Glycyrrhizin as a Nitric Oxide Regulator in Cancer Chemotherapy

Round 1

Reviewer 1 Report

This manuscript reviews the anticancer and MDR-reversal effect of Nitric Oxide and glycyrrhizin separately. Also revises the role of Glycyrrhizin as a Nitric Oxide Regulator. Finally, and more importantly, the authors suggest a very interesting idea: GL could enhance chemotherapy efficacy acting as both an NO regulator and direct MDR inhibitor. The article is well written and includes relevant citations on the field.

However, I felt that the authors extended too much the introductory sections of the review (sections 1, 2 and 3) and the sections 5.2, 5.3 and 6 could be more developed.

Despite that, I consider that this review contributes positively to the discussion in the field and could help investigators to make decisions about what directions to go. In general, Iconsider that the authors did a good job. However, there are some minor adjustments that I think may help:

Page 1, section 1

“Therefore, inhibition of ABC transporters is necessary for successful treatment of cancer” – This affirmation should be reviewed. The inhibition of ABC transporters is an approach that has been extensively investigated to treat MDR cancers. However, despite some encouraging results obtained with ABC transporter inhibitors, until now, no approved inhibitor is available in the clinic. Thus, the effectivity of this strategy to overcome MDR has not yet been proven.

Page 2, section 2

“Cancer treatment options include surgery, radiotherapy, and chemotherapy”- please review this sentence. Despite these treatments represent the most common, it exists other relevant options.

Page 9, section 4.4

“ …There are two isoforms of topoisomerase isoforms….”,  Please correct

Page 9, section 4.4

The authors refer that “Since ABC transporters are ATP-dependent proteins, the ability of topo II to inhibit ATPase affects the activity of ABC transporter proteins”. This affirmation is not correct, Topo II does not inhibit the ATPase activity. For the contrary, the action of topo II enzyme in maintaining of the level of intracellular DNA supercoiling, generally requires the hydrolysis of ATP. I recommend that the authors should read again the studies that they have referenced, and then reformulate all the sentence.

In addition, these studies also mentioned that, in some situations, the inhibition of catalytic-, and ATPase activities of topo II by NO could result in induction of drug resistance in cancer cells instead of reversion of MDR. The authors should also do a deeper analysis of the available literature regarding the MDR reversing/inducing effect of NO and made a critical analysis of this dual effect.

Figure 3- The authors suggest a direct correlation between the NO-induced inhibition of topoisomerase II ATPase activity and the inhibition of efflux function of ABC transporters. Please explain this correlation.

Page 11, section 5

The authors mentioned that: “Several studies have shown that GL can act as an NO regulator, indicating that GL inhibits the development of MDR in cancer cells. In addition, several studies have shown that GL itself can inhibit ABC transporter activity.” The references regarding the mentioned studies should be added.

Page 12, section 5.1

The authors should explain the relevance of this section for the thematic of the review. In my opinion, this section should be removed.

Page 13, section 5.2

This section abords the central thematic for the aim of this review, but unfortunately, only 3 articles are referred. To increase the overall interest of the review, I recommend the authors to extensively look for additional studies on the effect of GL as a NO regulator. A critical analysis on what has already been shown to be not promising and what looks promising should also be done.

All my suggestions are minor revisions and I consider this article suitable to be published in this journal.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

The review article "Glycyrrhizin as a Nitric Oxide Regulator in Cancer Chemotherapy" describes the role of glycyrrhizin in regulating NO in cancer.

The goal of the review is very intriguing but very little amount of data are present to highlight this behavior.
I think taht literature dtaa must be explained in order to easily understand the role of glycyrrhizin in the regulation of NO. Schemes must be useful in understanding these.

Some chemical structures of compounds herein described must be inserted in the main text. 

Also pharmaceutics must be included, polymers able to release NO, but also carriers of glycyrrhizin in cancer therapy.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf