Anti-Glycolytic Drugs in the Treatment of Hepatocellular Carcinoma: Systemic and Locoregional Options
, Leila Haghani 1, Ken Zhao 1, Anita Karimi 1, Brett Marinelli 1, Joseph P. Erinjeri 1, Jean-Francois H. Geschwind 2 and Hooman Yarmohammadi 1,*
Round 1
Reviewer 1 Report
Nice review. I enjoyed reading it and would read it again.
I just suggest adding references where facts are stated for example:
In Warburg effect section: I would add references after this sentence "However, studies have demonstrated that the process of aerobic glycolysis is extremely efficient and faster than anaerobic glycolysis", would add references after the end of the paragraph and after this sentence: "HCC cells, similar to other aggressive cancer cells, overexpress multiple enzymes that are involved in glycolysis."
Author Response
Thank you for your comments.
Two references were added as addressed:
S. Ganapathy-Kanniappan and J. F. Geschwind. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 2013 Vol. 12 Pages 152 Accession Number: 24298908 PMCID: PMC4223729 DOI: 10.1186/1476-4598-12-152
X. Z. Wu, G. R. Xie and D. Chen. Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma J Gastroenterol Hepatol 2007 Vol. 22 Issue 8 Pages 1178-82
Reviewer 2 Report
The manuscript provides a review on the adaptation mechanisms of hepatocellular carcinoma (HCC), specifically focusing on glycolysis, and discusses previously reported or potential anti-glycolytic treatments through systemic and locoregional approaches for HCC treatment. Prior to the recommendation for acceptance of your manuscript, I would like to give some suggestions for the improvement and best interest of this study.
In Introduction, the author stated that “Liver transplant, surgical resection, and ablation are among the curative treatment options”. The background and significance of drugs treating against HCC should be further discussed. For example, PMID: 32067923 and 32532615 could be cited to introduce that TCMs can be effective in preventing recurrence and metastasis of HCC.
In part of Warburg effect, the discussion on HCC cells overexpressing multiple enzymes that are involved in glycolysis needs to be supported by the relevant references.
In part of Effect of arterial embolization of HCC microenvironment, the logic is currently messy. The author stated that “hypoxia plays a double role in treatment of HCC”. What’s the relationship with arterial embolization? Hypoxia express a positive or negative effect on HCC? And what’s the implications for antitumoral drug development? I suppose to make a summary.
Mechanisms of some drugs have not been introduced in text, for example, GLUT-1 antibody and Ritonavir.
In Discussion, it was stated that “the effective systemic dose of these drugs have at times been associated with severe side effects“. How to reduce the toxicity of these HCC therapeutic drugs to normal cells would be a research focus. Is there any good solutions right now?
Moderate editing of English language required
Author Response
Thank you very much for your comments.
The following is our responses:
In Introduction, the author stated that “Liver transplant, surgical resection, and ablation are among the curative treatment options”. The background and significance of drugs treating against HCC should be further discussed. For example, PMID: 32067923 and 32532615 could be cited to introduce that TCMs can be effective in preventing recurrence and metastasis of HCC.
Response: The article is focused on anti-glycolytic treatment options. A variety of other options exist. However, in order to keep the focus on anti-glycolytic therapy we decided not to discuss other options.
In part of Warburg effect, the discussion on HCC cells overexpressing multiple enzymes that are involved in glycolysis needs to be supported by the relevant references.
Response: The reference has been added.
In part of Effect of arterial embolization of HCC microenvironment, the logic is currently messy. The author stated that “hypoxia plays a double role in treatment of HCC”. What’s the relationship with arterial embolization? Hypoxia express a positive or negative effect on HCC? And what’s the implications for antitumoral drug development? I suppose to make a summary.
Response: Yes, arterial embolization causes hypoxia. The hypoxia kills the tumor. However, hypoxia results in resistance in some of the tumors that manage to survive the hypoxic attack. Therefore, at the same time that hypoxia kills the tumor, at the same time it makes the residual disease become more resistant to hypoxia.
This part is revised to make it more clear.
Mechanisms of some drugs have not been introduced in text, for example, GLUT-1 antibody and Ritonavir.
Response: Revised. Mechanism is now added to each section.
Mechanism of action of Ritonavir is by blocking GLUT-4. This has been explained in line 171.
In Discussion, it was stated that “the effective systemic dose of these drugs have at times been associated with severe side effects“. How to reduce the toxicity of these HCC therapeutic drugs to normal cells would be a research focus. Is there any good solutions right now?
Response: There are ongoing studies to find the solution. Most studies are focused on using these drugs as a locoregional option.
Reviewer 3 Report
This is a very well written review article summarizing the role of glycolysis in tumor growth. Authors also summarized the anti-glycolytic drugs including their mode of action which makes this review very informative. I have no comments or suggestions and this manuscript may be accepted for publication in the current form.
Author Response
Thank you for your comments.
