Review Reports - Inhibitory Potential of Resveratrol in Cancer Metastasis: From Biology to Therapy

Round 1

Reviewer 1 Report

The article comprehensively reviewed and discussed the research progress on potential clinical application of Resveratrol as an anti-cancer agent. While the authors attempted to review the role of resveratrol in anti-metastasis, they took up too much space discussing general mechanisms of cancer metastasis and the models used in this area. This caused the paper to lack focus and thus weaken its impact. It would be better reorganized the sessions by incorporating studies related to Resveratrol into the sections 4 and 5.

It is OK.

Author Response

The article comprehensively reviewed and discussed the research progress on the potential clinical application of Resveratrol as an anti-cancer agent. While the authors attempted to review the role of resveratrol in anti-metastasis, they took up too much space discussing general mechanisms of cancer metastasis and the models used in this area. This caused the paper to lack focus and thus weaken its impact. It would be better to reorganize the sessions by incorporating studies related to Resveratrol into the sections 4 and 5.

Response: Thank you for taking the time to review our manuscript (Manuscript ID: cancers-2361665) and for providing us with valuable feedback. We understand that a significant portion of the manuscript has been dedicated to discussing the general mechanisms of cancer metastasis. However, we would like to clarify that this will not impact the relevance of the Resveratrol content presented in sections 4 and 5. This is because the majority of readers (students and researchers) in the pharmaceutical industry or traditional Chinese medicine may not be familiar with the mechanical mechanisms of cancer metastasis, and insights into the characteristics of various in vivo metastatic models are essential in the development of new anti-metastatic drugs. Therefore, we believe that it is important to retain these sections in our manuscript. We appreciate your understanding and once again, thank you for your valuable guidance.

Reviewer 2 Report

The article is well written. It would be beneficial to have a separate section on nanotechnological developments utilized to treat cancer with resveratrol.

Minor:

1) Please check for the typo errors like in table.1 in vitro and in vivo is not in italics.

2) Grammar mistakes should be fixed in the article.

Whole manuscript

Author Response

The article is well written. It would be beneficial to have a separate section on nanotechnological developments utilized to treat cancer with resveratrol.

Response: Thank you for taking the time to read our manuscript (Manuscript ID: cancers-2361665). We really appreciate your valuable comments and suggestions! A paragraph has been included to address the new nanoformulations as below.

Nanotechnology has emerged as a promising approach to address the physicochemical and pharmacokinetic limitations of RES. Various nanoformulations, such as liposomes, solid lipid nanoparticles, polymeric nanoparticles, and cyclodextrins, have been developed to specifically target cells and reduce toxicity by lowering the required doses. [115]. Despite the potential benefits of RES nanoencapsulation, it remains an emerging field with several challenges that need to be addressed, such as the long-term safety of nanoparticles, their interaction with biological systems, and the need to develop stable and reproducible nanoformulations with high RES loading capacity. To enhance the effectiveness of hydrophobic drugs like resveratrol, alternative nanoparticles need to be explored, and research in nanomaterial synthesis and inorganic nanoparticles needs to be increased. Notably, recent studies have reported that RES nanoformulations can inhibit cancer metastasis, indicating their therapeutic potential. For instance, in B16F10 melanoma-bearing C57BL/6J mice, RES-loaded oil core Poly(ε-caprolactone) (PCL) nanocapsules showed promising results by increasing necrosis and inflammation in tumor tissue, reducing pulmonary hemorrhage, and pre-venting lung metastasis. [116]. Similarly, Pradhan et al. reported that nanoformulation resveratrol inhibited metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells. [117]. These findings suggest that RES nanoencapsulation could be a promising alternative therapy for cancer metastasis.

Minor:

Point 1: Please check for the typo errors like in table.1 in vitro and in vivo is not in italics.

Response 1: Thank you for your suggestion. We have corrected Table 1 in vivo and in vitro italics.

Point 2: Grammar mistakes should be fixed in the article.

Response 2: Thank you for your suggestion. In the revised manuscript we have double-checked the grammar.

Reviewer 3 Report

The review by Song et al., described the state of the art of resveratrol in cancer metastasis. The review is focused on some specific aspects regarding the molecular mechanism of resveratrol and the clinical trials done using the molecule. In addition, the review deals with the pharmacokinetics and toxicology of resveratrol and the limits of the animal models available to study the metastatic processes. There is much research on resveratrol since its discovery and possible use in cancer. Although the topic proposed by the authors is interesting and important either from a clinical or molecular point of view, the description of the different sections seems too general and not well organized, so it becomes difficult to catch the new information reported in comparison to other reviews. The authors suggest the description of new strategies to accelerate drug development in cancer metastasis research. Still, in the text, they do not describe these "new strategies” such as new nano-delivery or organ on a chip, for instance.

The authors in the introduction, suggest the description of new strategies to accelerate drug development in cancer metastasis research, but in the text, they do not mention such “new strategies. Why?
In line 368 Costance at al. as a reference is wrong
Line 375-377: is not clear. Does RES inhibit or not NF-kB?
Line 565: the studies are required to determine safe doses or likely, more effective on?
Based on what has been reported in section 6.2, the combination of natural products and RES is better than RES alone. Could this be explained and discussed in more detail?
Do the authors have performed a search on possible new RES delivery methodology (nanomedicine), and or new strategies to study metastasis (i.e. organ on a chip)

Author Response

The review by Song et al. described the state of the art of resveratrol in cancer metastasis. The review is focused on some specific aspects regarding the molecular mechanism of resveratrol and the clinical trials done using the molecule. In addition, the review deals with the pharmacokinetics and toxicology of resveratrol and the limits of the animal models available to study the metastatic processes. There is much research on resveratrol since its discovery and possible use in cancer. Although the topic proposed by the authors is interesting and important either from a clinical or molecular point of view, the description of the different sections seems too general and not well organized, so it becomes difficult to catch the new information reported in comparison to other reviews. The authors suggest the description of new strategies to accelerate drug development in cancer metastasis research. Still, in the text, they do not describe these "new strategies” such as new nano-delivery or organ on a chip, for instance.

Point 1: The authors in the introduction, suggest the description of new strategies to accelerate drug development in cancer metastasis research, but in the text, they do not mention such “new strategies”. Why?

Response 1: Thanks for your comments. We really appreciate your valuable comments. As our introduction explains, proposing "new strategies" is important to accelerate drug development to treat metastatic cancers. Therefore, we have added these "new strategies" in Section 8 (Conclusion and Future Perspectives) of the revised manuscript. For example, new dosage forms of RES for the treatment of cancer metastasis, organ chips for cancer metastasis research, in vitro cancer metastasis model screening, and other new strategies.

Point 2: In line 368 Constance et al. as a reference is wrong.

Response 2: Thanks for your comments. We have rewritten the study of Constance et al. as follows.

In a recent in vitro model, Constance et al. reported that 3D alginate HCT116 cells in multicellular TME cultures consisting of fibroblasts and T lymphocytes to investigate the impact of TNF-β, Sirt1-ASO, and/or RES on colorectal cancer proliferation and invasion, with a focus on cancer stem cells. The study revealed that RES inhibited the Sirt1 axis through the regulation of paracrine agent secretion and the NF-κB signaling pathway. Additionally, it decreased the production of T lymphocyte/fibroblast (TNF-β, TGF-β3) proteins, thereby highlighting the potential of RES in preventing colorectal cancer metastasis [63].

Point 3: Line 375-377: is not clear. Does RES inhibit or not NF-κB?

Response 3: Thanks for your comments. We have rewritten this sentence as follows:

In addition, another study demonstrated that treatment with 5 μM RES resulted in the down-regulation of TNF-β/TNF-βR-induced epithelial-mesenchymal transition (EMT) in colorectal cancer cells, specifically HCT116, RKO, and SW480 cells. This effect was achieved through the specific suppression of the NF-κB pathway and focal adhesion kinase (FAK).

Point 4: Line 565: the studies are required to determine safe doses or likely, more effective on?

Response 4: Thanks for your comments. We agree with you that this sentence needs more careful wording, and we have rewritten this sentence as follows:

In summary, RES has been shown to be well-tolerated in various preclinical and clinical studies. However, further research is needed to determine the optimal and safe dosage for humans, as well as its potential long-term effects.

Point 5: Based on what has been reported in section 6.2, the combination of natural products and RES is better than RES alone. Could this be explained and discussed in more detail?

Response 5: We thank the reviewer for the insights. We strongly agree with your suggestion. We have added to the discussion after reference [105] as follows:

Based on the results of the study, it seems that cancer patients who take a combination of multiple natural products in capsule form experience fewer side effects compared to those who take RES alone orally. While RES may be present in small quantities in these capsules, the multi-component therapy approach allows for multiple targets to be addressed simultaneously, while also minimizing the risk of toxic side effects that may result from high doses of a single drug. This approach helps to ensure medication safety.

Point 6: Do the authors have performed a search on possible new RES delivery methodology (nanomedicine), and or new strategies to study metastasis (i.e. organ on a chip)?

Response 6: Thanks for your comments. In the revised manuscript we added a discussion of RES nanoformulations in 7.1 (Issues of pharmacokinetics) as a possible new strategy to improve the low bioavailability of RES, as follows:

Nanotechnology has emerged as a promising approach to address the physicochemical and pharmacokinetic limitations of RES. Various nanoformulations, such as liposomes, solid lipid nanoparticles, polymeric nanoparticles, and cyclodextrins, have been developed to specifically target cells and reduce toxicity by lowering the required doses [115]. Despite the potential benefits of RES nanoencapsulation, it remains an emerging field with several challenges that need to be addressed, such as the long-term safety of nanoparticles, their interaction with biological systems, and the need to develop stable and reproducible nanoformulations with high RES loading capacity. To enhance the effectiveness of hydrophobic drugs like resveratrol, alternative nanoparticles need to be explored, and research in nanomaterial synthesis and inorganic nanoparticles needs to be increased. Notably, recent studies have reported that RES nanoformulations can inhibit cancer metastasis, indicating their therapeutic potential. For instance, in B16F10 melanoma-bearing C57BL/6J mice, RES-loaded oil core Poly(ε-caprolactone) (PCL) nanocapsules showed promising results by increasing necrosis and inflammation in tumor tissue, reducing pulmonary hemorrhage, and pre-venting lung metastasis. [116]. Similarly, Pradhan et al. reported that nano formulated resveratrol inhibited metastasis and angiogenesis by reducing inflammatory cytokines in oral cancer cells. [117]. These findings suggest that RES nanoencapsulation could be a promising alternative therapy for cancer metastasis.