Targeting Pathways and Mechanisms in Gynecological Cancer with Antioxidant and Anti-Inflammatory Phytochemical Drugs

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript entitled “Targeting Pathways and Mechanisms in Gynecological Cancer with Antioxidant and Anti-Inflammatory Phytochemical Drugs” is a critical survey that showcases the benefits of plant-derived drugs for specific cancers. However, the quality of the manuscript can be strengthened by addressing the following queries.

 

1. Authors should add the specific plant names targeted in this review for better presentation, and the same can be elaborated in detail in the introduction section.
2. Repetitive terms such as "gynecologic cancers, such as ovarian, endometrial, and cervical cancers" have been used throughout the manuscript and may be avoided for better presentation. The caption of Figure 1 is not readable; hence, the quality/resolution may be improved.
3. The figure numbering should be corrected to Figure 5 instead of Figure 1.
4. It is clear from Figures 5 and 6 that only polyphenols, terpenoids, and thiols are targeted for cancer treatment, which may be emphasized in the abstract section.
5. A table may be added to summarize plant-derived extracts used in cancer treatment.

Author Response

Comments 1: Authors should add the specific plant names targeted in this review for better presentation, and the same can be elaborated in detail in the introduction section.

Response 1:

Thank you for your valuable suggestion. We agree with the reviewer’s comment. Accordingly, we have added Table 1 in the Introduction section, which presents the specific plant-derived phytochemicals along with their botanical sources and associated molecular targets in pre-clinical cancer treatment trials. This addition enhances the clarity and comprehensiveness of the manuscript.

The corresponding sentence has been included in the revised manuscript on Page 4, Paragraph 5, Lines 147–148, and is marked in red as follows:

“Plant-derived phytochemicals, their botanical sources, and the molecular targets they are examining in pre-clinical cancer treatment trials are listed in Table 1.”

Table 1 is inserted in the manuscript on Page 1, Lines 583–585, and is highlighted accordingly for the reviewer’s convenience.

 

Comments 2: Repetitive terms such as "gynecologic cancers, such as ovarian, endometrial, and cervical cancers" have been used throughout the manuscript and may be avoided for better presentation. The caption of Figure 1 is not readable; hence, the quality/resolution may be improved.

Response 2:
Thank you for this valuable suggestion. We agree with the reviewer’s comment regarding the repetitive use of the phrase "gynecologic cancers, such as ovarian, endometrial, and cervical cancers." We have carefully revised the manuscript to reduce redundancy and improve overall clarity by replacing repetitive instances with more concise terminology, such as simply "gynecologic cancers" where appropriate. These modifications can be found on Page 3, and throughout the manuscript where applicable.

Regarding Figure 1, we have improved its resolution and replaced it with a high-quality image to enhance readability. Additionally, we have updated the figure caption for better clarity. The revised figure and its improved caption are included in the revised manuscript on Page 3.

Revised text (Page 5, Line 146, 151, and 171):
“Gynecologic cancers remain a significant health burden globally, with ovarian, endometrial, and cervical cancers being the most prevalent types.” → “Gynecologic cancers”

 

Comments 3: The figure numbering should be corrected to Figure 5 instead of Figure 1.

Response 3:
Thank you for your careful observation. We agree with this correction. Accordingly, the numbering has been updated throughout the manuscript to reflect the correct figure sequence. The figure initially labeled as Figure 1 is now correctly numbered as Figure 6. This revision is reflected on page 13, Line 490- 491, where the figure is cited and discussed.

 

Comments 4: It is clear from Figures 5 and 6 that only polyphenols, terpenoids, and thiols are targeted for cancer treatment, which may be emphasized in the abstract section.

Response 4:
Thank you for this insightful suggestion. We agree and have modified the abstract to emphasize that polyphenols, terpenoids, and thiols are the principal classes of phytochemicals reviewed for their roles in gynecological cancer treatment. This update is found on page 1, abstract, lines 36–38.

“This review focuses on how these drugs, which include polyphenols, terpenoids, and thiols-related phytochemical-derived compounds target different pathways associated with developing and progressing gynecologic cancer.”

 

Comments 5: A table may be added to summarize plant-derived extracts used in cancer treatment.

Response 5:
Thank you for your valuable suggestion. We have added a new table (Table 1-2) summarizing major plant-derived extracts of phytochemicals, their active compounds, target pathways, Dose range, Clinical Indication, Duration, and their specific effects in gynecological cancer models. This table enhances the clarity and accessibility of the information presented. The addition can be found on page 15-16, following the discussion section.

“Table 1: Plant-derived phytochemicals, their botanical sources, and molecular targets investigated in pre-clinical trials for cancer treatment.”

“Table 2. Clinically trials evaluated phytochemicals in breast cancer treatment: Phytochemical classes, dose ranges, clinical indication, and duration.”

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors, I have read your manuscript with interest, and I send you my comments:

1) Section 1: Please add the aim of the study.

2) Please add methods: type of review and methods used to take the references.

3) Section 2: Please separate clinical manifestation from diagnosis. It seems that endometriosis is the only clinical manifestation.

4) Section 3: You describe "the effect of drugs," but then you report the use of nutrients. Please, are drugs and nutrients similar?

5) Section 3: You describe quercetin only. Why? Please add other drugs and nutrients able to reduce inflammation, add molecules, dosage, clinical indications, and time of treatment. Nutrients are used before, after drug or together?

6) Section 5, "Clinical Evidence and Future Directions." You report NON-CLINICAL DATA but only review experimental studies. Please revise this section.

7) Conclusion: Please reduce this section.

 

Author Response

Comments 1:
Section 1: Please add the aim of the study.

Response 1:
Thank you for pointing this out. We agree with the comment. Therefore, we have added a clear statement outlining the aim of the study at the end of Section 2. Methodology: Aim to provide better clarity and focus for the readers. This addition can be found on page 6, paragraph 1, lines 205–212.

2. Methodology: Aim, Review Process, Search Strategy, Data Extraction, and Analysis

The review aims to collect and analyze the molecular targets and mechanisms by which antioxidant and anti-inflammatory phytochemicals exert their anti-cancer effects in gynecological cancer. The main focus is on identifying plant chemicals that have shown efficacy in preclinical studies (in vitro and in vivo) by targeting specific molecular pathways such as apoptotic induction, proliferation inhibition, metastasis suppression, and PI3K and MAPK modulation.

 

Comments 2:
Please add methods: type of review and methods used to take the references.

Response 2:
Thank you for pointing this out. We agree with the comment. Therefore, we have added a clear statement outlining the aim of the study at the end of Section 2. Methodology: Aim, Review Process, Search Strategy, Data Extraction, and Analysis to provide better clarity and focus for the readers. This addition can be found on page 6, paragraph 1, lines 205–227.

2. Methodology: Aim, Review Process, Search Strategy, Data Extraction, and Analysis

The review aims to collect and analyze the molecular targets and mechanisms by which antioxidant and anti-inflammatory phytochemicals exert their anti-cancer effects in gynecological cancer. The main focus is on identifying plant chemicals that have shown efficacy in preclinical studies (in vitro and in vivo) by targeting specific molecular pathways such as apoptotic induction, proliferation inhibition, metastasis suppression, and PI3K and MAPK modulation. Systematic searches using databases such as PubMed, Google Scholar, and ScienceDirect were carried out for peer-reviewed articles published between 2000 and 2024. The survey included keywords such as plant chemicals, gynecological cancer, preclinical studies, molecular pathways, apoptosis, anti-inflammatory, antioxidant, natural compounds, and specific tumor types such as ovarian, cervical, and endometrial carcinoma. Boolean operators (AND), and (OR) have been used to refine the search predicate. Predicate The articles were included if they: (1) evaluated plant-derived compounds for the treatment of gynecological cancer; (2) described the molecular mechanisms of action; and (3) were original research papers or peer-reviewed articles. Studies that were focused on clinical trials or did not have sufficient molecular data were excluded. Data collection involved searching the selected articles for details of botanical names, phytochemical class, tumor model, and target molecular pathway. The extracted data were summarized in tables for a summary of the mysterious interactions between the substances and the culprits. This review highlights the therapeutic potential of natural compounds to modulate inflammation and oxidative stress in the case of gynecological cancer and provides a basis for future translational and clinical studies.

 

Comments 3:
Section 2: Please separate clinical manifestation from diagnosis. It seems that endometriosis is the only clinical manifestation.

Response 3:
Thank you for this observation. We have revised Section 3. Clinical Manifestations of Gynecological Cancers by clearly separating clinical manifestations from diagnostic approaches to improve clarity. A dedicated paragraph for clinical manifestations has been added, followed by a distinct paragraph for diagnosis. This revision can be found on page 6, paragraph 1, lines 228–247. We added a separate section of 4. Clinical Diagnosis of Gynecological Cancer on page 6, paragraph 1, lines 229 and 5. Treatment of Gynecological Cancer on page 6, paragraph 1, lines 270.

 

3. Clinical Manifestations of Gynecological Cancers

The various clinical manifestations of gynecological cancers, which include cancers of the cervix, uterus, ovaries, vagina, and vulva, frequently differ based on the tumor site, stage, and histological type. Early-stage illnesses can have no symptoms, which makes prompt diagnosis more difficult. Abnormal vaginal bleeding, which can appear as intermenstrual, postcoital, or postmenopausal bleeding, is the most frequent initial symptom, especially in endometrial and cervical cancers [29, 30]. Pelvic pressure or pain, which is frequently a sign of advanced disease, can be linked to uterine or ovarian cancers. The ambiguous symptoms of ovarian cancer, often referred to as a "silent killer," include bloating, early satiety, and urgency in the urine. These symptoms can be mistaken for benign urological or gastrointestinal disorders [31-33]. Cancers of the vagina or vulvar region may manifest as visible lesions, bleeding, ulceration, or itching. Anemia, weariness, and inadvertent weight loss are examples of constitutional symptoms that frequently appear later [34]. Both metastasis and local invasion may cause symptoms related to the digestive or urinary systems. High level of suspicion, especially in women who have experienced menopause or who have known risk factors (e.g. A. Early detection of HPV infection and genetic predispositions is crucial. Early identification of these clinical characteristics, in conjunction with suitable diagnostic tests, is essential for enhancing prognosis and directing treatment plans in gynecological oncology.

 

 

Comments 4:
Section 3: You describe "the effect of drugs," but then you report the use of nutrients. Please, are drugs and nutrients similar?

Response 4:
Thank you for this pertinent clarification request. We acknowledge the confusion caused by the interchangeable use of the terms “drugs” and “nutrients.” Therefore, we have revised Section 3 to “ 6. Molecular Pathways Targeted by Antioxidant and Anti-inflammatory Drugs for Gynecological Cancer” to clearly distinguish between phytochemical-based drugs (such as standardized plant-derived formulations) and dietary nutrients (natural compounds with medicinal properties). Clarifications have been added to page 9, paragraph 1, lines 359-373, specifying the classification and context of each.

“In this section, we differentiate between phytochemical-based therapeutic agents classified as drugs (e.g., curcumin-based formulations) and dietary nutrients or bioactive compounds (e.g., flavonoids) with potential anti-cancer effects. While both categories share biochemical mechanisms, their regulatory classification and clinical applications vary.”

 

6. Molecular Pathways Targeted by Antioxidant and Anti-inflammatory Drugs for Gynecological Cancer

 

Phytochemical-based antioxidant and anti-inflammatory drugs and dietary nutrients both originate from natural sources, but they have quite different purposes, regulations, and applications. Phytochemical-based drugs are defined as standardized, pharmacologically active formulations made from plants; they are usually the subject of rigorous clinical trials and regulatory approval. These compounds are meant to be used therapeutically and have specific dosages, modes of action, and safety profiles. Conversely, dietary components such as vitamins, minerals, and particular bioactive compounds (e.g. flavonoids, carotenoids) primarily support physiological functions and general health. While some nutrients have therapeutic properties, they are typically consumed as dietary supplements or as part of a regular diet and lack the precise precision and targeted efficacy of pharmaceuticals. Consequently, foodstuffs contain nutrients that support or prevent health, while drugs based on phytochemicals are therapeutic agents.

 

 

Comments 5:
Section 3: You describe quercetin only. Why? Please add other drugs and nutrients able to reduce inflammation, add molecules, dosage, clinical indications, and time of treatment. Nutrients are used before, after drug or together?

Response 5:

We agree with the reviewer’s suggestion and have expanded Section 6. Molecular Pathways Targeted by Antioxidant and Anti-inflammatory Drugs for Gynecological Cancer to include additional phytochemicals with their clinical indication such as curcumin, polyphenon E (EGCG), indole-3-carbinol , diindolylmethane (BR-DIM), flaxseed lignans (SDG), secoisolariciresinol diglucoside (SDG), scutellaria barbata (BZL101), Grape seed proanthocyanidin (GSPE).  In Table 2, we have included information on their molecular targets, dosage ranges, clinical indications, and proposed duration of administration. These additions can be found on pages 16, paragraphs 2–4, lines 586–588.

 

 

Comments 6:
Section 5, "Clinical Evidence and Future Directions." You report NON-CLINICAL DATA but only review experimental studies. Please revise this section.

Response 6:Thank you for pointing this out. We have revised Section 5 with 9. Clinical Evidence and Future Directions for Treatment of Gynecological Cancer

By clearly separating preclinical and clinical findings. Clinical trial data, where available, have been summarized. These changes can be found on page 16, in paragraph 2, lines 591-608.

In preclinical research and early-stage clinical trials, curcumin, a polyphenolic compound present in turmeric, has demonstrated effectiveness in modifying signaling pathways implicated in ovarian and endometrial cancer cell proliferation, apoptosis, and metastasis. The compound epigallocatechin gallate (EGCG), which is found in polyphenols E, which is made from green tea, has been studied in clinical trials for its ability to stop tumor growth and improve the efficiency of traditional chemicals. In preclinical research, indole-3-carbinol (I3C) and its derivative diindolylmethane (BR-DIM) from cruciferous vegetables showed anticancer properties [163-165]. In clinical trials, they were evaluated for their ability to alter estrogen metabolism and lower the risk of cancers driven by estrogen. Clinical trials suggest that flaxseed lignans, especially Secoisolariciresinol diglucoside (SDG), may help manage breast cancer. They have also been associated with decreased tumor growth and the growth of cancer cells. Additionally, clinical trials have shown promise for the antioxidative and anticancer effects of grape seed proanthocyanidin extract (GSPE) and Scutellaria barbata (BZL101). When used alone or in conjunction with traditional therapies, these phytochemicals present encouraging avenues for future research and treatment, helping to lower treatment resistance and increase overall survival rates for patients with gynecological cancer [157, 166, 167].

 

Comments 7:
Conclusion: Please reduce this section.

Response 7:
Agree. We have condensed the conclusion to succinctly summarize the key findings and future perspectives without repeating earlier sections. The revised conclusion is now more focused and concise. This can be found on page 17, paragraph 1, lines 631–649.

In conclusion, research shows that anti-inflammatory and antioxidant substances can be used to treat gynecological cancers by lowering oxidative stress, addressing chronic inflammation, and focusing on important oncogenic pathways. By encouraging tumor suppression, triggering apoptosis, and increasing sensitivity to traditional therapies, these substances—which include curcumin, polyphenon E (EGCG), indole-3-carbinol, diindolylmethane (BR-DIM), flaxseed lignans (SDG), secoisolariciresinol diglucoside (SDG), Scutellaria barbata (BZL101), and grape seed proanthocyanidin (GSPE)—have shown encouraging preclinical results. These phytochemical compounds' therapeutic efficacy is further supported by recent clinical trials that show promise in enhancing immune responses and lowering treatment-related toxicities. To maximize their integration into clinical practice, more research is required as the clinical application of these agents is still in its infancy. To maximize therapeutic benefits and reduce side effects, future research should concentrate on enhancing drug formulations, dosage schedules, and combination strategies with traditional therapies. Finding predictive biomarkers will also guarantee the effectiveness of these treatments and allow for individualized treatment plans. In general, developing our knowledge of the molecular pathways that connect oxidative stress, inflammation, and the biology of gynecological cancer will be essential to turning these promising substances into cutting-edge, successful treatment plans that will eventually enhance patient outcomes and quality of life.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

I have revised you manuscript and it has been improved.

However the form must be revised in order to improve the english form