Amphibian-Derived Natural Anticancer Peptides and Proteins: Mechanism of Action, Application Strategies, and Prospects
Round 1
Reviewer 1 Report
Dear Authors,
This is a very interesting topic and work. The protective pathways are well described and detailed.
I have a few questions:
1/ can the authors precise the mode of intake which is the most considered for clinical studies in the future? Oral, injections (I have seen the discussion on peptidase for sure and the inclusion of d-AAs)?
2/ Are there a lot of clinical studies or are they “all” evoked here?
3/ Could the authors include a short paragraph on doses in vitro and in vivo? They are rarely precised and how do they compare with other natural drugs, for ex vegetal: (alcaloids, essential oils/terpenes)?
4/ Could the authors discuss more the possible link between antioxidant activity of these peptides with cancer initiation and development?
The respiration by skin for the amphibians may have contributed to their strong antioxidant skin capacity (among other parameters like sun exposure) which may improve their resistance to cancer processes.
Like in this paper:
Yang H, Wang X, Liu X, Wu J, Liu C, Gong W, Zhao Z, Hong J, Lin D, Wang Y, Lai R. Antioxidant peptidomics reveals novel skin antioxidant system. Mol Cell Proteomics. 2009 Mar;8(3):571-83. doi: 10.1074/mcp.M800297-MCP200
Could you discuss in particular the presence of certain amino acids in some of the peptides from your review in comparison to this last publication, like for Antioxidin-RP1 (AMRLTYNKPCLYGT):
“It has been mentioned above that all the groups of antioxidant peptides contain proline residue in their sequences. Furthermore sulfur-containing amino acids (methionine and cysteine) (32, 37), a phenol-containing amino acid (tyrosine) (32), tryptophan (37), and proline (38) have been suggested to contribute antioxidant functions.”
Proline, methionine, free cysteine, tyrosine, and tryptophan seem to be key.
“The replacement of proline, methionine, free cysteine, or tyrosine obviously decreased their antioxidant capability, whereas tryptophan replacement just had a slight effect on the antioxidant capability. Replacing all these amino acid residues eliminated their antioxidant function. For the peptides containing both antioxidant and antimicrobial activities (pleurain-A, -D, -E, -G, -J, -M, -N, and -R), the amino acid replacements had no obvious effects on their antimicrobial capability, although their antioxidant functions had been intensively destroyed or even completely eliminated.”
“Antioxidin-RP1 has been found to be the most potent antioxidant peptide and to contain most of the amino residues responsible for antioxidant function (methionine, free cysteine, tyrosine, and proline).”
For small corrections:
L 26
However (é times)
L 37
In fact, as of June 2023, 108 out of 276 natural anticancer peptides are 37 derived from amphibians(https://aps.unmc.edu/database/anti).
Would you have another reference to reinforce that?
With these adds and answers/discussions, I recommend this work for publication.
Best regards
Author Response
Dear reviewer and editor, attached is our response, thanks again for your comment!
Author Response File: 
Author Response.docx
Reviewer 2 Report
I found the manuscript coauthored by Chen, Wu, Li, Ye, Yang and Mu to be interesting and quite well written. The authors describe a large amount of research and do so in a manner that I found easy to read. Importantly, the manuscript serves as a rich source of useful insights concerning the roles of amphibian-derived peptides and proteins as anticancer agents. As indicated in the manuscript’s title, the authors describe “mechanism of action, application strategies and prospects” and do so in a scholarly manner that I believe will be of interest and use to readers.
A few minor issues that deserve attention include:
• The authors write: “Cancer has become the leading cause of premature death in most…” Is it the LEADING cause?
• Note “however” is repeated in “therapeutic efficacy. However, However, “
• The authors write “Therefore, there is an urgent need for more” Is the need truly urgent?
Please read my review.
Author Response
Dear reviewer and editor, attached is our response, thanks again for your comment!
Author Response File: Author Response.docx
Reviewer 3 Report
This manuscript provides a review on therapeutic potential of amphibian-derived natural anticancer peptides and proteins. The manuscript also includes the physicochemical properties of natural anticancer substances found in amphibians, mechanism of action, application strategies, and future development prospects. Considering the importance of therapies based on natural substances in cancer treatments, this manuscript significantly contributes to the corresponding field. However, I suggest several things to improve the quality of this manuscript.
<Minor points>
1. Introduction is too short. Introduction can include the importance of natural products from amphibians, representative examples of amphibian-derived anticancer products, and their therapeutic effects in more detail.
2. The word ‘However’ is repeated (page 1, line 26).
3. Why does the story of HuaChansu suddenly appear? Are they also amphibian-derived anticancer products? If not, the story of HuaChansu disturbs the natural flow of sentences.
4. In Tables 1 and 2, the number of amino acid residues comprising the respective peptides can be added in a separate column.
5. in Section 3, many references are missing (e.g. page 5, lines 73-77, lines 94-96, etc.).
6. In Table 2, how were the values of charge calculated? Please explain it at the bottom of the table.
7. Peptide-based drugs usually have several intrinsic limitations such as low solubility, low bioavailability, and low specificity. In Section 5, the authors can state these limitations, strategies to overcome these limitations, and current development situation/trend.
Minor editing of English language required
Author Response
Dear reviewer and editor, attached is our response, thanks again for your comment!
Author Response File: Author Response.docx
