About this Research Topic
Background: Cancer is among the leading causes of deaths worldwide. The complete cure of cancers by anti-tumor drug therapy is still difficult to achieve, even though billions of dollars have been invested in anti-tumor drug development worldwide. Thus, cancer prevention, which means to prevent or delay oncogenesis by either making lifestyle changes or taking medicines, could be a more cost-effective solution compared to anti-tumor drug therapy. In this line of thinking, people have chosen to take natural medicines as cancer preventive agents as it has shown definite effects on the modulation of human bio-functions, and are generally thought to be safer and harmless on a long-term basis. For example, it was shown that consumption of Chinese herbal products reduces the incidence of invasive breast cancer according to a survey based on a nationwide, 1-million-person representative sample covered by National Health Insurance in Taiwan followed from 1999 to 2012. Other natural products have also been discovered as promising chemopreventive agent, such as resveratrol. This naturally occurring polyphenolic compound is found in various plants including berries and red wine grapes, and has shown to prevent the formation and growth of sporadic colorectal cancer in genetically engineered mouse model of sporadic colon cancer by downregulating Kras expression.
However, there are two main issues that we are confronting in terms of natural medicine-based cancer prevention. First, the solid connection between natural medicines and clinical chemoprotective effects remains elusive and controversial. For natural medicines, their antitumor effects are recognized. However, being a different concept, antitumor activity does not encompass cancer preventive effects and so far, there is still no large scale clinical investigation to test the clinical cancer preventive effects of specific natural medicines.
Second, while our knowledge on more detailed mechanisms for tumor proliferation, metastasis, and invasion is continually growing, we have known little on how normal cells are transformed into tumor cells. This in turn prevents us from discovering additional potential natural medicines of cancer preventive activity. For example, although pathways such as the Wnt and Nfκb pathway are involved in tumorigenesis, how tumor cell originates from a normal cell remains unclear. It remains elusive whether tumor stem cells are the direct products of neoplastically transformed normal tissue stem cells, or if cancer stem cells arise when transit-amplifying cells with mutant genomes dedifferentiate and enter the stem cell state. The mutation of normal cells and tumor stem cell activity are universally recognized as the two crucial factors in cancer prevention studies and natural products, such as echinacoside and Berberine that inhibit DNA damage and induces apoptosis of cancer stem cells respectively, are potentially good candidates in addressing these factor. Given this, further research is needed to collect additional evidence to substantiate or disprove the chemopreventive effects of natural medicines and to explore more key oncogenic pathways for cancer preventive drug discovery.
Goal: This Research Topic encourages contributors to provide evidence-based experimental results on cancer chemoprevention, and to reveal and discuss the underlying pharmacological mechanisms. More specifically, pharmacological effects of either mitigating the injury caused by the oncogenesis or reducing the size or/and numbers of tumors are both acceptable. Only medical interventions are welcomed, and food-type interventions can only be accepted if they exhibited therapeutic benefits as highlighted in the 4 pillars of best practice under section 4(c). This article collection aims to help further understand the chemopreventive effects of natural medicines and at the same time the key oncogenic pathways that are important for cancer prevention.
Scope: The focus of this Research Topic will be on the in vivo effects of natural medicines on cancer prevention. Data derived from in vivo models should be justified by well defined research questions and prospective contributions to the field. For papers with only in vitro results, only those with solid evidence and good novelty (such as results from cancer stem cells or cells treated with gene knock-in or knockout techniques) can be considered for acceptance.
Details for Authors: Repeatability is one of the most important factors for the acceptance of the submitted papers, which means the constituents of the sample for cancer preventive evaluation should be clarified. Reviews of high quality on this Research Topic are also welcomed. Potential authors should submit an abstract and a full paper on the recommended topic areas but not limited to the following themes:
1. Gastrointestinal cancer: This theme includes mainly intestinal and gastric cancer prevention. Research on inflammation-related cancer, such as colitis-associated cancer, are also welcomed.
2. Lung cancer: This theme mainly focus on the preventive effects of natural medicines on carcinogen-induced lung cancer. To be noted, the carcinogens will not be limited to be tobacco-specific - other substances, including mineral dusts, would also be considered as good research focuses in this theme.
3. Liver cancer: This theme covers natural medicines preventing the carcinogenesis of primary liver cancer caused by all carcinogens. As hepatic fibrosis is the early and key symptom in the carcinogenesis of hepatoma, papers reporting natural medicines reversing or suppressing the progression of hepatic fibrosis will also fall into the scope of this theme.
The four pillars of best practice in ethnopharmacology
With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.
1) Pharmacology
a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.
b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.
Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.
c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.
d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.
e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach.
f) Docking studies must be justified with affinity experiments, or other well established experimental methods to support a proposed mechanism of action. Algorithmic docking studies will not be accepted; these indicate if a compound will "fit" into a binding site but do not indicate the binding affinity or the ability to induce a conformational change.
2) Composition:
a) Botanical:
The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.
b) Chemical
- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph
- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration
- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.
c) Multiherbal preparations:
Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.
3) Basic requirements and research ethics
Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:
a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.
b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).
c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).
d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.
e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.
4) Other specific requirements
a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.
b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.
c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.
However, there are two main issues that we are confronting in terms of natural medicine-based cancer prevention. First, the solid connection between natural medicines and clinical chemoprotective effects remains elusive and controversial. For natural medicines, their antitumor effects are recognized. However, being a different concept, antitumor activity does not encompass cancer preventive effects and so far, there is still no large scale clinical investigation to test the clinical cancer preventive effects of specific natural medicines.
Second, while our knowledge on more detailed mechanisms for tumor proliferation, metastasis, and invasion is continually growing, we have known little on how normal cells are transformed into tumor cells. This in turn prevents us from discovering additional potential natural medicines of cancer preventive activity. For example, although pathways such as the Wnt and Nfκb pathway are involved in tumorigenesis, how tumor cell originates from a normal cell remains unclear. It remains elusive whether tumor stem cells are the direct products of neoplastically transformed normal tissue stem cells, or if cancer stem cells arise when transit-amplifying cells with mutant genomes dedifferentiate and enter the stem cell state. The mutation of normal cells and tumor stem cell activity are universally recognized as the two crucial factors in cancer prevention studies and natural products, such as echinacoside and Berberine that inhibit DNA damage and induces apoptosis of cancer stem cells respectively, are potentially good candidates in addressing these factor. Given this, further research is needed to collect additional evidence to substantiate or disprove the chemopreventive effects of natural medicines and to explore more key oncogenic pathways for cancer preventive drug discovery.
Goal: This Research Topic encourages contributors to provide evidence-based experimental results on cancer chemoprevention, and to reveal and discuss the underlying pharmacological mechanisms. More specifically, pharmacological effects of either mitigating the injury caused by the oncogenesis or reducing the size or/and numbers of tumors are both acceptable. Only medical interventions are welcomed, and food-type interventions can only be accepted if they exhibited therapeutic benefits as highlighted in the 4 pillars of best practice under section 4(c). This article collection aims to help further understand the chemopreventive effects of natural medicines and at the same time the key oncogenic pathways that are important for cancer prevention.
Scope: The focus of this Research Topic will be on the in vivo effects of natural medicines on cancer prevention. Data derived from in vivo models should be justified by well defined research questions and prospective contributions to the field. For papers with only in vitro results, only those with solid evidence and good novelty (such as results from cancer stem cells or cells treated with gene knock-in or knockout techniques) can be considered for acceptance.
Details for Authors: Repeatability is one of the most important factors for the acceptance of the submitted papers, which means the constituents of the sample for cancer preventive evaluation should be clarified. Reviews of high quality on this Research Topic are also welcomed. Potential authors should submit an abstract and a full paper on the recommended topic areas but not limited to the following themes:
1. Gastrointestinal cancer: This theme includes mainly intestinal and gastric cancer prevention. Research on inflammation-related cancer, such as colitis-associated cancer, are also welcomed.
2. Lung cancer: This theme mainly focus on the preventive effects of natural medicines on carcinogen-induced lung cancer. To be noted, the carcinogens will not be limited to be tobacco-specific - other substances, including mineral dusts, would also be considered as good research focuses in this theme.
3. Liver cancer: This theme covers natural medicines preventing the carcinogenesis of primary liver cancer caused by all carcinogens. As hepatic fibrosis is the early and key symptom in the carcinogenesis of hepatoma, papers reporting natural medicines reversing or suppressing the progression of hepatic fibrosis will also fall into the scope of this theme.
The four pillars of best practice in ethnopharmacology
With these guidelines we define in detail what constitutes best practice for manuscripts submitted to Frontiers in Pharmacology; Section Ethnopharmacology. They provide a basis for the peer review and build on the general requirements of Frontiers in Pharmacology.
1) Pharmacology
a) The manuscript (MS) must report a substantive body of ethnopharmacological research, to be considered as an independent addition to the literature. In general, we expect that such studies are based on local / traditional uses of plants or other natural substances which need to be spelled out clearly.
b) For pharmacological studies, the model used must be one which is either generally accepted in the field as valid or a credible alternative whose general development, and application in the reported instance, has been justified.
Specifically antioxidant activity must be based on a pharmacologically relevant in vivo or cell based model. Simple in silico and pharmacologically irrelevant assays for antioxidant activity (e.g. the DPPH assay, FRAP (Ferric Reducing Ability of Plasma), ABTS (2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid)) are not acceptable as a main tool for assessing an extract or a compound for activity.
c) Similarly, simple screening for anti-microbial effects of crude extracts is no longer state-of-the-art. Authors must follow the widely accepted standards for microbiological testing (cf. Cos et al. 2006 Anti-infective potential of natural products: How to develop a stronger in vitro ‘proof-of-concept’ Journal of Ethnopharmacology 106: 290–302) and subsequent methods papers. Such research is only meaningful if it contributes to our mechanistic understanding of anti-microbial effects, its specificity or identifies novel leads.
d) The dose ranges must be therapeutically relevant. While it will be impossible to define an exact cut-off, the literature in the field is now replete with studies which test extracts at implausibly high doses. Single dose studies will only be of relevance in exceptional circumstances (e.g. in case of specific complex pharmacological models). And of course, positive and negative controls must be included.
e) In order to establish therapeutic benefits, selectivity data are essential. How specific is the effect? Many compounds have non-selective in vitro effects and research on common compounds must be justified in terms of the potential therapeutic benefits. While such research may be relevant and have potential applications, authors will need to assess the specificity of a single compound or an extract rich in a well-studied compound (like rutin, curcumin, or quercitin) and provide evidence for the relevance and novelty of the approach.
f) Docking studies must be justified with affinity experiments, or other well established experimental methods to support a proposed mechanism of action. Algorithmic docking studies will not be accepted; these indicate if a compound will "fit" into a binding site but do not indicate the binding affinity or the ability to induce a conformational change.
2) Composition:
a) Botanical:
The identification of the study material must be described well. All species are fully validated using Kew MPNS portal or The Plant List initiative or Plants of the World Online Of course, full botanical documentation is essential (i.e. a voucher specimen deposited in a recognised herbarium). A scan of the voucher(s) is welcome as supplementary material and encourage authors to include the coordinates of the location where the material had been collected.
b) Chemical
- The composition of the study material must be described in sufficient detail. Chromatograms with a characterisation of the dominating compound(s) are preferable. If preparations are used which are available commercially quality parameters provided in pharmacopoeia must be provided. The material under study must be characterised using the methods of the relevant monograph
- If ‘pure’ compounds are used sufficient information on the level of purity must be included. Especially in in vitro models, the authors must be confident that the compounds are stable under the conditions used (for example, they do not degrade due to high concentrations of DMSO). A critical aspect that should be considered is how these assays and extraction protocols are linked to local and traditional uses. In this way, variables such as the solubility of the compound in the traditional preparation and in the analytical extraction protocol should be taken into consideration
- All chemical line structures must be drawn using a internationally accepted structure drawing programme, must be consistent and - if possible and relevant - the stereochemistry needs to be given.
c) Multiherbal preparations:
Very often multiherbal preparations are used. Full information on their composition (in terms of the botanical drugs / species included) and information on the rationale for studying this preparation needs to be included. It is essential that in these cases sufficient details are provided on the botanical (2a) and chemical (2b) characterisation.
3) Basic requirements and research ethics
Frontiers has very well developed guidelines relating to ethical aspects of a MS. Specifically, for Frontiers in Pharmacology (Ethnopharmacology) the following key requirements are essential:
a) The objectives of the research reported must be spelled out clearly and in detail. All MS must critically assess the scientific basis of the work and provide meaningful conclusions, which are based on a clear hypothesis / research question as defined in the introduction. Ethnopharmacological research must assess whether a compound or plant extract has a certain effect and it cannot be about ‘confirming an extract’s or compound’s effects or efficacy’.
b) Research must add new and scientifically substantive knowledge to our understanding of the pharmacology and use of medicinal plants. A key basis for this is a review of literature relevant to the pharmacological activity already reported on the species including possibly related taxa or compounds. This must be up-to-date, and clearly demonstrate the substantive addition to the literature the MS submitted represents. Simply using advanced measurements/techniques/protocols reproducing previous studies of the same plant product will only be accepted in exceptional circumstances (e.g. previously unknown, highly active components are discovered).
c) Compliance with all international ethical standards is essential. In the context of ethnopharmacology, the Convention on Biological Diversity and, most recently, the Nagoya Protocol are of particular relevance (https://www.cbd.int/abs/).
d) Research in ethnopharmacology is based on local and traditional knowledge often passed on orally over generations. Ultimately, research in this field must therefore benefit those populations who are or were the original keeper of this knowledge.
e) The use of animals must be justified in the context of novelty (see also part 1). It is ethically not acceptable to have yet another in vivo study on an already well-studied species, demonstrating some common activity (e.g. an anti-inflammatory effect studied in the rat-paw edema). The same is true for species which are chemically very similar (and generally are rich in common ingredient) to ones already studied pharmacologically. Such studies must ‘meet(s) the standards of rigor’ we expect in ethnopharmacology as defined in the Frontiers’ guidelines.
4) Other specific requirements
a) Studies focusing on local and traditional uses of plants (ethnopharmacological field studies) must be based on substantial, original data. The relevance of the MS in the context of previous studies in the geographical region must be spelled out clearly and it must contribute to the understanding of the therapeutic uses of plant species and inform experimental or clinical studies This includes an adequate presentation and discussion of the data. Also, social science centered studies (e.g. ethnobotanical studies or health system research of local and traditional medical systems) are welcome. This journal subscribes to the ConSEFS standards including any updates.
b) In case of reviews, we expect clearly defined scientific aims (objectives), a comprehensive, critical and specific assessment of the relevant information linking local and other medical uses to the biomedical and bioscientific evidence. Reviews need to define future research needs and priorities. It is essential that the scientific quality of the original articles cited is assessed. If pharmacological studies are reviewed, particular attention must be paid to assessing the quality of the studies.
c) Food plants are commonly reported to have pharmacological effects. Frontiers in Ethnopharmacology focuses on therapeutic benefits of such species and not on the general food/nutritional properties.
Keywords: natural medicine, cancer prevention, mechanism, constituents, oncogenesis
Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
