Usefulness of Natural Phenolic Compounds in the Fight against Esophageal Cancer: A Systematic Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this manuscript titled "Usefulness of Natural Phenolic Compounds in the Fight Against Esophageal Cancer: A Systematic Review", Eugene Jamot Ndebia et al. discussed the anti-esophageal cancer effects of natural phenolic compounds. The manuscript is well done overall, and I think the following modifications are needed:

 

1. The author should add sufficiently attractive mechanism pictures to make the reader's reading smoother.

 

In summary, I think the manuscript needs to be revised.

Author Response

Question 1: The author should add sufficiently attractive mechanism pictures to make the reader's reading smoother.

Response 1: Figure 2 has been included to present the overall mechanism of action of the different phenolic compounds.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

After thorough evaluation, I regret to inform you that the manuscript falls short of the standards required for publication in its current form. The review merely presents a collection of natural compounds from various studies along with their IC₅₀ values, without providing any substantial analysis/study. The manuscript lacks a clear discussion on the comparative effectiveness of these natural compounds relative to conventional therapies, such as chemotherapy. It also fails to explore the potential of these compounds to alleviate side effects or their prospects for clinical application. Additionally, the introduction is notably inadequate, offering little background on oesophageal cancer or the significance of phenolic compounds. There is no clear articulation of the research gap the review aims to address, nor does the manuscript present any visual representations of the data, such as mechanistic diagrams, which are crucial for understanding the context and implications of the findings. Given these significant shortcomings in depth, analysis, and presentation, the manuscript does not meet the criteria for publication. We recommend that the authors undertake a major revision, including a more comprehensive discussion, improved organization, and additional tables and figures, before resubmitting to any other journal.

Recommendation: Rejection

In this review, the authors have primarily compiled and presented data from various studies. The review focuses on 20 plant-derived phenolic compounds and reports their IC₅₀ values against oesophageal cancer cells, but it falls short in several critical areas.

The review lacks a thorough discussion of the mechanisms of action by which these phenolic compounds exert their anticancer effects. Simply presenting IC₅₀ values without accompanying mechanistic insights limits the usefulness of the review. Readers would benefit from a detailed exploration of how these compounds interact with cancer cell pathways, induce apoptosis, inhibit proliferation, or modulate other key biological processes.

The absence of plausible mechanistic figures or diagrams is a significant shortcoming. Visual representations can effectively illustrate the molecular pathways affected by these compounds, making the data more accessible and understandable for the reader. Including such figures would enhance the clarity and impact of the review.

The review fails to bridge the gap between in vitro findings and clinical application. There is no discussion of the translational potential of these compounds, such as their bioavailability, pharmacokinetics, or any existing clinical trial data. Without addressing the clinical relevance, the review does not sufficiently inform on the practical applicability of these findings in a real-world context.

The authors have not critically evaluated the strengths and limitations of the studies they included. There is no discussion of the methodological quality of the studies, potential biases, or variability in experimental conditions that could affect the reliability of the reported IC₅₀ values. A more rigorous analysis would provide a deeper understanding of the data's robustness and generalizability.

The review does not provide any substantial discussion on future research directions or how these phenolic compounds could be further developed into viable therapeutic agents. Identifying gaps in the current research and suggesting areas for future investigation would make the review more forward-looking and valuable to the scientific community.

The review compiles relevant data on phenolic compounds and their potential anticancer activity, it falls short in providing a comprehensive and insightful analysis. The lack of mechanistic explanation, absence of clinical relevance, and minimal original contribution significantly limit the review’s impact. The authors are encouraged to delve deeper into the mechanisms of action, critically evaluate the studies they included, and explore the translational potential of these compounds to enhance the review's value and relevance.

The introduction fails to provide essential background information about esophageal cancer, including its epidemiology, risk factors, and clinical challenges. There is no discussion of why oesophageal cancer is a significant health issue or what makes it particularly difficult to treat. This lack of context leaves readers without a clear understanding of the problem the review aims to address.

This review merely presents different compounds from various plants along with their IC50 values, but it fails to provide any meaningful explanation or analysis beyond this. There is no discussion on the relevance of these findings, the mechanisms of action of the compounds, or how these compounds might translate into practical therapeutic options.

This review does not adequately explain how natural compounds compare to chemotherapy or other conventional therapies in terms of effectiveness. Additionally, the review fails to discuss how natural compounds might alleviate the side effects caused by other medications. There is also a lack of information on how these natural compounds could be transitioned into clinical use.

Typically, one table and one figure may not be sufficient for a comprehensive review article, especially if the review covers a broad or complex topic. The purpose of tables and figures in a review is to effectively summarize, organize, and visually present key information, making it easier for readers to understand the content.

Comments for author File: Comments.docx

Author Response

Analysis and Discussion:

Question 1: The manuscript presents only IC₅₀ values for natural compounds without a thorough analysis.

Response 1: In addition to IC₅₀ values, the Results section includes in vivo findings, available mechanisms of action, and potential toxicological and pharmacokinetic information. However, the discussion and results were compared and evaluated using the cutoff defined by Kuete and Effeth.

Question 2: There is a lack of discussion on the mechanisms of action of the compounds and their comparison with conventional therapies such as chemotherapy.

Response 2: The discussion on the mechanisms of action of the compounds and their comparison with conventional therapies, including chemotherapy, has been addressed in the Discussion section, lines 383-399.

Clinical Application:

Question 3: There is no discussion on the clinical relevance of the compounds, their bioavailability, pharmacokinetics, or clinical trial data.

Response 3: The lack of information on these aspects is acknowledged and has been noted as a limitation in the Limitations section (lines 409-426).

Question 4: There is no link between the in vitro results and their potential clinical application.

Response 4: The connection between the results and their potential clinical application has been added to lines 395-399.

Question 5: There is no critique of the strengths and limitations of the included studies, nor any analysis of biases or experimental variability.

Response 5: The strengths and limitations of the included studies have been critiqued in lines 409-426.

Question 6: The introduction is insufficient, lacking context on esophageal cancer and the significance of phenolic compounds.

Response 6: The reviewer's recommendations regarding the lack of context on esophageal cancer and the significance of phenolic compounds have been incorporated. Please refer to the Introduction, lines 36-40 and 44-60.

Question 7: There are no figures or mechanistic diagrams to illustrate the molecular pathways affected by the compounds.

Response 7: Figure 2 has been included to present the overall mechanism of action of the different phenolic compounds.

Question 8: The manuscript does not provide a discussion on future research directions or the potential development of the compounds as therapeutic agents.

Response 8: Future research directions and potential development of the compounds as therapeutic agents are discussed in the Limitations and Future Perspectives section (lines 409-426).

Question 9: The number of tables and figures is insufficient to effectively summarize and organize key information.

Response 9: Figure 2 illustrates the mechanism of action, and Table 2 summarizes the in vitro and in vivo activities of the various phenolic compounds.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The article submitted for review concerns natural compounds described in the literature with a proven effect against esophageal cancer, both squamous cell cancer and adenocarcinoma.

            The Authors analyzed publications from recent years, selected significant ones, and then selected 25 phenol-derived compounds with documented anti-cancer activity.

            Each of them is further discussed and then those that are already interesting themselves or whose metabolites could be active against esophageal cancer.

            The submitted text is a summary of extensive exploratory research and, as the Authors suggest, may be helpful in the search for new effective drugs with low adverse side effects and especially low toxicity to healthy human cells.

            After reading the text, I admit that it is well thought out and edited and can be published, but with a slight correction.

            The Abstract and Introduction do not emphasize the existence of two basic types of Esophageal Cancer, this information appears in chapter 2, point 2.1 (EAC, ESCC). It seems to me that both in the Abstract and in the Introduction, this should have already been signaled.

            While reading, I found only a few "slip-ups". The molecular formulas of Purpurogallin (p. 9, point 3.8) and Plumbagin (p. 12, point 3.23) should have numerical subscripts: C11H4O(OH)4 C₁₁H₄O(OH)₄ and C11H8O3 C₁₁H₈O₃

            Name 3.18: Theaflavin-3-3'-digallate (in Table 1, page 6, repeated twice more in point 3.18) should be: Theaflavin-3,3'-digallate.

            In addition, the description of compound 13 (2,6-Bis-benzylidenocyclohexanone, in the name "deno" and not "dine") and the corresponding point 3.14 (the others should be shifted) have been "lost"

            For ease of reading, in the first column of Table 1 it would be necessary to provide the number of the selected chemical compound, consistent with the later description.

 The above are such minor defects that it is embarrassing to point them out.

I have no more comments.

Author Response

Question 1: The Abstract and Introduction do not emphasize the existence of two basic types of Esophageal Cancer, this information appears in chapter 2, point 2.1 (EAC, ESCC). It seems to me that both in the Abstract and in the Introduction, this should have already been signaled.

Response 1: This suggestion has been addressed as recommended by the reviewer; please refer to the Introduction, lines 49-52.

Question 2: While reading, I found only a few "slip-ups". The molecular formulas of Purpurogallin (p. 9, point 3.8) and Plumbagin (p. 12, point 3.23) should have numerical subscripts: C₁₁H₄O(OH)₄ C11H4O(OH)4 and C11H8O3 C₁₁H₈O₃

Response 2: This suggestion has been corrected as advised by the reviewer; see lines 180 and 332.

Question 3: Name 3.18: Theaflavin-3-3'-digallate (in Table 1, page 6, repeated twice more in point 3.18) should be: Theaflavin-3,3'-digallate.

Response 3: This suggestion has been revised as suggested by the reviewer; please check line 294.

Question 4: In addition, the description of compound 13 (2,6-Bis-benzylidenocyclohexanone, in the name "deno" and not "dine") and the corresponding point 3.14 (the others should be shifted) have been "lost"

Response 4: This suggestion has been amended according to the reviewer's recommendation; see line 246.

Question 5: For ease of reading, in the first column of Table 1 it would be necessary to provide the number of the selected chemical compound, consistent with the later description.

Response 5: This suggestion has been updated as per the reviewer's advice; refer to Table 1.

Author Response File: Author Response.docx

Reviewer 4 Report

Comments and Suggestions for Authors

The article “Usefulness of Natural Phenolic Compunds in the Fight Against Esophagal Cancer: A Systematic Review” has concise target expressed in the title that was achieved. Everything has been carried out in a straightforward manner; I learned about new compounds and agents I wasn’t familiar with before. I have almost no criticism but one or two remarks.

1. Regarding the order of introduction of abbreviations

Before the abbreviation EC is used (Abstract, line 22) it should be defined. 

Simply Line 8: Esophagal Cancer (EC)

 

In line 88 and 89 the abbreviations ESCC and EAC are used but are defined only afterwards in the legend of Table 1.

 

Last line in the first paragraph of the Discussion (For some reason the line numbering stopped after line 89). : Delete one dot.

2. A more general observation and food for thought: The authors follow the idea to choose a promising structure and derive a drug from it, the usual approach of pharmaceutical companies and their research. However, recently another approach has been made popular: Use all the differences between cancer cells and normal cells to starve cancer and then to kill it. This approach is beautifully described in Jane McLellands book: “How to starve cancer without starving yourself” and her updated book: “How to starve cancer and then kill it with ferroptosis.” Here, it is not a single, unique drug doing its magic but a combination of many natural substances. (although later she also includes off-label medications like, for instance, Metformin). The CareOncology Clinic in the UK follows very similar protocols (https://careoncologyclinic.com). This different approach was successful not only for McLelland herself but for many people who implemented it. It really works as can be learned from McLeelands facebook site https://www.facebook.com/howtostarvecancer/.

This change of approach is a consequence of learning that cancer is first and foremost a metabolic disease (which, of course, also includes epigenetics.)

To repeat; I don’t believe in magic bullets but certainly in targeted agent combinations.

I wish the authors all success!

Comments for author File: Comments.pdf

Author Response

Question 1: Regarding the order of introduction of abbreviations. Before the abbreviation EC is used (Abstract, line 22) it should be defined.

Response 1: This suggestion has been amended according to the reviewer's recommendation; see line 8.

Question 2: In line 88 and 89 the abbreviations ESCC and EAC are used but are defined only afterwards in the legend of Table 1.

Response 2: This suggestion has been amended according to the reviewer's recommendation; see lines 50-51.

Question 3: In the last line of the first paragraph of the Discussion (for some reason, the line numbering stopped after line 89): Remove one dot.

Response 3: This suggestion has been amended according to the reviewer's recommendation

Observation: A more general observation and food for thought:

Response: The authors would like to thank the reviewer for this insightful observation, which also represents another potential therapeutic avenue for esophageal cancer. We will consider exploring this approach in our future work. Regards.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

accept

Reviewer 2 Report

Comments and Suggestions for Authors

Authors have answered all my comments very well. Hence, I am happy to accept this manuscript. Before going to publish please put the source of Figure 2, whether created using biorender /any other app or acceessed from any other paper.