw and Shevde, 2019). Currently, many kinds of clinical treatments, including surgery, chemotherapy, radiotherapy, immunotherapy and gene therapy have been applied to treat cancer. (Fesnak et al., 2016; Chen and Mellman, 2017; Chen et al., 2019). However, the limited application scope and severe side effects restrain of above methods make the use of anticancer drugs crucial in treating cancer.

Notably, natural products (referring to natural compounds derived from Traditional Chinese Medicine (TCM) plants and derivatives are not considered herein) constitute an important source of anti-cancer drugs, and about 50% of the anti-cancer drugs currently in use are directly or indirectly derived from natural products, including flavonoids, alkaloids and terpenoids and others (Mondal et al., 2019; Deng et al., 2020; Kopustinskiene et al., 2020). Over the past two decades, a large number of natural anti-cancer products have been extracted, isolated and purified from Chinese herbal medicines. For example, paclitaxel, extracted from the bark of Taxus chinensis, is recognized as one of the most potent and broad-spectrum anti-cancer drugs especially for advanced, metastatic ovarian cancer, breast cancer, lung cancer (Abu Samaan et al., 2019; de Goeje et al., 2019; Zhu and Chen, 2019; Lau et al., 2020). Recently, accumulating evidences have shown that compounds derived from natural products could regulate various targets and signaling pathways and displayed great therapeutic potential in cancer. Curcumin, a polyphenolic compound mainly extracted from Curcuma longa, Curcuma zedoaria and Acorus calamus L., has been shown to induce autophagy through 5'AMP-activated protein kinase (AMPK) activation, resulting in the degradation of Akt, thereby inhibiting cell proliferation and migration of human breast cancer MDA-MB-231 cells (Guan et al., 2016). Additionally, curcumin induces apoptosis and autophagy in human non-small cell lung cancer A549 cells by inhibiting the phosphatidylinositol 3 kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway (Liu et al., 2018). Berberine, an isoquinoline alkaloid, induces autophagic cell death in cancer cells by increasing the level of Glucose regulated protein 78 (GRP78) and enhancing its ability to bind to vacuolar protein sorting 34(VPS34) (La et al., 2017). Berberine also inhibits the epithelial mesenchymal transformation of mouse melanoma B16 cells through PI3K/Akt pathway (Kou et al., 2016). Moreover, ursolic acid, isolated from Spreng (bearberry), Rhododendron hymenanthes Makino, Eriobotrya japonica, etc., plays an anti-cancer role in human ovarian cancer cells through apoptosis induction, cell cycle arrest and down-regulation of PI3K/AKT pathway, which is mediated by reactive oxygen species (Ros) and matrix metalloprotein (MMP). Interestingly, monomer compounds isolated from natural products can also be used as lead compounds for the synthesis of anticancer drugs. Through structural modification, they eventually play an important role in the treatment of many malignant tumors such as breast cancer, cervical cancer and leukemia, and greatly promote the development of new candidate drugs. (Rodrigues et al., 2016; Spradlin et al., 2019; Wang et al., 2019; Patel et al., 2020).

Currently, a few traditional Chinese medicine web servers are available online to facilitate resource search, such as and Traditional Chinese Medicine database (TCM-database) and Traditional Chinese Medicine Systems Pharmacology database and Analysis Platform (TCMSP). However, few databases of natural anti-cancer products have been constructed, and the existing databases only constitute the framework of active ingredient-targets-disease, while no databases holds a systematic summary of the specific mechanism of natural products against cancer. (Zhang et al., 2019). Thus, we have constructed an online database, ACNPD, focusing on the information of compounds (referring to natural compounds derived from Traditional Chinese Medicine (TCM) plants) and their pharmacological mechanisms. ACNPD is expected to help deepen the understanding of the intricate molecular mechanism of natural products in treating cancer, with a view to providing new clues for the development of anticancer drugs.

Cancer, also known as malignant tumor, is characterized by cells with abnormal proliferation, which is caused by mutated genes generated by external and internal factors. Hitherto, malignant tumors have been threatening human health in modern society. Recently, with the continuous upgrading of tumor biology and the emergence of drug problems such as anti-cancer drug resistance in clinical use, it is urgent to develop novel anti-cancer drugs. Notably, natural products, with their potent anti-cancer effectiveness and abundant resources, have become the top priority of anti-cancer drug research and development.

Accumulating evidence has indicated that small-molecule compounds derived from natural plant products inhibit cell proliferation, metastasis, and invasion, regulate cell cycle, and induce cell apoptosis in various types of cancer through different targets and signaling pathways. For example, a large group of natural products, flavonoids, display pro-apoptosis effect, with Genistein, which acts on the p53 non-apoptotic pathway, and quercetin, which acts on the cytochrome C pathway. (Safarzadeh et al., 2014; George et al., 2018). Resveratrol inhibits the metastasis of cancer cells by down-regulating the expression of MMP-2, 9 by inhibiting the c-Jun N-terminal kinase (JNK) pathway (Bae et al., 2017). Quercetin, shikonin, and nobiletin are also demonstrated to inhibit cancer metastasis through suppressing MMP. (Jang et al., 2014). In addition, many compounds, including evodiamine, oridonin and jaceosidin, act on the PI3K/Akt pathway, which is a common inflammatory and cancer transformation pathway. Phosphorylation of its substrate GSK-3β can inhibit the translocation of Bax and the degradation of Bcl-2, leading to apoptosis inhibition of cancer cells (Mohan et al., 2016; Woo and Kwon, 2016). Arctigenin, a lignanolids isolated from Arctium lappa L. inhibits the angiogenesis through downregulating MMP-2, MMP-9 and heparinase (Lou et al., 2017). In recent years, emerging research suggested that the number and diversity of therapeutic targets in cancer far exceeds the oncogenes identified so far, expanding the understanding of cancer biology and corresponding therapeutic strategies (Hahn et al., 2021). In addition to traditional anti-cancer targets, natural products have also been found to act on several emerging targets, including targeted inhibition of histone deacetylase (HDAC), targeted inhibition of heat shock protein HSP90, targeted glycolysis, and others (Palermo et al., 2005; Yoon and Eom, 2016). Although natural products have unique anti-cancer properties, there is a lag in the construction of relevant mechanism databases, thus, the development of ACNPD has broad application prospects and far-reaching practical significance.

Importantly, ACNPD is an online webserver that provides users with the pharmacological mechanisms of natural anti-cancer products. The database contains 10 common cancer types, 521 compounds, 131 pharmacological pathways, including PI3K/Akt, STAT3, PI3K/Akt/mTOR, Wnt/β-catenin and other signaling pathways. The web interface allows users to query related information in a variety of ways, providing basic chemical information, such as IUPAC Name and CAS number, and detailed pharmacological mechanisms of natural compounds. Importantly, we divided the pharmacological effects in a more detailed way and provided the signaling pathways involved, which is a supplement to the previous database and helps users to obtain information quickly and intuitively. At present, ACNPD only contains 10 common cancer types with high incidence, and the number of compounds remains to be expanded. With the extraction and separation of more natural products and the in-depth study of their pharmacological mechanism, we will continue to expand the scope of cancer and add new natural compounds to update ACNPD.

In summary, we believe that ACNPD is a valuable database to fill the gaps between the therapeutic mechanism and natural anti-cancer products. The database is expected to help study the biological function and pharmacological activity of natural products in cancer, break the development bottleneck between natural anticancer compounds and modern anticancer drugs, and usher in a promising prospect for the innovative anticancer drugs.