Introduction

In recent decades, significant advances in recognizing the molecular mechanisms of cancer biology have facilitated the discovery of numerous anticancer drugs, positioning chemotherapy as a primary modality in conventional cancer therapy1. Anticancer drugs are widely used in clinical practice. However, monotherapy still faces various challenges, such as limited therapeutic effect2 adverse drug reaction3 and acquired drug resistance4. Therefore, combination therapy is regarded as a promising strategy5,6,7,8. For example, cisplatin and pemetrexed are used for non-squamous cell lung cancer (NSCLC)9 5-fluorouracil, leucovorin, and oxaliplatin are used for first-line treatment of colorectal cancer, whereas 5-fluorouracil, leucovorin, and irinotecan are used for second-line treatment of colorectal cancer10. Drug-drug interaction (DDI) occurs when the administration of two or more drugs, either simultaneously or sequentially, leads to a significant alteration in the effect of one or more of the drugs involved11. Conversely, adverse DDIs can undermine treatment efficacy in two primary ways: (1) by reducing drug efficacy through pharmacokinetic interference, such as enzyme induction that lowers active drug concentrations12 or (2) by increasing toxicity via pharmacodynamic synergism, exemplified by QT prolongation when used concurrently with CYP3A4 inhibitors13. These interactions can precipitate clinically significant adverse events that undermine treatment efficacy14.Notably, phytochemicals have garnered significant attention as potential interventions for both the prevention and treatment of a wide range of diseases15. phytochemicals are secondary metabolites with various chemical structures and functions that are naturally found in plants including fruits, vegetables, seeds, nuts, whole grains and herbs16,17 which are beneficial to human health18,19. Additionally, they also exist in diverse parts of plants such as stems, roots, rhizomes, leaves, seeds, flowers or fruits.

The theory of Cold/Hot natures is a foundational concept in Traditional Chinese Medicine (TCM), a comprehensive medical system rooted in ancient Chinese philosophical principles, including Yin-Yang theory and the Five Elements framework20. Characterized by a holistic worldview and syndrome differentiation21 TCM employs medicinal plants as one of its primary therapeutic modalities. The “Shennong Bencao Jing” is an ancient Chinese book on medicinal plants, explicitly describes the concept of the Four Natures (cold, hot, warm, cool)22. Clinically, this theory dictates using cold-natured medicinal plants to treat Hot syndromes and hot-natured medicinal plants to address Cold syndromes23. Hot syndromes are marked by symptoms such as thirst with a preference for cold drinks, red face and eyes, short and red urine, constipation, red tongue, yellow and dry coating on the tongue, and rapid pulse, whereas Cold syndromes typically manifest as fear of cold with a preference for warm drinks, pale face, long and white urine, loose stools, pale tongue, white and moist coating on the tongue, and slow pulse24,25. Notably, many anticancer drugs exhibit adverse reactions that align with TCM’s Cold/Hot categorization. For example, EGFR tyrosine kinase inhibitors (EGFR-TKIs) used in NSCLC frequently cause side effects like erythematous acneiform rash, thirst, dry tongue, and yellow tongue coating—symptoms consistent with “Hot” nature in TCM pharmacology26. Conversely, oxaliplatin, a colorectal cancer drug associated with peripheral neuropathy characterized by limb coldness and neurogenic pain, is analogous to “Cold” nature27. Intriguingly, network nodes implicated in Cold/Hot syndrome pathogenesis may also correlate with tumor initiation and progression28,29. Thus, classifying anticancer drugs into Cold/Hot categories based on their side effects and therapeutic profiles, and integrating the TCM theory of cold and hot, emphasizes the framework’s potential to create individualized cancer treatment strategies and drug discovery30.

Medicinal plants are a rich source of phytochemicals, which have been shown to play a significant role in treating human diseases31,32,33. A prominent example is artemisinin, which is extracted from the medicinal plant Artemisia annua and serves as a first-line drug for uncomplicated malaria. Interestingly, some researchers have reported that artemisinin also possesses anticancer activity and can enhance anticancer efficacy when used in combination with other anticancer drugs34,35,36. Currently, combinations of phytochemicals with anticancer drugs are frequently explored to improve efficacy, minimize adverse effects, and overcome drug resistance through multiple cancer-specific molecular mechanisms37,38,39. Successful drug-phytochemical combinations can aid researchers and clinicians in identifying beneficial phytochemical-based therapies for cancer patients40,41. However, some phytochemicals may have antagonistic effects on drugs42,43,44 which means it is equally important to identify ineffective or harmful drug combinations in order to help researchers and clinicians avoid these detrimental drug-phytochemical combinations. Consequently, the strategy of exploring interactions between phytochemicals and anticancer drugs is being regarded as a framework in drug discovery.

So far, numerous valuable databases have been developed to provide information related to phytochemicals, attracting significant interest from research communities. As outlined in Table 1, some of these databases, such as HERB45 SymMap46 HIT 2.047 , ETCM 2.048 , TCMBank49 NPcVar50 focus on global phytochemicals data. Others, including NP-MRD51 SuperNatural 3.052 , TCMID 2.053 , COCONUT54 StreptomeDB 3.055 , OrthoDB v9.156 , NPAtlas 2.057 , emphasize the structural characteristics and species classification of phytochemicals. However, these platforms generally lack pharmacological data on the interactions between phytochemicals and drugs for cancer treatment. Although certain databases, such as DDInter58 NPCDR59 DDID60 DrugBank61 have partially addressed DDIs, they fall short in detailing regulatory molecules and therapeutic effects of phytochemicals and drugs interactions, especially in the context of cancer-specific molecular processes. This gap hinders systematic guidance for combination therapy. Currently, no existing database offers a platform that integrates pharmacological and herbal information on the interaction effects of phytochemicals and drugs in cancer treatment. Therefore, there is an urgent need for a DDI database that encompasses a wide range of phytochemicals and drugs specifically tailored for cancer therapy.

Table 1 A range of databases available for providing information on phytochemicals or their interactions. The first database is the newly constructed one from this work, followed by other databases classified in alphabetic order.
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Herein, we presented InterPAD, a novel database dedicated to exploring drug-drug Interaction between Phytochemicals and Anticancer Drugs. The database provides comprehensive integrative molecular regulation data, emphasizing the synergistic effects (e.g., enhancing drug efficacy, reversing drug resistance, and decreasing drug toxicity) or antagonistic effects (e.g., reducing drug efficacy and enhancing drug toxicity) of these combinations across various cancer cell lines and model organisms (Fig. 1). Synergism refers to the interaction of two or more drugs whose combined therapeutic effect exceeds the sum of their individual effects. Antagonism refers to the interaction between two or more drugs that mutually inhibit each other, resulting in diminished or nullified therapeutic effects. Subsequently, the biological phenomena (e.g., apoptosis, cell cycle arrest, autophagy, ) associated with each interaction were summarized. The underlying molecular regulations, including expression, phosphorylation, cleavage, and activity alterations, were thoroughly analyzed. Additionally, the medicinal plant theory (e.g., cold, hot) was considered to enhance drug efficacy and reduce drug toxicity. Furthermore, cross-links to other databases such as UniProt62 TTD63 Pfam64 KEGG65 NCBI Gene66 Cellosaurus67 TCDB68 ChEMBL69 DDInter58 DrugBank61 HERB45 PubChem70 and others, were established to provide more detailed information. InterPAD delineates the connections of synergistic and antagonistic effects in cancer therapy, offering valuable insights for researchers in clinical oncology, network pharmacology, medical biochemistry, medicinal chemistry, drug design and related fields. InterPAD is free and open to all users without a login requirement at: https://bddg.hznu.edu.cn/interpad/.

Fig. 1
figure 1

The creative contents and characteristics of InterPAD are distinguished by its comprehensive coverage of phytochemicals and their interactions with anticancer drugs. Workflow and functional construction of InterPAD.

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Methods

Data collection and curation

The InterPAD database was systematically collected data on interactions between phytochemicals and drugs through a structured process. Initially, a comprehensive collection of phytochemicals was compiled from well-established natural product databases such as MedChemExpress, HERB45 ETCM v2.048 and TCMBank49. Subsequently, an extensive literature review of these 21,700 phytochemicals was conducted via PubMed over the past 20 years, employing a series of keyword combinations, such as “phytochemical name + anticancer drug”, “phytochemical name + anticancer drug + synergy” and “phytochemical name + drug name + antagonism”. This review yielded over 20,000 articles, from which only researches and clinical trials were retained. After rigorous screening, 983 interactions involving 331 phytochemicals and 244 anticancer drugs were included. To further expand the coverage of interactions in InterPAD, the 983 interactions were rigorously searched through the ClinicalTrials website, identifying 72 interactions with registered clinical trials. Ultimately thorough screening, a total of 1,020 articles were retained, 1,055 interactions—comprising 331 phytochemical entities and 244 anticancer drugs—were incorporated into the analysis. To ensure data accuracy, 9 PhD students participated in the entire process of information retrieval and manual data curation. Working in groups of three, any discrepancies among reviewers were resolved through discussion, with consultation of a third reviewer if necessary. All results underwent a tripartite cross-validation by three independent groups, with consensus discussions held for any divergent results.

Moreover, the InterPAD database provides comprehensive information on both phytochemicals and anticancer drugs, encompassing details such as name, indications, clinical status, molecular weight, synonyms, formula, canonical SMILES, InChI, InChIKey, CAS, drug type, ChEMBL ID, ChEBI ID, TTD ID, Herb ID, KEGG ID and Toxicity. This data is meticulously compiled from reputable sources, including IUPHAR/BPS71 , PubChem70 ChEMBL69 TTD63 HERB45. Moreover, the database offers 2D and 3D structural representations of these compounds, which are accessible online and can be downloaded in SDF file format. Of particular note is the database’s focus on herbs containing phytochemicals, providing insights into their classification, four natures (cold, hot, warm and cool), habitat, medicinal part, meridian tropism (Medicinal plants act on specific sites or pathways within the human body)72 and five tastes (sour, bitter, sweet, pungent and salty).

Collection of phytochemicals and drugs interactions-centered regulation information

In the analysis of 1,055 interactions of phytochemicals and drugs for cancer therapy, interactions were categorized into two primary effects: synergism and antagonism. Synergistic effects involved enhancing drug efficacy, reversing drug resistance, and decreasing drug toxicity, whereas antagonistic effects entailed reducing drug efficacy and enhancing drug toxicity. These interactions were meticulously mapped to cancer-specific molecular mechanisms, with a comprehensive list of clinical or experimental validations provided for the therapeutic effects. Our analysis involved a thorough review of the scientific literature, focusing on experiments designed to validate potential therapeutic targets both in vitro and in vivo. We meticulously examined these studies, paying particular attention to changes in downstream signaling pathways, to evaluate the effectiveness of mechanisms of action. The data were manually curated to include regulatory molecules, biological phenomenon, mechanisms, cell lines, and in vivo models. Moreover, the molecules in InterPAD were annotated with essential information, including Gene Name, synonyms, sequence, pathway map, UniProt ID, Gene ID, T.C. Number, KEGG ID, TTD ID, and Pfam, sourced from databases such as UniProt62 KEGG65 TTD63 and Pfam64. Additionally, by analyzing the theory of cold and hot, and correlating therapeutic effects with adverse reactions. We established classification criteria by mapping anticancer drug adverse reactions to TCM’s Cold/Hot syndrome diagnostics, using the ADReCs database as the primary data source73. In addition, modern pharmacological research and clinical practice have provided valuable results26,27,74. Furthermore, we used the authoritative book “Traditional Chinese Medicine Oncology” as a guide for classification standards. Notably, 6 professional Chinese medicine doctors specializing in the cancer treatment and 3 clinical pharmacologists independently reviewed classifications for 32 anticancer drugs. When there is a conflict of opinion, a third party will participate in the annotation. The framework facilitates the selection of appropriate phytomedicines within established guidelines to enhance medication relevance.

InterPAD data standardization, access, and customized retrieval

To enhance user access and facilitate the analysis of InterPAD data, the collected original data underwent a systematic cleaning and standardization process. This process comprised several key steps: (i) disease terms were standardized according to the latest version of the International Classification of Disease (ICD-11) issued by the World Health Organization (WHO)75. ICD-11 is widely recognized and used globally, which facilitates the comparison and integration of data across different studies and regions. Its detailed and comprehensive framework encompasses both common and rare diseases. Crucially, ICD-11 offers specific diagnostic codes, enabling precise classification essential for accurate data analysis and efficient retrieval within our system. Furthermore, the adoption of ICD-11 promotes robust data standardization by enforcing consistent terminology across all database entries. Finally, utilizing a globally accepted classification system like ICD-11 enhances InterPAD’s interoperability with other health information systems and research databases, thereby enabling broader collaborative research endeavors. (ii) the structures of phytochemicals and drugs were converted into canonical SDF format, encompassing both 2D and 3D representations; and (iii) all entities within the InterPAD database, including phytochemicals, anticancer drugs, species, genes, pathways, disease indications, and cell lines, were cross-referenced with reputable databases, such as CAS Registry Number76 ClinicalTrial.gov77 Drugs@FDA78 DrugBank61 ChEBI69 InChl79 KEGG65 NCBI Gene-Taxonomy80,81 PubChem70 TTD63 and UniProt62. This cross-referencing offers several key advantages for data management. First, it bolsters data accuracy by verifying information against authoritative sources, ensuring consistency and minimizing errors. Second, it enriches the overall completeness of the database by integrating supplementary details drawn from multiple, disparate sources. Finally, cross-referencing enhances interoperability by aligning our data with established standards and formats employed by other databases. The interface includes a quick search tool, enabling users to search the entire InterPAD text section for phytochemicals and anticancer drugs data via the main search box and drop-down menu.

Results

InterPAD consists of five data parts, including phytochemicals, anticancer drugs, drug interactions, cancer types and regulatory molecules. Each interaction is verified by corresponding references.

Data contents in InterPAD

InterPAD is an extensive database designed to enhance our understanding of interactions between phytochemicals and anticancer drugs. The final database documented 1,055 interactions, wherein 331 phytochemicals interact with 244 anticancer drugs. Additionally, InterPAD curates from 680 medicinal plants, providing detailed phytochemicals-related plant information. The database also includes 619 regulatory molecules and 74 cancer types to elucidate cancer-specific molecular mechanism and therapeutic effects. It is worth mentioning that we also provided the systematic data on the interactions of phytochemicals and anticancer drugs and their molecular mechanisms that were collected from reference retrieval and database mining. InterPAD introduces two significant advancements over previous phytochemical-based interaction databases. Firstly, it offers extensive information on drug interactions involving phytochemicals and anticancer drugs, detailing their clinically or experimentally validated synergistic and antagonistic effects. Secondly, it integrates medicinal plants theory and cancer-specific molecular mechanisms to demonstrate the biological effects of phytochemicals-based anticancer interactions. Consequently, the InterPAD database serves as a valuable resource for understanding the relevance of phytochemicals, anticancer drugs, their interactions, and therapeutic effects, thereby aiding in the discovery of beneficial phytochemicals-related and the avoidance of harmful ones.

Phytochemical-related anticancer drug combinations and their therapeutic effects

The limitations of conventional anticancer drugs, such as limited efficacy, adverse drug reactions, and acquired resistance, have been well-documented. In contrast, phytochemicals present distinct advantages, including multi-pharmacological regulation82,83 low toxicity84,85 and good tolerance86,87,88,89 which help mitigate some of the drawbacks associated with conventional anticancer drugs. The effectiveness and safety of a drug are largely contingent upon its multi-dimensional interactions with various molecular types within its combination90,91,92. A comprehensive and integrative understanding of these interactions is crucial for determining whether phytochemical-drug combinations exhibit synergistic or antagonistic effects. These concomitant drugs have been categorized according to five interaction effects of phytochemicals: (i) drugs whose efficacy can be enhanced by the phytochemicals, (ii) drugs whose resistance can be reversed by the phytochemicals, (iii) drugs whose toxicity can be decreased by the phytochemicals, (iv) drugs whose efficacy can be decreased by the phytochemicals, (v) drugs whose toxicity can be increased by the phytochemicals. Among these interactions, enhancing drug efficacy, reversing drug resistance, and decreasing drug toxicity are considered as synergistic effects, whereas reducing drug efficacy and enhancing drug toxicity are considered as antagonistic effects.

In the InterPAD database, the interactions between phytochemicals and drugs are systematically visualized and analyzed. The database reveals that 307 phytochemicals enhanced the efficacy of 198 anticancer drugs across 760 interactions, benefitting the treatment of 66 cancer types, 72 phytochemicals have been identified to reverse drug resistance in 28 anticancer drugs through 93 interactions, addressing 19 cancer types. Furthermore, 65 phytochemicals were noted for their ability to reduce the toxicity of 34 anticancer drugs in 82 interactions, impacting 29 cancer types. Furthermore, the cold and hot theory in TCM is valuable framework for understanding the therapeutic application of medicinal plants. It helps evaluate clinical symptoms and potential adverse reactions of anticancer drugs, guiding in the selection of medicinal plants to mitigate these symptoms. This information is accessible in the “Search for Interaction by Effect” section of Drug Interaction in InterPAD.

The analysis identified that 3 phytochemicals reduced the efficacy of 41 anticancer drugs across 41 interactions, while 7 phytochemicals were linked to increased toxicity of 6 anticancer drugs across 7 interactions. Figure 2 illustrates the therapeutic efficacy of each phytochemical-drug interaction, and the InterPAD database provides detailed clinically or experimentally observed treatment effects. The identification of successful drug combinations can guide researchers and doctors in selecting beneficial phytochemicals-based therapies for cancer patients. Conversely, recognizing ineffective drug combinations can help avoid detrimental interactions. In summary, InterPAD offers an extensive collection phytochemical drug interaction and represents the first comprehensive knowledge base to elucidate both synergistic and antagonistic effects of these interactions in cancer therapy.

Fig. 2
figure 2

A typical InterPAD webpage for drug interaction. The phytochemicals were reported to produce synergistic effects by enhancing drug efficacy, reversing drug resistance, and decreasing drug toxicity, or antagonistic effects by reducing drug efficacy and enhancing drug toxicity. The therapeutic effects of various interaction between phytochemicals and anticancer drugs are then displayed. Using “Artesunate, Fluorouracil” as an example, based on the theory of cold and hot, this theory was fully applied to anticancer drugs, and appropriate medicinal plants were selected within the guidelines to enhance the efficacy of this interaction and decrease the toxicity of fluorouracil.

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The interaction pattern of the collected phytochemicals with diverse medicinal plants

In recent years, the value of medicinal plants has been increasingly recognized, serving as a vital resource for modern drug development93,94,95. For instance, the combination of active ingredients-Honokiol, magnolol, baicalin-from Huangqin Houpo decoction exhibits synergistic anticancer effects in both in vivo and in vitro models of colorectal cancer96. Additionally, paclitaxel, derived from the mature Pacific yew tree (Taxus brevifolia), possesses broad-spectrum anticancer effects, including breast97,98 ovarian99 and gastric cancer100. Notably, recent advances in synthetic biology have for the first time revealed the enzymes that catalyze the final two modifications of paclitaxel biosynthesis, that is, C2′α hydroxylation and 3′-N benzoylation101. This provides new insights into the sustainable production of complex phytochemicals, thereby overcoming supply constraints. As a result, medicinal plants provide a foundation for exploring new research directions from a modern scientific perspective. The InterPAD database has cataloged 680 phytochemicals-related medicinal plants, providing detailed medicinal plant information on its webpage. This information includes the plant’s name, classification (kingdom, phylum, class, order, family, genus, species), habitat, four natures, five tastes, medicinal part, and meridian tropism. For instance, Curcumin, a prominent phytochemical, can be sourced from several medicinal plants, such as Curcuma longa, Curcuma kwangsiensis and Alpinia officinarum, as illustrated in Fig. 3, Curcuma longa, in particular, is classified as having a warm nature, with its tuberoid part being utilized. It is cultivated in regions such as Sichuan, Fujian, Guangdong, Zhejiang, and Jiangxi in China. The plant is characterized by a pungent and bitter, and is associated with the spleen and liver meridians. Additionally, the systematic classification of Curcuma longa into kingdom, phylum, class, order, family, genus and species was comprehensively summarized. The data were sourced from the Chinese Pharmacopoeia (2020 Edition), HERB45 ETCM v2.048 and SymMap46. In traditional medicine practice, the nature of medicinal plants is highlighted in color after their name. Diverse medicinal plants with similar properties can be used to treat diseases exhibiting opposite properties. Thus, understanding the cold-hot-warm-cool nature of medicinal plants is crucial for appreciating their synergistic therapeutic effects alongside anticancer drug.

Fig. 3
figure 3

The interaction diagram of the collected phytochemicals with diverse medicinal plants. Taking “Curcumin” as an example, its related medicinal plants information is detailedly presented in the webpage, including medicinal plant name, four natures, use part, habitat, flavor, meridian tropism, and classification (kingdom, phylum, class, order, family, genus, species).

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Description and visualization of the drug’s interaction pattern

InterPAD provides users the ability to explore specific cancer types and their associated phytochemical-drug interactions through interactive visual diagrams. For instance, Fig. 4A illustrates the various phytochemicals and drugs associated with “Lung cancer” through an interactive diagram. By hovering over the diagram and selecting “Click to details”. Users can access more in-depth information about each interaction. Additionally, users can select a combination of drugs to discover the corresponding disease type, as demonstrated in Fig. 4B. The platform also enables users to search for specific phytochemicals within the drug interactions interface, presenting all associated cancer types and drugs in the interaction graph. For example, Fig. 4C showcases the different cancer types and anticancer drugs linked to “Curcumin” in an interactive format. Similarly, as illustrated in Fig. 4D with “Fluorouracil” displays the diverse cancer types and phytochemicals correlated with “Fluorouracil”. This functionality enables users to explore specific anticancer drugs and uncover all related cancer types and phytochemicals, enhancing the platform’s utility for research and clinical applications. Furthermore, InterPAD provides comprehensive information on the clinical status of phytochemicals, drugs, and their combinations, as sourced from ClinicalTrials.gov77. Each interaction is meticulously annotated and can be accessed interactively online, ensuring thorough exploration and understanding of the data.

Fig. 4
figure 4

A typical InterPAD webpage for interactive diagram. (A) Using “lung cancer” as an example, the diagram displays the various phytochemicals and drugs associated with it, along with interaction effects and clinical status for the treatment of lung cancer. (B) Using “Epigallocatechin gallate, Irinotecan” as an example, the diagram displays the various diseases associated with this combination. (C) Taking “Curcumin” as an example, the interactive diagram shows the various cancer types and anticancer drugs associated with it. (D) Taking “Fluorouracil” as an example, the interactive diagram presents the varied cancer types and phytochemicals interrelated with it.

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The biological effects of phytochemical-related anticancer drug interactions and potential molecular mechanisms

The InterPAD database catalogues 619 molecules, including proteins and RNAs, along with 613 signaling pathways influenced by interactions between phytochemicals and anticancer drugs. Each original publication was meticulously analyzed to establish the correlation between these interactions and cancer-related molecular regulations. As shown in Fig. 5, InterPAD offers detailed curation of the biological phenomena resulting from each combination, such as the induction of mitochondria-mediated apoptosis, cell cycle arrest, glycolysis, reactive oxygen species (ROS) generation, endoplasmic reticulum stress, immunomodulatory effects, and the inhibition of epithelial-mesenchymal transition (EMT). Beyond documenting these biological phenomena, InterPAD also elucidates the underlying molecular mechanisms, highlighting specific molecular modifications like cleavage, activity changes, phosphorylation, and acetylation. Consequently, the molecular regulation and biological activity data provided by InterPAD are essential for understanding the mechanisms of phytochemicals in combination with specific anticancer drugs. This understanding is critical for improving drug efficacy, overcoming drug resistance, minimizing toxicity, and preventing both reduced effectiveness and increased adverse effects of drugs.

Fig. 5
figure 5

Detailed interactions of phytochemicals and drugs are categorized based on their therapeutic effects. Mechanisms of molecular regulation, signaling pathways, and biological phenomenon are comprehensively described. These interaction data are associated with diverse cell lines and model organisms, and the resultant changes in mechanism of action are detailed. An extended explanation of each regulated molecule can be accessed by clicking on the “gene name”.

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InterPAD offers comprehensive data on the therapeutic effects of each combination by systematically presenting molecular mechanisms, biological activity information, and experimental details on the clinical or experimental validation page. The database includes 479 cell lines from various disease and species origins, alongside four model organisms, such as zebrafish, mice, rats and rabbits, which are utilized to characterize the regulatory information for each interaction. Disease models, both in vitro and in vivo, were categorized base on the disease names from the original publications. Moreover, the database documents diverse experimental techniques used to access molecular regulation and biological activity, including western blotting, quantitative polymerase chain reaction (qPCR), short hairpin RNA (shRNA), small interfering RNA (siRNA), flow cytometry assays. These findings are manually linked to the KEGG database65 with corresponding regulatory molecules highlighted on their pathway maps. Users can access extended information on each regulatory molecule by clicking on its name, as demonstrated in Fig. 6. Finally, by clicking on the “References” icon, users can navigate to the bottom bar of the screen to explore the cited literature further.

Fig. 6
figure 6

Detailed interactions of phytochemicals and drugs are categorized based on regulated molecules. For instance, “NFE2L2” is used as an example, with its general information displayed in front part. The interaction effects of NFE2L2 on a list of interactions between phytochemicals and drugs that have been clinically or experimentally validated are collected in the lower.

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InterPAD case study

The database has been thoroughly validated by researchers and clinicians, whose feedback has directly enriched and enhanced the convenience of InterPAD. The research content of InterPAD focuses on the interactions between phytochemicals and anticancer drugs, providing extensive support for relevant scientific research. Taking the interaction between curcumin and fluorouracil as a key example, the process is as follows: Firstly, on the drug interaction interface, search by drug interaction classification. Then, click on “Synergistic Effect: Decreasing Drug Toxicity” (Fig. 7A) to display all interactions related to this entry. Next, select the interaction entry for curcumin and fluorouracil to show the registered clinical trials corresponding to this interaction in the study (Fig. 7B). Subsequently, clicking on the pair name will display the basic information of curcumin and fluorouracil (Fig. 7C). Moreover, this section presents content related to the “The theory of cold and hot”, inferring the potential nature of fluorouracil based on its adverse reactions and providing potential recommendations (Fig. 7D). Finally, it details both in vivo and in vitro experimental results for this interaction (Fig. 7E). All blue-highlighted text is linkable to relevant websites for further information. Thus, the database can be searched directly through interaction to obtain information related to phytochemicals and anticancer drugs, providing a convenient and integrated search channel for research in this field.

Fig. 7
figure 7

A case study of InterPAD. (A)The “Search for Interaction by Effect” interface of Drug Interaction in InterPAD. (B) Search interface for information on “Decreasing Drug Toxicity”. (C) The basic information of curcumin and fluorouracil. (D) The information of “The theory of cold and hot”. (E) The information of gene regulation and animal experiments.

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Discussions

Nature, as a unique origin system, is abundant with medicinal plants that exhibit significant biological activities and medicinal properties, making it a crucial source for medicine plant development. The systematic exploration of drug interaction is essential for advancing phytomedicine research and development. In this study, InterPAD enables users to conduct multi-dimensional and multi-level correlation analyses among phytochemicals, medicinal plants, anticancer drugs, interactions, cancer types, and molecules. The data provided by InterPAD sheds light on the complex mechanisms underlying phytochemical-anticancer drug interactions, aligning with the “multiple-regulatory molecules and multiple-signaling pathways” model of comprehensive cancer therapy. This approach improves the synergy effects of the conventional anticancer drugs and avoids potential antagonistic effects. Importantly, we propose that the classification of anticancer drugs based on the “cold and hot” theory is a valuable approach that integrates traditional wisdom with modern scientific understanding. While further validation is needed, the existing literature provides a foundation for this classification.

The detection of interactions between phytochemicals and anticancer drugs primarily depends on in vitro, in vivo experimental methods102,103 and some clinical trials104,105. Notably, the combination therapy of epigallocatechin gallate with gefitinib has been shown to effectively activate the AMPK pathway while inhibiting the ERK/MAPK and AKT/mTOR pathways. This leads to cell cycle arrest and apoptosis, particularly in drug-resistant NSCLC cells, thereby demonstrating the synergistic effects of this combination therapy in vitro106. Similarly, the combination of ginseng polysaccharide and αPD-1 monoclonal antibody may offer a novel strategy to enhance the sensitivity of NSCLC patients to anti-PD-1 immunotherapy, demonstrating the synergistic antitumor effects of this combination therapy in vivo8. In addition, a phase II clinical trial suggests the safety and feasibility of combination therapy with curcumin and gemcitabine107. Moreover, the findings of a phase I clinical trial investigating the combination of curcumin and docetaxel in patients with advanced and metastatic breast cancer indicated tolerability and feasibility108.

Despite the promising progress of numerous combination therapies entering clinical trials, these trials may still be put on hold or terminated due to inadequate efficacy or safety issues. It is crucial to acknowledge inherent limitations in extrapolating preclinical data on phytochemical-anticancer drug combinations to human clinical outcomes. These limitations arise from several factors: (i) While our database is grounded in robust preclinical research and some clinical evidence, the synergistic mechanisms underlying phytochemical-anticancer drug combinations remain incompletely elucidated due to the inherent complexity and uncertainty surrounding the target regulatory networks of phytochemicals, which can impede their clinical translation. Furthermore, certain phytochemicals may exhibit antagonistic interactions with anticancer drugs, thereby attenuating therapeutic efficacy. (ii) Although phytochemicals are generally recognized for their low toxicity profiles, a subset exhibits significant toxicity, restricting their clinical utility109. (iii) Tumor heterogeneity contributes to variations in the efficacy of combined phytochemical-anticancer drug therapy across different patients, thereby increasing the complexity of clinical research. (iv) Preclinical studies often employ higher phytochemical doses and shorter treatment durations compared to clinical trials, potentially leading to an overestimation of treatment efficacy and an underestimation of long-term adverse effects, complicating the precise control of combination dosages and drug ratios. (v) Variability in planting cycles and harvesting seasons can influence phytochemical composition, leading to challenges in quality control and standardization of data across different batches of combination drugs. Despite these limitations, the combination of phytochemicals and anticancer drugs continues to hold significant therapeutic potential. To address these challenges, we propose potential solutions for researchers, including the use of organoid models to screen for interactions between phytochemicals and anticancer drugs62,110 establishing a “chemical fingerprint profile” of phytochemicals using Ultra high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS) to ensure batch-to-batch consistency111,112 and enhancing the bioavailability and stability of phytochemicals through nanotechnology and other advanced delivery systems113.

Although several databases document phytochemicals and their species classification, there remains a notable absence of a comprehensive database specifically detailing phytochemical-anticancer drug interactions and their clinically or experimentally validated synergistic and antagonistic effects. To address this gap, we developed a database (InterPAD) to provide a valuable resource for understanding the relevance of phytochemicals, anticancer drugs, interactions, regulatory molecules, mechanism of action and therapeutic effects. Firstly, InterPAD encompasses extensive information on drug combinations involving phytochemicals and conventional anticancer drugs, including both synergistic and antagonistic effects validated through clinical or experimental studies, which are often neglected in basic research but are crucial in clinical practice. Secondly, InterPAD provides comprehensive details about the anticancer properties of phytochemicals and their source medicinal plants, including specific bioactivities, characteristics and traditional medicinal plant theory. Thirdly, our study represents a significant step forward by integrating insights from multiple disciplines, including pharmacology, drug design, botany, medicinal chemistry, bioinformatics, and systems biology. This interdisciplinary approach allows us to tackle the complex issue of drug interactions from multiple angles, providing a more holistic understanding than studies confined to a single discipline. For example, InterPAD facilitates users in conducting multi-level and multi-dimensional correlation analyses among medicinal plants, phytochemicals, anticancer drugs, diseases, and regulatory molecules.

In InterPAD, we focus on the interactions between phytochemicals and anticancer drugs. As interest in phytochemicals-based interactions continues to grow, the volume of data on these interactions is anticipated to expand significantly. InterPAD bridges the gap between phytochemicals and modern pharmaceutical research, laying the groundwork for future studies on predictive models and web tools for phytochemical-drug interactions. Currently, interaction studies based on artificial intelligence (AI) are increasingly gaining attention114,115. For instance, the study on food/herb–drug interactions and hepatoprotective effect predictions based on structure–activity relationships116. In addition, a novel deep multimodal feature fusion framework for predicting DDIs has been developed, which integrates drug molecular graphs, DDI networks, and biochemical similarity features of drugs to predict DDIs117. However, research on the prediction of interactions between phytochemicals and anticancer drugs remains limited. Therefore, collecting data on interactions between phytochemicals and anticancer drugs provides a basis for AI algorithms to analyze, thereby enabling more effective and evidenced research strategies.