Natural products (NPs) play a very important role in anticancer drug discovery and a large number of NPs have been proven to have potential anticancer effects. NPs have historically been a mainstay source of anticancer drugs, but in the 1990's they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many solid tumors, which revitalized the interest in NPs. NPs strike back in the cancer wars. Compared with newly synthesized chemical compounds, NPs show a favorable profile in terms of their absorption and metabolism in the body with low toxicity. A recent analysis of the strategies used in the discovery of new medicines showed that 36% of the first-in-classs mall-molecules approved by U.S. Food and Drug Administration (FDA) between 1999 and 2008 were NPs or NPs derivatives. Researchers from National Cancer Institute of NIH have conducted a series of analysis on the sources of new and approved drugs for the treatment of human diseases. An analysis of new and approved drugs for cancer by the United States Food and Drug Administration (US-FDA) over the period of 1981-2002 showed that 62% of these cancer drugs were of natural origin. From 1940s to 2006, of the 155 small molecules, 73% are other than synthetic, with 47% actually being either NPs or directly derived there from. From 1940s-2010, of the 175 small molecules, 74.8% are other than synthetic, with 48.6% actually being either NPs or directly derived there from. Except for cancer, within the whole diseases area, the percentage of FDA approved New chemical entities (NCEs) where the designation is basically a NP or a semi-synthetic modification derived from a NP fluctuates around 40% per year from 1981-2010. In 2010, this proportion had reached 50%, the highest in the past 30 years, that is half of the FDA approved NCEs are NPs or their derived compounds. The therapeutic areas of oncology have largely benefited from NPs, which indeed for many years have been source or inspiration for the majority of FDA approved drugs. Recently, systematically traced NPs drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases.
Except for Cragg and Newman's reviews focusing on FDA approved drugs, reviewed NP and NP-derived compounds that are being evaluated in clinical trials or are in registration, and discussed NP-derived drugs launched in the United States of America, Europe and Japan since 1998-2007 and new NP templates discovered since 1990-2007. described NPs, semi-synthetic NPs and NP-derived compounds that have undergone clinical evaluation or registration from 2005 to 2010 by disease area which are infectious (bacterial, fungal, parasitic and viral), immunological, cardiovascular, logical, inflammatory and related diseases and oncology. On the mean while, discovery, isolation, biochemical/pharmacological characterization, pre-clinical and clinical trials of drugs derived from the marine environment are continuously developing and increasing. One of the most promising area is cancer therapy. It is clear NP and/or NP structures continued to play a highly significant role in the drug discovery and development process, and effective drug development depends on multidisciplinary collaborations.
Advances in bibliometric methodologies and technology enable efficient investigation of publications/patents, their contents, and relationships for large sets of documents in order to assess the status of the field. Such studies are not intended to replace the expert, but in order to providing useful and objective instruments to characterize and map the structure of scientific fields and their development over time, thus constitute an effective complement for the opinions and judgements of experts in specific field. Medical researchers have made increasing use of these techniques as a powerful way to reveal patterns in medical research that would not be evident with traditional methods of reviewing the medical literature. But to our knowledge, there are only a few bibliometric studies in the field of nature products and medicines to date. performed a bibliometric study on scientific publication related to phytotherapy in the psychiatry area during the period 1986-2006. They measured annual amount of scientific production, and included the national anticipation index to evaluate countries′ contribution. Bartol (2012) assessed the development in databases by identifying general terms that describe herbal medicine with optimal retrieval recall and to identify possible special trends in co-occurrence of specific and general concepts, which will be helpful for retrieval of relevant documents. took five representative of international well-known journals in NPs and medicines fields, namely Planta Medica, Journal of Natural Products, Tetrahedron, Phytochemisry, and Organic Letters as publications dataset, analyzed bibliometric indicators of China in above journals from 2006-2010, and evaluated the productivity of China in this field in relative to other seven representative countries including USA, Germany, France, UK, Japan, Korea and India.
Nevertheless, within the specific area of NPs against cancer there are as yet no studies analyzing the evolution of scientific production except of drug discoveries. This provided the motivation for the present bibliometric study, which set out to analyze multi-source data including research projects, publications, patents and drugs with a comprehensive viewpoint. We try to draw the whole landscape of the research and development community on the subject of NPs against cancer.
MATERIALS AND METHODS
We used a keyword search approach to identify the "NPs against cancer"- related publications, patents and drugs data from PubMed, Derwent Innovation Index and Thomson Reuters Cortellis™, respectively. We firstly conducted a search of the Web of Science, identifying the U.S. National Institutes of Health (NIH) as the leading funding organization, followed by the National Natural Science Institute of China (NSFC), so we included the awards data from the NIH/NSFC to reveal research funding tendancy in this area. Considering most Asia-Pacific regions including China, Japan, South Korea and India are important contributors in NPs and medicines research, we selected PubMed as the scientific publications data sources instead of Web of Science due to the imbalance of biomedical journals published in U.S., Europe Union, and Asia Pacific regions indexed in it. PubMed is a bibliographical database known for its excellent coverage and indexing of journal publications in the biomedical research fields. Derwent Innovation Index (DII), covering the most patents in the main countries or regions, was one of the databases frequently used.
NPs related keywords of are based on "Drugs, Chinese Herbal"[ Medical Subject Headings (MeSH)] (only in PubMed), "medicinal plantFNx01", "mineral medicineFNx01", "animal medicineFNx01", "planta medica", phytotherapy, phytomedicine, herbalFNx01, "natural medicineFNx01", "natural productFNx01" and "natural drugFNx01". In order to cover NPs related publications as exhaustive as possible, 14 representative of international well-known journals were also selected, including Journal of Natural Products, Planta Medica, Tetrahedron, Phytochemisry, Organic Letters, Tetrahedron Letters, Phytomedicine, Journal of Natural Medicines, Chinese Journal of Natural Medicines, Natural Product Communications, Natural Product Research, Natural Product Reports, Natural Product Letters, Natural Products and Molecular Therapy. Cancer related keywords of are based on "Antineoplastic Agents"[MeSH] (only in PubMed), cancerFNx01, tumorFNx01, tumourFNx01, neoplasmFNx01, carcinoma, ontology, antineoplastic, anti-neoplastic, antitumor, antitumour and anticancer.
For NIH/NSFC award data, PubMed scientific publications and patents at DII, the search was performed on "title" and ′′abstract′′ sections. For drugs data, from US and global perspectives respectively, we firstly indentified drugs approved by the USFDA, and then collected drugs data with the descriptors "Neoplasm" in [Indication] and "Natural product" in [Technologies], we limited the highest development Status as "Launched or Under clinical trials (Phase 3, Phase 2, Phase 1)". Our collection covers data from 1990 to 2013. For Pubmed we expand the window to 1965 − 2013.
Figure 1 shows our research framework, of which general trends of NIH and NSFC awards data were analyzed, including annual number of research projects and expenditures. Top 10 countries/territories producing the most publications, patents and drugs were indentified to compare their contributions in basic research, technology development and drug discovery. Within PubMed scientific publications, the MeSH terms were used to detect the evolution of research topics in three intervals (1965-1990, 1991-2002 and 2003-2013). NPs or NPs derived compounds, cell lines/animal models and laboratory technologies, and activation mechanisms related high frequency MeSH terms were classified to identify hot topics in the above three subfields during the last 10 years. We clustered the technique focus of patents based on the co-occurrence analysis of Derwent Manual Codes at DII. We also analyzed the development status, originator company and active indications of drugs that have been launched or are being under clinical trials. Final, data results from multi-sources were compared and concluded.
The software Thomson Data Analyzer was used to process and analyze data, and Vosviewer was used to conduct cluster analysis and data visualization.
Based on the above data sources and search strategy, we collected 7598 Publications in 1965-2013, 3010 NIH granted projects in 1990-2013, 712 NSFC granted projects in 1993-2013 and 641 patents in 1990-2013.
As is shown in Figure 2, annual publications showed a significant growth trend since 1997, and fluctuated increasing first and then decreasing during 2008-2013. The number of NIH-funded projects has been significant increased since 1997, showed a peak in 2009, and decreased from 2010, probably due to the reduction of NIH total fund from 2010. But the number of projects granted by the NSFC has shown a significant growth trend, demonstrating China's increased research funding in NPs against cancer. Compared with the rapidly increased publications and research funding, the global patents applications increases slowly since 1999 and started remaining stable from 2005 till 2013.
According to the report of United States pharmaceutical manufacturers Association (PhRMA) in 2014, the United States pharmaceutical companies put more and more expenditures on drug discovery from 1997-2006, but the output number of the new molecular entity drugs is decreasing annually. This is a kind of translational gap. Starting from 2007, the R and D investment of new drugs slowly increased in a relative stable manner, while the number of new drugs approved by FDA increased during this period, it means the translational gap are narrowing. But compared with that of all new drugs approved by FDA, the number of anticancer drugs shows a continuous increasing.
NPs or NPs derivatives include NP and semi-synthetic modifications derived from a NP. The number of FDA approved anticancer drugs which were NPs or NPs derivatives was peaked in 1993 and 2010 respectively, and waved during the last decade. In general, the more of new drugs approved at one specific year, the less will be approved in the following one or two years. But it would be increased again after 3 years [Figure 3].
In PubMed publications, only the first author's affiliation were included before 2013, thus countries/territories extracted in our dataset reflected the major contributor in this area. The priority countries of granted patents and the host countries of originator company/institutions of drugs that have been launched or under clinical trials were listed in Table 1. From the publications and patents perspectives, Peoples R China, USA, South Korea, Taiwan and India are major countries/territories. Particularly, Peoples Republic of China published more than a quarter of worldwide publications and was the priority country of more than two fifths of patents application around the word, much higher than USA. But the drug discovery performance of Peoples Republic China are no better than USA and Japan. Of 70 drugs, originator companies from USA account for nearly one third. But Peoples Republic of China only developed seven drugs, of which three are developed by scientific research institutions and the other four by companies. While with respect to Japan, eight drugs originated from companies and only one from scientific research institutions. Asia-Pacific countries are important and non-negligible contributing powers in the research and development area of NPs against cancer.
We then analyzed annual publications and patents of several important Asia-Pacific countries/territories and compare that with USA [Figure 4]. The results showed that publications and patents of Peoples Republic China increased most rapidly. There were few publications before 2004, but starting from 2005, the annual publications had surpassed USA, whose amount of publications kept steady and decreased in the past 2 years. The publications of Japan remain relatively stable in the last decade. Publications in South Korea, Taiwan and India are increasing with the similar and slightly moderate speed.
Patent applications with priority in Germany, USA and Canada began to decline significantly since 2003, 2006 and 2008 respectively. In contrast, a significant upward trend in China was observed, reflecting the new drug discovery related patent activities and market status were hot in China.
Research topics of scientific publications
According to annual amount of publications in PubMed, the interval could be separated into three parts for comparison purposes: 1965-1990 (slowly increasing, 484), 1991-2002 (rapidly increasing, 2001) and 2003-2013 (fluctuately increasing, 5473), which is helpful for describe the evolution of research topics.
In PubMed publications, a MeSH term that is one of the main topics discussed in the article denoted by an asterisk on the MeSH term or MeSH/Subheading combination, called MeSH Major Topic, revealing the most targeted research content of one article. We extracted all 3195 MeSH Major Topics (without Subheading combination) in 7958 publications. We firstly count the frequency and percentage of each MeSH Major Topic within each three intervals. The percentage reflected the relative term frequency with total term frequency in the corresponding interval, which is suitable to compare and detect term changes in different intervals. Then we calculated the percentage growth from 1965-1990 to 1991-2002 (the first growth) and from 1991-2002 to 2003-2013 (the second growth) for each MeSH Major Topic, and chose top 30 MeSH major topics within the first and second growth intervals respectively. Twelve MeSH major topics occurred in both the first and second growth, thus leaving fourteen eight MeSH major topics in our analysis dataset [Figure 5].
As is shown in Figure 5, top 48 MeSH major topics during the first and second growth process. They are placed in an anti-clockwise direction, ordered by their growth range from the first growth (blue line) to the second growth (red line), which, to some extent, reflected the evolution of research topics over time. On the left side, the majority of topics growth range are declining, such as porifera, cnidaria, enzyme inhibitors, paclitaxel, anticarcinogenic agents, trees, antiviral agents and anti-infective agents, spiro compounds. On right side, we can see several topics growth range is expanding. Abruptly increasing topics are shifting to phytogenic antineoplastic agents, chinese herbal drugs, phytotherapy and traditional Chinese medicine. A greater focus was observed on (1) several NPs or NPs derivatives such as plant extracts, alkaloids, sesquiterpenes, flavonoids, triterpenes, diterpenes, lignans and glycosides; (2) activation mechanisms, such as apoptosis, cell proliferation, angiogenesis inhibitors, and antioxidants; (3) major cancer type including breast neoplasms, liver neoplasms, lung neoplasms, hepatocellular carcinoma and colonic neoplasms.
Inspired by the results from Figure 5, we decided to make a more detailed analysis of hot research topics reflected by publications in the recent 10 years (2003-2013), which account for 72% of all publications between 1965 and 2013. We manually classified MeSH terms into three categories: (1) NPs or NPs derivatives; (2) Cell line/Animal model and laboratory technologies; and (3) Activation mechanisms.
We firstly classified top 73 NPs or NPs derivatives related keywords [MeSH terms] indexed to more than 30 papers in the field of anticancer NPs and medicines research Table 2 shows the NPs or NPs derivatives widely mentioned in the literature include (1) general NPs or derived compounds, (2) antineoplastic TCM and their families and genera, (3) parts or fractions of antineoplastic medicinal plants, (4) the antineoplastic compounds and their structure types in herbal medicine, and (5) the structure type of antineoplastic component derived from marine NPs. The general NPs or derived compounds related MeSH terms include phytogenic antineoplastic agents, chinese herbal drugs, phytotherapy, medicinal plants and TCM.
Then we analyzed the frequency differences of the above-mentioned 73 MeSH terms in 2003-2013. It shows that antineoplastic agents, phytogenic, drugs, chinese herbal have a large amount, and the frequencies keep growing in recent 10 years, means a high degree of concern. Alkaloids increase dramatically in recent 5 years. Although the total amount of phytotherapy, plant extracts, triterpenes, sesquiterpenes, flavanones frequency is high, it dropped significantly in recent 3 years. there is a notable growth of plants, medicinal in 2003-2008, but a remarkable drop in recent 5 years. Diterpenes, TCM have a reduction in recent 2 years.
Table 3 shows the main research materials and laboratory technics. From the view of research materials, HeLa Cells, HL-60 Cells, HT29 Cells, Leukemia P388, Hep G2 Cells, K562 Cells, HCT116 Cells, MCF-7 Cells, Jurkat Cells and Sarcoma 180 correspond to cervical cancer, acute promyelocytic leukemia, colonic adenocarcinoma, Leukemia, liver carcinoma, leukemia, colonic adenocarcinoma, breast adenocarcinoma, T-cell acute lymphoblastic leukemia and sarcoma.
We choose activation mechanisms related keywords [MeSH terms] most frequently indexed to papers in the field of anticancer NPs and medicines research. Using Vosviewer to do the co-occurrence analysis for 106 mechanism category terms with frequency more than 30 [Figure 6].
According to the interpretation in MeSH terms of each cluster, it can be divided into 5 clusters: (1) Immunomodulatory mechanism of natural antitumor drugs and the response of inflammatory cells and factors; (2) The antitumor mechanism of peptide antibiotic as antineoplastic agent from natural sources; (3) The apoptosis mechanisms of tumor cells induced by natural drugs; (4) Antioxidant and free radical scavenging mechanisms of natural antineoplastic agent; and (5) Antagonistic mechanism of natural drugs on multidrug resistance of tumorous cells.
Technology fields of patents
Derwent's Manual Code system is a hierarchical classification system developed by Derwent to enable precise retrieval of patent technology within the Derwent database, with the function asute promyelocytic leukemia, colonic adenocarcinoma, Leukemitechnology fields by co-occurrence analysis of Derwent Manual Codes indexed for each patent [Table 4].
The most frequently indexed Manual Codes are B14-H and B04-A, concerning anticancer drugs pharmaceutical activities and alkaloids, counting for 92% and 74% respectively. It can be divided into four groups, include: (1) Pharmaceutical activities: Acting on specific cancers, (2) Anticancer drugs: Compounds types and activation mechanisms, (3) Plant extracts and foodstuffs for treatment, and (4) Animal extract for treatment.
According to annual change trend, we detected the topics with larger change range of the 65 technology fields, including: With sustained growth trend, there are three: B14-H01, B04-A10 and B04-A09, indicate that the patents applications is growing in anticancer drugs pharmaceutical activities and alkaloids (plant extracts) fields. According to annual change trend, we detected the topics with larger change range of the 65 technology fields, include: With sustained growth trend, there are three: B14-H01, B04-A10 and B04-A09, indicating that the patents applications is growing in anticancer drugs pharmaceutical activities and alkaloids (plant extracts) fields. "B14-S18 Miscellaneous activity terms/Drug combination" grows significantly in recent 5 years. "B04-A08 Alkaloids, plant extracts/Plant divisions and whole plants" and "B14-E02 Drugs acting on the gastrointestinal system/Antidiarrhoeal" have a burst increasing in 2013. "B04-A98 Alkaloids, plant extracts/Patent with herbal composition" and "B04-A08G2 Dicots" grows in recent 3 years. While "B14-C03 Antiinflammatory"and "B04-A08C2 Angiosperms" decreased in recent 3 or 4 years.
Drug discovery profiles
Of 70 anti-neoplasm drugs from NPs, according to highest development status, there are 28 drugs that have been launched and the other 42 drugs are under development, of which 9, 19 and 14 drugs are being evaluated in Phase 3, Phase 2 and Phase 1 clinical trials, respectively. Table 5 shows active indications, highest status of those drugs under the highest development status, either have been launched or under Phase 3 clinical trials.
We then analyze the most frequently mentioned active indications of these 70 drugs and compare this with the most widely investigated cancers/diseases by site in publications and patents [Figure 6]. Breast neoplasms are the most diseases studied in publications and drug discovery, but relatively less investigated in patents. Drugs development for non-small-cell lung cancer is the most, followed by breast cancer and then ovary tumor, colorectal tumor, lung tumor, non-hodgkin lymphoma and stomach tumor. In addition, basic research targeted to lung neoplasms, liver neoplasms, prostatic neoplasms, hepatocellular carcinoma, colonic neoplasms reflected by scientific publications are very active during the past 10 years. Chemicals or compounds discovery for blood and cardiovascular system, gastrointestinal system, immune system, muscular and nervous systems, skin diseases, respiratory system, liver diseases, kidney diseases and eye disorders are also very active. They all provide promising for drug design and discovery [Table 6].
Current bibliometric analysis in biomedical fields tend to focus only on publications or patents. There are few studies based on data integration of research projects, publications and patents, or any two of them. introduces a method for analyzing publications, patents and research grants of microarrays as proxies for "triple-helix interfaces" between university, industry and government activities presents the development of a new knowledge mapping system, called Nano Mapper, which integrates the analysis of nanotechnology patents and research grants into a Web-based platform presents a longitudinal analysis of the global nanotechnology development as reflected in the United States Patent and Trade Office (USPTO) patents and Web of Science publications in nanoscale science and engineering (NSE) for the interval 1991-2012; and identifies the effect of basic research funded by NSF on both indicators.
Looking for drugs with antitumor activity or potentials for inducing apoptosis of tumor cells from natural resources is one of the hot topics in the field of anticancer drugs discovery. From a comprehensive viewpoint, this paper collected multi-source data from awards, publications, patents and drugs, analyzed the differences and relationships among them.
As the overwhelming funding organization in the research area of NPs against cancer, in the past 10 years, NIH had spend about 20-30 million dollars every fiscal year and NSFC also demonstrated a sustained expenditure growth in this area. The amount of publications is continuously increasing during the last 50 years, with a slowly and moderately rising in the recent 10 years. Yet the annual patent applications worldwide and FDA drug approvals were little changed or not obviously fluctuated in 2003-2013. There still exits translational gap in this area according to current publications.
Except USA, Asia-pacific countries/territories are important contributing powers in the research and development area of NPs against cancer. China published the most publications and received the most patent applications, with the most growth rate annually. This is in accordance with. Their 2006-2010 publications results showed that China, USA, Germany, France, UK, Japan, Korea, and India are the leading powers in NPs and medicines research. In addition, as one of the countries with the richest resources of natural medicines, China present the most increasing developmental tendency. But China's company/institution drug discovery performance is no better than USA and Japan.
We described the evolution of major research topics by those MeSH major topics indexed in PubMed with the largest growth range in three intervals, and analyzed hot research topics in the recent 10 years which include NPs or NPs derivatives, cell line/animal model, laboratory technologies and activation mechanisms. Research on structures and compounds originated from antineoplastic TCM, medicinal plants, herbal medicine and marine NPs are hot topics. The most concerned activation mechanisms include nomodulatory mechanism, peptide antibiotic, the apoptosis inducing mechanisms, anti-oxidant and free radical scavenging mechanisms, and antagonistic against multidrug resistance (Dimaio et al., 2014; Mason et al., 2013). Major technology fields in patent applications include research on pharmaceutical activities acting on specific cancers, compounds types and activation mechanisms of anticancer drugs, and plant extracts, foodstuffs animal extracts for treatment. There are 70 anticancer drugs from NPs that have been launched or under development. Basic research and chemicals development targeted to specific type of cancer provide promising for drug design and discovery. We hope to bring beneficial information and inspirations to basic research scientists and drug discovery investigators.
We are grateful to Ting Gong from Institute of Materia Medica, Chinese Academy of Medical Sciences her help with the interpretational labeling of the clusters of NPs or NPs derivatives, and activation mechanisms. This study was supported by the National Science and Technology Library, NSTL (Grant No. 2012XM25, 2012XM26).