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  • Yu-Po Lee1,
  • Hui-Ting Chan1,2 and
  • Robert YL Wang1,4,5,*
  • et al.

Reviewer 1: Vladimir Kalinin Reviewer 2: Anonymous Reviewer 3: Anonymous Reviewer 4: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article is a review concerning anticancer mechanisms of ginsenoside compound K. The “compound K”, namely 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol, is a product of artificial degradation of different glycosides of protopanaxadiol isolated from the roots of Panax ginseng. The use of the compound K instead of saponin mixture seems for any pharmacological purposes seems to be more appropriated because of more standard properties of individual substance in opposite relation to any mixture with different content of individual component. The authors note that the compound K possesses anti-inflammatory, anti-cancer activities and is able to provide cardiovascular, hepatic, and renal protection. It may easy traverse the blood-brain barrier and be administrated orally or by an injection. It may be used in combination with other anticancer preparations, and possesses minimal toxicity and side effects. The compound K has multiple mechanisms for inhibiting cancer and shows great potential in tumor suppression applications. The authors reviewed all studied mechanisms of the compound K antitumor activities illustrating each cell signaling way by very clear and understandable schemes. The article is good popular review that may be useful for the readers and should be published, of course. However, several very minor corrections are necessary.

1. The general formulae of the ginsenosides should be a little corrected and the value of radicals should be depicted as “R1, R2 and R3 = SUGARS”.

2. The structural formula of the compound K also should be presented.

3. Lines 220–226. All the alphabetic references should be converted or expanded into the numbering ones and presented in the References in the end of the manuscript. All other reference numbering should be changed and carefully checked.

4. Line 237. Replace, please “[31].In cancer” with “[31]. In cancer”.

My general opinion: the review should be published after minor revision.

Author Response

GENERAL COMMENTS

The article is a review concerning anticancer mechanisms of ginsenoside compound K. The “compound K”, namely 20-O-β-D-glucopyranosyl-20(S)-protopanaxadiol, is a product of artificial degradation of different glycosides of protopanaxadiol isolated from the roots of Panax ginseng. The use of the compound K instead of saponin mixture seems for any pharmacological purposes seems to be more appropriated because of more standard properties of individual substance in opposite relation to any mixture with different content of individual component. The authors note that the compound K possesses anti-inflammatory, anti-cancer activities and is able to provide cardiovascular, hepatic, and renal protection. It may easy traverse the blood-brain barrier and be administrated orally or by an injection. It may be used in combination with other anticancer preparations, and possesses minimal toxicity and side effects. The compound K has multiple mechanisms for inhibiting cancer and shows great potential in tumor suppression applications. The authors reviewed all studied mechanisms of the compound K antitumor activities illustrating each cell signaling way by very clear and understandable schemes. The article is good popular review that may be useful for the readers and should be published, of course..

Reply: Thank you for your positive comments on the manuscript. We have made relevant deletions and modifications based on your suggestions.

  1. The general formulae of the ginsenosides should be a little corrected and the value of radicals should be depicted as “R1, R2and R3 = SUGARS”.

Response: Thank you for bringing this issue to our attention. Indeed, there are numerous types of ginsenosides, with current academic research focusing on the dammarane-type diol ginsenosides and triol ginsenosides. To make them clear, we have modified the Figure 1 as it showed in the revised manuscript. In addition, we added a table to present the various types and quantities of sugar groups as you will find in the revised figure1.

  1. The structural formula of the compound K also should be presented.

Response: Thank you for your valuable input on this critical aspect of compound K. We have added the structural formula of CK as shown in new Figure 3. Hence, in the revised manuscript, all remaining figure numbers have been corrected.

  1. Lines 220–226. All the alphabetic references should be converted or expanded into the numbering ones and presented in the References in the end of the manuscript. All other reference numbering should be changed and carefully checked.

Response: Thank you for bringing this issue to our attention. We have changed the format of these references, as the numbering is shown in the revised manuscript.

  1. Line 237. Replace, please “[31].In cancer” with “[31]. In cancer”.

Response: We have changed as shown in the revised manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

Abstract is general, need to justify the title and specific to cancer.

Introduction-

-very long, author should divde in subsections.

- In last para author should idetify the gap in current literature and why this is important.

Write the botanical name of Ginseng.

Methodology- Section missing.

In Section 2, mechanism of Ginseng, Include a summerize table.

Conclusion- It is general, author must be able to conclude after reviewing and propose a general mechanism. Also state the future direction of research. 

Referencees: remove unnecessary references include only which are relevant.

 

 

Comments for author File: Comments.pdf

Author Response

1.    Abstract is general, need to justify the title and specific to cancer. 
Response: Thank you for your valuable input on Abstract. We have revised the Abstract (lane 27-48) as shown in the revised manuscript.
2.    Introduction- -very long, author should divide in subsections.
Response: Thank you for your valuable input. Based on your suggestion, we have divided the introduction into three sections. Please refer to our revised manuscript. (1.1. Cancer incidence and etiology; 1.2. Structural difference, chemical and drug properties of ginsenosides; 1.3. The biological metabolism of ginsenosides, the chemical and drug properties of ginsenoside compound K). 
3.    - In last para author should identify the gap in current literature and why this is important.
Response: Thanks for your comment. We have added a section to mention that: “Despite the proliferation of studies on CK, a comprehensive review that consolidates its molecular mechanisms against cancer remains lacking. Furthermore, the objective of this review is to elucidate the pharmacological mechanisms of action of ginsenoside CK by graphically illustrating these complex interactions, with the aim of demonstrating its dramatic effect on suppressing cancer cells. It is hypothesized that, in consideration of the effects of CK on cancer cell proliferation, migration, invasion and angiogenesis of tumor tissues, as well as immune regulation, researchers in the field of drug development will be able to further understand the overall differences caused by CK on cancer signs in non-clinical and clinical outcomes through these microscopic mechanisms related to each other”. Please refer to the revised manuscript (lanes 251-259).
4.    Write the botanical name of Ginseng.
Response: Panax notoginseng, Panax ginseng, and Panax quinquefolius (as shown in lanes 95-96).
5.    Methodology- Section missing.
Response: Thanks for your comment. In fact, this manuscript is a review article, so no methodology section is needed.
6.    In Section 2, mechanism of Ginseng, Include a summerize table.
Response: Thank you for your valuable input. In fact, ginseng itself is a plant containing various active components, such as polysaccharides, ginsenosides, amino acids, vitamins, minerals, flavonoids, and so on. The mechanisms involved are extremely broad, so this review article will focus solely on the 10 mechanisms and effects of ginsenoside CK on cancer.


7.    Conclusion- It is general, author must be able to conclude after reviewing and propose a general mechanism. Also state the future direction of research.
Response: Thank you very much for your valuable input. Yes, we agree with your suggestion and have rewritten the conclusion section as shown in the revised manuscript. (lanes 597-630)

8.    References: remove unnecessary references include only which are relevant
Response: Thank you very much for your valuable input. In the revised manuscript, we have removed some of the "very old" references and added 11 new and relevant references. All references have been reorganized and double-checked throughout the manuscript.

 

Reviewer 3 Report

Comments and Suggestions for Authors

The authors explore the therapeutic potential of ginsenoside CK in cancer treatment. The compound appears to have several promising biological properties, and summarizing available data in a comprehensive way could be valuable to the field. That being said, there are some major and minor issues that should be addressed to improve the quality of the manuscript before it can be considered for publication.

Major points

  1. The introduction contains some elements that, in my opinion, do not fully fit into a scientific manuscript. There is a lot of focus on historical and traditional medicine aspects, such as references to Traditional Chinese Medicine, without providing strong scientific backing. Also, certain parts, for example the etymology of the words “ginsenoside” or “saponin,” seem unnecessary and somewhat off-topic for a research article. I suggest shortening or removing those sections to focus more on the scientific background and rationale for the study. Additionally, there are general statements that are not referenced, such as: “From antiquity to the present day, a total of 3,521 prescriptions have included ginseng.” (Lines 87–88). This kind of sentence requires proper referencing; otherwise, it could be seen as anecdotal or speculative.
  2. Solubility of Ginsenoside CK- Since the authors mention that ginsenoside CK is poorly soluble in water, it raises a practical concern about its administration. How do the authors envision the delivery of this compound in a clinical setting? Oral, intravenous, or maybe through some advanced formulation? Some discussion here would be useful.
  3. In Line 176–177, it is stated that the content of certain ginsenosides is “only 0.001% and 0.003%.” It’s unclear what these values refer to—are they calculated per gram of dry tissue, wet tissue, or something else?
  4. Toxicity and Side Effects - The manuscript refers to ginsenoside CK as having "minimal toxicity" or "minimal side effects," but these statements remain vague. Are there any numerical data available? Even approximate ranges or results from animal models would help to make these claims more credible.
  5. In the conclusion, the authors suggest that ginsenoside CK could be used alongside other cancer therapies. Could the authors give more details or cite examples? Are there any studies on combination therapies involving CK and, for example, chemotherapy or immunotherapy?
  6. In Section 2, many results are summarized, but it’s not always clear whether they come from cell line experiments, animal models, or clinical studies. This distinction is important, especially in the context of doses used and the real-world applicability of these findings. Please clarify where possible.

 

Minor points

Several statements need references. For example: Line 83, Description of AKT1 (Lines 455–459), Lines 430–434. Please make sure that all major biological or mechanistic claims are supported by appropriate literature.

Author Response

  1. The introduction contains some elements that, in my opinion, do not fully fit into a scientific manuscript. There is a lot of focus on historical and traditional medicine aspects, such as references to Traditional Chinese Medicine, without providing strong scientific backing. Also, certain parts, for example the etymology of the words “ginsenoside” or “saponin,” seem unnecessary and somewhat off-topic for a research article. I suggest shortening or removing those sections to focus more on the scientific background and rationale for the study. Additionally, there are general statements that are not referenced, such as: “From antiquity to the present day, a total of 3,521 prescriptions have included ginseng.” (Lines 87–88). This kind of sentence requires proper referencing; otherwise, it could be seen as anecdotal or speculative.

Response: Thank you for your valuable input. We have revised the introduction section as shown in the revised manuscript. The revised manuscript is focused on the pharmacological mechanisms of action of ginsenoside CK by graphically illustrating these complex interactions, with the aim of demonstrating its dramatic effect on suppressing cancer cells.

  1. Solubility of Ginsenoside CK- Since the authors mention that ginsenoside CK is poorly soluble in water, it raises a practical concern about its administration. How do the authors envision the delivery of this compound in a clinical setting? Oral, intravenous, or maybe through some advanced formulation? Some discussion here would be useful.

Response: Thank you very much for your valuable input. Regarding the solubility and administration of ginsenoside CK, we have added the detail description in the section 1.3. The general routes of administration encompass various methods, including eye drops, skin application, sublingual absorption, oral administration, subcutaneous injection, peritoneal injection, intramuscular injection, and intravenous injection, among others. Hydrophilic substances are known to exhibit high biocompatibility, with the capacity to mitigate tissue irritation and inflammatory responses when in contact with the human body. Ginsenoside CK is characterized by its extreme hydrophobicity, which precludes its dissolution in water-soluble preparations. Consequently, researchers frequently employ excipients to enhance the solubility of active principles. Excipient types may include surfactants, glidants, disintegrants, binders, buffers, colorants, flavorings, antioxidants, preservatives, and film-forming agents. Among them, excipients with surfactant properties, such as polyethylene glycol (PEG), have been shown to enhance the solubility of CK in water-soluble preparations. Presently, the predominant administration modalities of CK in non-clinical trials are oral and intravenous injection [new 1, 2, 3], while only oral trials are available in clinical trials [new 11]. The synthesis of ginsenoside CK is challenging, and the cost is significant. In the event that CK is administered orally, a significant portion of the substance may be lost following digestion and metabolism within the gastrointestinal tract. Therefore, in order to maintain a therapeutic dose, it may be more appropriate to administer CK preparations intravenously. Please refer to the revised manuscript (lane )

 

  1. In Line 176–177, it is stated that the content of certain ginsenosides is “only 0.001% and 0.003%.” It’s unclear what these values refer to—are they calculated per gram of dry tissue, wet tissue, or something else?

Response: Thank you for your comment. We have added this description in section 1.3. “However, despite the potential for ginsenoside CK formation through gastrointestinal degradation and microbial transformation in vivo, research by Hasegawa in 1996 indicated that rats fed a total ginsenosides dose of 1g/kg/day showed only a 0.001% conversion rate of CK in their blood after 24 hours” (lanes 172-176). The reference is also provided.

 

  1. Toxicity and Side Effects - The manuscript refers to ginsenoside CK as having "minimal toxicity" or "minimal side effects," but these statements remain vague. Are there any numerical data available? Even approximate ranges or results from animal models would help to make these claims more credible.

Response: Thank you for your valuable input. We have added Tables 1 and 2, and supplemented the description in Section 1.3, Paragraph 4, stating that the effective dose of the drug was found to be mostly within the “no observed adverse effect level (NOAEL)” range in in vivo tests. Please refer to the revised manuscript (lanes 206-217).

 

  1. In the conclusion, the authors suggest that ginsenoside CK could be used alongside other cancer therapies. Could the authors give more details or cite examples? Are there any studies on combination therapies involving CK and, for example, chemotherapy or immunotherapy.

Response: Thank you very much for useful comments. Based on the second reviewer's comments, we revised the original overly broad summary to focus on the topic of this paper: the anti-cancer mechanism of CK. Combination therapy for cancer should not only discuss the original treatment mechanism but also explore the impact of CK on the original treatment mechanism. Therefore, we hope to discuss this issue in a new review paper in the future. Please refer to the new conclusion section as shown in the revised manuscript (lanes 597-630).

 

  1. In Section 2, many results are summarized, but it’s not always clear whether they come from cell line experiments, animal models, or clinical studies. This distinction is important, especially in the context of doses used and the real-world applicability of these findings. Please clarify where possible.

Response: Thank you very much for your valuable input. We provide a summarize table 3.

 

  1. Several statements need references. For example: Line 83, Description of AKT1 (Lines 455–459), Lines 430–434. Please make sure that all major biological or mechanistic claims are supported by appropriate literature.

Response: In addition to the original line 83 being deleted, the text suggested by the reviewer has been added to the end of the relevant sentences with reference numbers.

 

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Author,

"Anticancer Mechanisms of Ginsenoside Compound K: A Review" is an interesting article. There are some strengths and weaknesses in this review. The author covers essential background and prospects that are valuable for researchers. I have a few suggestions and comments, as listed below:

  1. The introduction should contain more qualitative terms.

  2. What are the IC50 and other toxicity values for Ginsenoside and its derivatives?

  3. What is the PK/PD of Ginsenoside?

  4. The introduction should be minimized to 3-5 paragraphs with a logical flow and coherence.

  5. A table summarizing case studies is missing.

  6. A table for patents and preclinical studies is essential.

 

 

Author Response

"Anticancer Mechanisms of Ginsenoside Compound K: A Review" is an interesting article. There are some strengths and weaknesses in this review. The author covers essential background and prospects that are valuable for researchers. I have a few suggestions and comments, as listed below:

  1. The introduction should contain more qualitative terms.

Response: Thank you for your valuable input. We have added new tables 1-3. In addition, the introduction section was revised and provided some qualitative evidence as shown in the revised manuscript.

 

  1. What are the IC50 and other toxicity values for Ginsenoside and its derivatives?

Response: Thank you for your comment. The IC50 of ginsenoside CK was provided as shown in Table 3.

 

  1. What is the PK/PD of Ginsenoside?

Response: Thank you for your valuable input. In fact, pharmacokinetics (PK) can primarily be divided into adsorption, distribution, metabolism, and excretion (ADME), which primarily explores the metabolic processes of drugs within the body. Pharmacodynamics (PD), on the other hand, primarily explores the mechanisms of drug action, efficacy, adverse reactions, safety assessment, and the relationship between dosage and efficacy. Research and discussion on PK/PD require support from multiple relevant research journals. Since this paper focuses on a review of the anti-cancer mechanism of CK and is limited in length, we plan to publish a review paper on CK and PK/PD in the future. We would like to share a review paper with you: Sharma A, Lee H-J. Ginsenoside Compound K: Insights into Recent Studies on Pharmacokinetics and Health-Promoting Activities. Biomolecules. 2020; 10(7):1028.

Additionally, we have added the dose-response results of CK for different types of cancer in both in vitro and in vivo experiments (including IC50 for in vitro experiments) to Tables 2 and 3.

 

  1. The introduction should be minimized to 3-5 paragraphs with a logical flow and coherence.

Response: Thank you very much for your comment. We have rewritten the introduction.

 

  1. A table summarizing case studies is missing.

Response: Thank you for your valuable input. We have added a Table 3.

 

  1. A table for patents and preclinical studies is essential.

Response: Thank you very much for your comment. Table 1 is the summary of safe doses and no observed adverse effect level (NOAEL) in current preclinical toxicity studies of ginsenoside CK. We searched for patents related to ginsenoside CK on the google patent platform and found at least 50-100 precise articles. There should also be more than 20 articles on ginsenoside CK + preclinical studies. However, this review article focuses on the anti-cancer mechanism and does not list relevant patents.

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

I have carefully examined the updated text and confirm that the authors have addressed all the previously raised concerns and implemented the required corrections.

I have not identified any further issues that require revision. In my opinion, the manuscript is now suitable for publication in its current form.

Reviewer 4 Report

Comments and Suggestions for Authors

Dear Author,

 

I appreciate the comments received from the author and strongly recommend accepting it.