Ashwagandha-Induced Programmed Cell Death in the Treatment of Breast Cancer

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript (review article) investigates the potential anticancer properties of Withania somnifera, or ashwagandha, especially in relation to Withaferin A (WA), and specifically how it might be used to treat breast cancer. One important strength is the emphasis on programmed cell death, particularly apoptosis, as the mechanism by which ashwagandha (primarily, Withaferin A) exerts its anticancer effects. This focus is consistent with current advancements in cancer treatment, which aim to specifically kill cancer cells by focusing on specific cellular pathways.

However, the author made no mention of any potential risks or challenges associated with using ashwagandha to treat breast cancer or any other type of cancer. A fair review should consider potential side effects, interactions with established treatments, and differences in response among different patient populations.

Also, there is no mention of clinical trials or real-world evidence supporting the use of Ashwagandha in breast cancer therapy. While experimental evidence from literature is valuable, clinical studies are crucial for validating the efficacy and safety of Ashwagandha in human patients. I recommend putting a small paragraph at the end of the main body mentioning its limitation of usage as well as the data/information of clinical trial.

Although there are a few review articles exist regarding the potentials of Withaferin A, this article elucidates specifically the potential of ashwagandha in the treatment of breast cancer by inducing programmed cell death, particularly through apoptosis. While, the article covers several types of breast cancer over an extensive period of time, it could also use some critical assessment of the clinical evidence and any potential limitations. By addressing these issues, the potential of ashwagandha in anticancer therapy would be better understood in a comprehensive and balanced manner.

 

 

 

 

 

 

 

 

Author Response

Comments to the Reviewer

We would like to thank the Reviewer for the valuable remarks and comments, which significantly helped us to improve our manuscript. Below we present point-by-point responses to the comments.

The comments are attached.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review examines experimental evidence supporting Ashwagandha's (Withania somnifera) role in inducing programmed cell death in breast cancer therapy. A literature search from 2004-2024 identified that active compounds, particularly Withaferin A (WA), demonstrate significant anticancer properties. The findings suggest its potential efficacy in treating both ER/PR positive and triple-negative breast cancer.

 

This review covers an intriguing and cutting-edge topic, namely the use of phytochemicals in cancer treatment, specifically from a plant that has been traditionally used by various cultures for years. The article is well-structured and provides detailed information on the mechanisms of action of the metabolites against breast cancer. It includes comprehensive graphical descriptions of these mechanisms and a well-founded conclusion. However, several observations are made to enhance the presentation and content, as outlined below:

 

1.       Line 27: In this assertion, it would be important to support it with a specific and current reference regarding the global incidence and prevalence of cancer and its relationship to annual mortality rates. This would emphasize the significance of this disease on a global scale.

2.       Line 29: It would be advisable to mention epigenetic modifications, as this is an essential concept in the etiology of cancer and is related, for instance, to diet.

3.       Line 33: It would be advisable to indicate the meaning of the receptor abbreviation.

4.       Line 50: The toxicity of phytochemical therapies is not mentioned, and addressing this aspect is crucial for validating their use as an alternative by reducing side effects, costs, and enhancing therapeutic efficiency.

5.       Line 65: Since metastasis involves several processes, it is advisable to mention which ones WS affects, such as angiogenesis, extracellular matrix modification, etc.

6.       Line 79: It is important to specify the total number of articles reviewed.

7.       Line 81: It is not specified whether the studies were preclinical, clinical, or both.

8.       Line 107: What about withanolide A (C28 H38 O6)?

9.       Line 110: What about Withanolide Glycosides in fruits?

10.   Line 116: I suggest using a different word, as this one, while referring to a substance that is part of a mixture, is more commonly used in culinary contexts.

11.   Figure 1: I suggest specifically indicating whether these ingredients are active as anticancer agents, as otherwise it might appear that they are the only compounds with biological activity in this plant. This is not the case, as compounds like chlorogenic acid, for example, are present in many plants and have therapeutic biological effects.

12.   Line 136: It would be highly advantageous to summarize the information and provide only brief descriptions of generalities. Furthermore, it is crucial to align the focus with the title on the mechanism of cell death induced by WS. While the information on the mechanisms involved in breast cancer is interesting and descriptive, emphasizing the WS effect is essential. Additionally, it would be appropriate to specify the concentrations and doses used in each study, whether they are preclinical or clinical, and the WS metabolites tested. As this is a review, providing such details ensures a comprehensive understanding of the topic. Lastly, why is there no mention of alterations in the cell cycle due to activation of proto-oncogenes and genes?

13.   Figure 2: The figure is not referenced in the text, and it would be advantageous to include a brief figure legend to clarify the intended presentation. Currently, the figure lacks clarity regarding WS's action in apoptosis pathways; these actions should be clearly delineated within the figure.

14.   Figure 3: The figure is not referenced in the text, and there is a lack of a brief figure description.

 

Author Response

We would like to thank the Reviewer for the valuable remarks and comments, which significantly helped us to improve our manuscript. 
In the Appendix we present point by point responses to comments.

Author Response File: Author Response.pdf