Comprehension of the Relationship between Autophagy and Reactive Oxygen Species for Superior Cancer Therapy with Histone Deacetylase Inhibitors

Round 1

Reviewer 1 Report

In this review, the authors describe several aspects involving ROS, HDAC inhibitors, hypoxia and autophagy. The paper addressed a timely issue but the structure of the manuscript is confusing, they focus too much on autophagy and the role of HDACs and ROS is not fully discussed.

In my opinion, the manuscript could be published after restructuring.

The manuscript needs a section on histone modifications and cancer.

If the focus of the paper is the interactions between autophagy and ROS in cancer, then the title should be changed.

A section on ROS and cancer is also needed.

A final section discussing the main theme of the review (HDACs and ROS in cancer) is mandatory.

English is fine but some mistakes need to be corrected  in order to make the manuscript easily readable.

Specific comments,

Line 29, please replace concerned with involved

Section 2 refers to ROS and autophagy and it is illustrated with a figure referring to ROS and HDAC inhibitors in cancer therapy (Figure 2).  The figure is not related to the text.

Line 152, on section 3, labeled Hypoxia and tumor progression, the authors state: “Radiation therapy kills tumors by generating ROS”. How is this related to the title of the section?

Title for section 5: Cells-fate either protection/survival or necrosis/ programmed cell death/apoptosis could be determined by the autophagy in all cancerous/normal types of cells” is confusing, please rephrase.

Author Response

For Reviewer 1: Thank you very much for the good evaluation on our manuscript and the good advices. According to the comments, we had improved the manuscript.

1. In this review, the authors describe several aspects involving ROS, HDAC inhibitors, hypoxia and autophagy. The paper addressed a timely issue but the structure of the manuscript is confusing, they focus too much on autophagy and the role of HDACs and ROS is not fully discussed. In my opinion, the manuscript could be published after restructuring. The manuscript needs a section on histone modifications and cancer. If the focus of the paper is the interactions between autophagy and ROS in cancer, then the title should be changed. A section on ROS and cancer is also needed. A final section discussing the main theme of the review (HDACs and ROS in cancer) is mandatory. English is fine but some mistakes need to be corrected in order to make the manuscript easily readable.

Responce: Thanks for the critical evaluation to our manuscript. This is valuable to us for the improvement of the manuscript. According to the suggestion, we have changed the title as, “Comprehension of the relationship between autophagy and reactive oxygen species for superior cancer therapy with histone deacetylase inhibitors”. In addition, we have improved the explanation about “ROS and cancer” at appropriate places in the text. Again, we have gone over the text/abstract and amended typos, misspellings and grammatical errors in the previous manuscript as much as possible in order to improve the manuscript more helpful to the readers.

2. Specific comments, Line 29, please replace concerned with involved

 Responce: we have replaced concerned with involved in line 29. Thank you.

3. Section 2 refers to ROS and autophagy and it is illustrated with a figure referring to ROS and HDAC inhibitors in cancer therapy (Figure 2). The figure is not related to the text.

 Responce: According to this indication, we have changed the place referring Figure 2. We have added the explanation in the figure legend of Figure 2.

4. Line 152, on section 3, labeled Hypoxia and tumor progression, the authors state: “Radiation therapy kills tumors by generating ROS”. How is this related to the title of the section?

Responce: We have improved the explanation for this in the text as “In addition, hypoxia is a common feature of solid tumors and it is defined as one of the most important causes for radiotherapy failure [50]. Radiation therapy kills tumors by generating ROS, since ROS are the effector molecules of radiation contributing to radiation-induced DNA damage and cancer cell death [50]”, on section 3.

5. Title for section 5: Cells-fate either protection/survival or necrosis/ programmed cell death/apoptosis could be determined by the autophagy in all cancerous/normal types of cells” is confusing, please rephrase.

 Responce: According to this suggestion, we have changed the title of section 5 as “A matter of cell-life or cell-death could be determined by autophagy in both cancerous and normal types of cells”.

Reviewer 2 Report

This review purports to be about the relationship between HDAC inhibitors and ROS, but there is only one sentence (lines 221-223) that links these two factors. The figures don't really make sense to link these two factors, either. This is really a report on autophagy, I think. The paper either needs to be significantly reworked to discuss the potential of HDAC inhibitors to reduce chemo- and radioresistance in tumor cells with high ROS or to discuss the broader role of autophagy in tumor cells and how these two factors can play into that role. Further, you use the term "cell fate," which is generally (particularly in epigenetics) used to describe the mechanisms involved in cell differentiation decisions, not in determining whether a cell undergoes apoptosis. I think this terminology is going to be very confusing to the reader. 

Figures 2 is very confusing. I think this comes from an attempt to shoehorn these two ideas together that you haven't really made a case for in the text.

The language requires significant revision.

Author Response

For Reviewer 2: Thank you very much for the critical evaluation on our manuscript and the good advices. According to the comments, we had improved the manuscript.

1. This review purports to be about the relationship between HDAC inhibitors and ROS, but there is only one sentence (lines 221-223) that links these two factors. The figures don't really make sense to link these two factors, either. This is really a report on autophagy, I think. The paper either needs to be significantly reworked to discuss the potential of HDAC inhibitors to reduce chemo- and radioresistance in tumor cells with high ROS or to discuss the broader role of autophagy in tumor cells and how these two factors can play into that role. Further, you use the term "cell fate," which is generally (particularly in epigenetics) used to describe the mechanisms involved in cell differentiation decisions, not in determining whether a cell undergoes apoptosis. I think this terminology is going to be very confusing to the reader.

Responce: According to the suggestion, we have changed the manuscript title as, “Comprehension of the relationship between autophagy and reactive oxygen species for superior cancer therapy with histone deacetylase inhibitors”. In addition, we have improved some explanation about the cancer therapy at the appropriate places. As for "cell fate", your suggestion is very very important. We should have used the term “destiny” instead of “fate”. Thank you very much. In relating to this point, we have changed the title of section 5 as “A matter of cell-life or cell-death could be determined by autophagy in both cancerous and normal types of cells. In addition, we have changed the “cell-destiny” term at several places in the text and in Figure 1.

2. Figures 2 is very confusing. I think this comes from an attempt to shoehorn these two ideas together that you haven't really made a case for in the text.

Responce: True. We have improved the explanation for Figure 2 in the text as well as in the figure-legend of Figure 2.

3. The language requires significant revision.

 Responce: We have gone over the text/abstract and amended typos, misspellings and grammatical errors in the previous manuscript as much as possible in order to improve the manuscript more helpful to the readers.

Round 2

Reviewer 1 Report

In this manuscript, the authors explore the role of autophagy and ROS during cancer therapy with HDAC inhibitors. The manuscript discusses several aspects related to cancer therapy but the main focus of the work remains confusing.  

Author Response

Thanks for the critical evaluation to our manuscript. According to the former suggestion, we have changed the title of final section 5 as, “Histone modification in cancer and future perspectives”. We have explained the histone modification in cancer therapy in the perspective section. In addition, we have again gone over the text/abstract and amended typos and grammatical errors as much as possible to improve the manuscript more helpful to the readers.

Reviewer 2 Report

Although this text reads much better in terms of the main thesis, the language still requires further revision. Consider having a colleague whose first language is English or an editing service revise this.

Author Response

According to the suggestion, again we have gone over the text/abstract and amended typos and grammatical errors with a help of English speaker as much as possible to improve the manuscript more helpful to the readers.