Preclinical Testing of Chronic ICA-1S Exposure: A Potent Protein Kinase C-ι Inhibitor as a Potential Carcinoma Therapeutic

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The paper entitled "Preclinical testing of chronic ICA-1S exposure: A potent protein kinase C-ι inhibitor as a potential carcinoma therapeutic" by Christopher et al. found that 5-amino-1-(2,3-dihydroxy-4-hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S) could potentially be used as an oral therapeutic either with or in place of some therapeutics currently in use and further efforts should be made to develop the compound for clinical use. This is interesting. The paper is well-written and organized. It is good to be published in this journal.

 

Author Response

Dear Madam/Sir,

Thank you for your review and comments on the manuscript. We will submit the revised version on or before 31st January.

Thank you. 

Sincerely, 

Christopher A. Apostolatos 

Reviewer 2 Report

Comments and Suggestions for Authors

Christopher A. Apostolatos, et al. investigated the preclinical testing of chronic ICA-1S exposure. Basically, this is a very good clinical study supported by persuasive data and discussion.

 

 

I just recommend the authors introduce more about the significance of using ICA-1S in carcinoma therapeutic as a kinase C-1 inhibitor, and particularly the uniqueness or the novelty of this study. 

Author Response

Dear Madam/Sir,

Thank you for your review and comments on the manuscript. We will submit the revised version on or before 31st January.

Thank you. 

Sincerely, 

Christopher A. Apostolatos 

Reviewer 3 Report

Comments and Suggestions for Authors

Review report on article entitled « Preclinical testing of chronic ICA-1S exposure: A potent protein kinase C-ι inhibitor as a potential carcinoma therapeutic » (ddc-2722109-peer-review-v1).

The authors propose a research article on preclinical testing studies around a kinase inhibitor. The article was primarly submitted to Molecules.

Some major corrections/optimizations need to be made to achieve the quality standard required by the DDC journal.

Please see the review report attached.

Comments for author File: Comments.docx

Comments on the Quality of English Language

In general, have the entire manuscript proofread by a native English-speaking scientist to correct the English (grammar, spelling, style).

Author Response

Dear Madam/Sir,

Thank you for your review and comments on the manuscript. We will submit the revised version on or before 31st January.

Thank you. 

Sincerely, 

Christopher A. Apostolatos 

Reviewer 4 Report

Comments and Suggestions for Authors

ICA-1S is a potent protein kinase C-iota inhibitor, which is the subject of the submitted study. Following toxicological approval, the compound was found effective against tumor growth in cell lines tests. Chronic mouse models were used to validate long term effects. The study design included the evaluation of the usual organs as heart, liver, kidney, brain, serum assessment of AST, ALK-P, GGT, troponin and CRP was done as well. For toxicity prediction in humans predictive in vitro and in silico methods were used.

The study design is excellent, the applied methods are relevant and the obtained results are properly presented.

Comments

1.       Introduction. Please mention where ICA-1S comes from? How was it found that it is an inhibitor of potein kinase C-iota? Is it synthetic? Is it difficult to produce? The mentioned compound might have a clinical / pharmacological potential, based on the results presented here. Does it have a realistic pharmacological production perspective?

2.       The Methods are written appropriately.

3.       The Results are written in logical way, the figures are good quality, the Discussion is relevant and remains in context with the Results.

Author Response

Dear Madam/Sir,

Thank you for your review and comments on the manuscript. We will submit the revised version on or before 31st January.

Thank you. 

Sincerely, 

Christopher A. Apostolatos 

Reviewer 5 Report

Comments and Suggestions for Authors

In the present manuscript Apostolatos et al. describe preclinical studies on the known protein kinase C-ι inhibitor ICA-1S. Investigations on chronical toxicity in a mouse model as well as studies by an in-vitro/in-silico based method to predict toxicity of ICA-1S on the liver and the kidney as established earlier were presented. This method uses high-content imaging (HCI) of treated human renal proximal tubule cells (HPTCs) and HepaRG cells and applies a number of parameters (either 5 or a 30 dimensions) to predict the toxicity compared to a reference compound library. The predictions gave no toxicity of ICA-1S on HPTCs. This was confirmed by the fact, that cell number after 16 hours of treatment was not negatively affected by up to 800 µM of ICA-1S. In contrast, hepatocyte toxicity of ICA-1S as predicted by the model applied, could not be confirmed with reference to cell number and the investigations on the cytoplasmic-to-nuclear translocation of the proto-oncogene RELA. The manuscript appears well written and comprehensive in most parts. After correcting some minor points, it would be well suited for being published in DDC.

Minor remarks:

1)      Plasma murine drug quantification: It is not clear at what time after the final daily dose the animals were sacrificed for each experiment, respectively. It is only said „either 6 or 18“. As shown in [9] this could have severe effects on plasma concentration.

2)      Figure 2 only gives the plasma concentration for 100 mg/kg/day. The other concentrations as measured should also be included, at least in the supplementary files.

3)      A wording matter: In the discussion the authors state „Our results suggest that not only does this potential therapeutic compound ICA-1S have zero toxic effect in animal tissues corroborated by no accumulation in any of the organs tested but preliminary predictive analysis also confirms the same would be true in human as well“. Based on the predictions with HepaRG cells and HPTCs the authors intend to suggest that the findings in mice were also valid for human. However, as the predictions are focused on toxicity, this statement can be misunderstood. The authors need to clarify, that at current no information on accumulation is available, only on potential toxicity in human tissue.

4)      Sometimes the authors write ICA-1, sometimes ICA-1S. Should be consistent.

Author Response

Dear Madam/Sir,

Thank you for your review and comments on the manuscript. We will submit the revised version on or before 31st January.

Thank you. 

Sincerely, 

Christopher A. Apostolatos 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

All corrections were done after review process 1.

English was optimized as well.