Natural Compounds in Gastric Cancer Therapy: Molecular Mechanisms and Potential Treatment Options

Round 1

Reviewer 1 Report (New Reviewer)

Comments and Suggestions for Authors

Cancer is firmly among the top three causes of death in humans. Despite advances in anticancer drug development, the pharmaceutical industry is constantly seeking new small-molecule bioactive compounds due to the observed effects of multidrug resistance and side effects. These findings suggest that the authors' review is important and relevant, but:

- I believe the title of the review does not reflect the substance of the material presented; it focuses solely on the literature review on the use of curcumin and resveratrol for the treatment of gastric cancer and the study of their mechanism of action.

- The review does not provide the structures of curcumin and resveratrol.

- Perhaps attention should be paid to research into the production of hybrid molecules based on these compounds, their targeted delivery, or a clearer delineation of the scope of this review from previously published studies.

- It is known that polyphenols have a targeted effect on topoisomerases, polymerases and other cellular targets.

Author Response

Dear Reviewers. Attached you can find the Word file with the answer to all the comments. Thank you in adance!

Author Response File: Author Response.pdf

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

This paper systematically reviews the multi target mechanisms of CUR and RSV in gastric cancer, covering aspects such as apoptosis, autophagy, cell cycle regulation, signaling pathway modulation, and epigenetic modifications. It also introduces novel drug delivery systems (e.g., nanoparticles, hydrogels) and combination strategies, while pointing out the need for large scale clinical trials and personalized therapy in the future, demonstrating certain guiding significance. The following suggestions are provided to the authors for further improving the manuscript:
1.    It is recommended to specify CUR, RSV, and Gastric Cancer more explicitly in the title.
2.    The abstract is overly lengthy, with some content overlapping with the Introduction. It should be condensed to highlight the core findings and innovations.
3.    The discussion on how novel delivery systems (e.g., nanoparticles, liposomes) can address key clinical bottlenecks such as low bioavailability and rapid metabolism of CUR and RSV should be further expanded.
4.    A critical discussion on the limitations of current clinical trial designs is suggested.
5.    The major obstacles and potential solutions in clinical translation should be further summarized.
6.    Inconsistent formatting in references (e.g., author abbreviations, journal name styles) should be unified according to the journal’s guidelines.

Author Response

Dear Reviewers. Attached you can find the Word file with the answer to all the comments. Thank you in adance!

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

I have no further suggestions and believe this manuscript is now acceptable for publication.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this review article, Dimaki et al., analyze the current applications and molecular mechanisms of natural polyphenolic compounds, particularly curcumin and resveratrol, in the treatment of gastric cancer, highlighting their potential as complementary therapeutic agents. In my opinion, the manuscript addresses a relevant topic in oncobiology; however, some aspects require improvement to enhance clarity and facilitate better understanding for the readers.

The introduction ofers a clear summary of the clinical challenges associated with gastric cancer and highlights the therapeutic promise of natural polyphenols such as curcumin and resveratrol. To improve this section, the authors might add updated epidemiological statistics to better represent current trends in gastric cancer incidence and mortality rates. Furthermore, providing more detailed information on the molecular mechanisms influenced by curcumin and resveratrol, supported by recent research, would deepen the scientific insight. It would also be valuable to address existing obstacles and challenges in advancing these compounds to clinical use, including issues related to bioavailability, delivery strategies, and findings from recent clinical trials. Incorporating these points would enrich the context and emphasize the potential for translating these natural agents into effective therapies.

In section 2, I suggest tyhe authors consider expanding the discussion on the molecular pathways inhibited by curcumin and resveratrol that modulate the metastatic cascade in various cancer types. Additionally, it would be valuable to include and cite more recent studies and references to strengthen the scientific relevance and update the mechanistic insights.

I strongly suggest that the authors consider adding an illustrative figure to the manuscript to facilitate readers’ understanding. Although the authors have included a table describing the differential targeting of oncogenic pathways by CUR and RES, a figure would be highly valuable to further enrich the manuscript. Additionally, I noticed that the table is labeled as "Table 2," but it appears to be the only table in the paper. For consistency, it should be labeled as "Table 1."

To improve the conclusion, the authors could highlight the importance of future studies focusing on improving drug delvery methods to address current challenges in the clinical use of CUR and RSV. They might also mention the necessity of rigorous clinical trials to confirm their combined effects with standard chemotherapy. Discussing issues such as bioavailability, optimal dosing, and safety concerns, as well as potential solutions, would provide a more comprehensive outlook on how these natural compounds can be effectively integrated into gastric cancer treatment.

Author Response

Dear Reviwers! We attached the word Document with the answer to Reviewers. Thank you for your comments and the suggestions!

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript "Natural Compounds in Cancer Therapy: Molecular Mechanisms and Translational Potential" is very hard to read due to the high number of the grammatical errors and poor language. General statements, without clear subject are presented in abstract and introduction.

For example:

line 19 in the abstract: This review examines the current applications and molecular mechanisms.

In introduction:

lines 43-45: Currently, treatment of GC patients is not ideal due to the fact that patients are normally treated in a uniform manner regardless of the disease type.

lines 45-46: GCs are immediately being examined in great detail outside the molecular level with the development of next-generation sequencing and alternative genomic innovations.

lines 46-48: Nevertheless, in the survival phase of patients with cancer, we have not discovered an extraordinary addition, in spite of the high amount of chemotherapeutic agents used.

lines 49-50: The present has led to a view of the surroundings as a rich source of antitumor drugs.

Usually the aims and objectives should be presented at the end of Introduction and I would suggest stating them clearly in this section.

Materials and Methods are placed between Discussion and Conclusions which is unusual, especially if one considers that systematic reviews should use the same structure as research articles and should ensure they conform to the PRISMA guidelines, as is required for Manuscript preparation.

There are serious weaknesses in some statements in the Discussion section:

For example, first sentence of the Discussion is: Curcumin(CUR) and Resveratrol( RSV) are also found to have excellent therapeutic effects.

or 4th phrase is: Its anti-tumor effect is accomplished through the inhibition of said pathways mentioned above.

Another confusing statements in the Discussion of this review are: Additionally, controlled drug release is also performed. Thus, the side effects that could arise are reduced. Furthermore, it was observed that they enhance the anticancer action with a reduced IC50 value (25μM compared to 50μM) - this kind of statements are improper for a review, one may think these results are obtained during the presented study.

The contributions of each authors are not mentioned in the specific section.

The authors made no statements on Data availability or conflict of interest.

Comments on the Quality of English Language

After extensive English editing, I encourage resubmission once the serious flaws are revised in order to be understood correctly by the readers.

Author Response

Dear Reviwers! We attached the word Document with the answer to Reviewers. Thank you for your comments and the suggestions!

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I thank the authors for their efforts to improve the quality of the manuscript