Benefit of Asian pigmented rice bioactive compound and its implication in breast cancer: a systematic review

Background: Utilizing the bioactive compounds found in pigmented rice might significantly reduce the risk of breast cancer. This study aims to systematically review existing literature on the benefit of Asian pigmented rice bioactive compounds and their implication in breast cancer. Methods: Searches of the literature were conducted in two databases (Scopus and PubMed) for a systematic review. The keywords resulted in a total of 407 articles, consisting of 103 PubMed and 304 Scopus articles. 32 manuscripts were excluded because the article was over 10 years old. After excluding book chapters and non-English languages, we had 278 potential articles to be reviewed. After checking and screening the title and abstract and eliminating duplicate articles, then 66 articles were obtained. After the selection and elimination of the full-text manuscripts, finally 10 of them which met the inclusion criteria. Result: The included studies in this review were entirely based in Asia. The year of publication ranged from 2013 to 2020. Half of included studies used black rice extract, two used red jasmine rice extracts, and three used Korean rice extracts (black, red, dark purple and brown rice). All studies were conducted in vitro and three studies were compared with in vivo tests on female mice. The pigmented rice is mainly black, red, and dark purple rice, and contains a variety of peonidin-3-glucoside, cyanidin-3-glucoside, γ-oryzanol, γ-tocotrienol, proanthocyanidin, cinnamic acid, and anthocyanins that may act as pro-apoptotic, anti-proliferative, and anti-metastasis of the breast cancer cells. Conclusion: Pigmented rice is a beneficial food which possessed bioactive compounds that may have significant potential concerning a breast cancer.


Introduction
Most deaths throughout the world are now caused by non-communicable diseases (NCDs). 1 The recognition of the challenges of NCDs has become a global spotlight as stated in the sustainable development goals (SDGs) on the target 3.4 by 2030, reduce by one-third pre-mature mortality from NCDs through prevention and treatment, and promote mental health and wellbeing. 2Cancer is one of NCDs that has become one of the leading causes of death worldwide with an estimate of 10.0 million deaths in 2020. 3 estimated 10.0 million people will die from cancer, a multifactorial illness, in the globe in 2020. 4Breast cancer is the most diagnosed cancer type found in women and poses a serious public health concern globally. 5An estimated breast cancer occurrence is 2.089 million in 2018 which is reported to increase continuously in all countries of the world. 3There are major risk factors for breast cancer, such as aging, family history, reproductive factors, and life style. 6Some of the factors are beyond individual controls and some are not.The factors that are within an individual's control that can be altered to minimize the chance of getting breast cancer, include diet and lifestyle. 7Different food patterns may be one of the most fundamental factors for this. 8Rice is a staple food of dietary calories for half of humanity and has been widely demonstrated as a chemopreventive component. 9Whole-grain pigmented rice, in contrast to white rice, contains a higher concentration of bioactive phytochemicals with various health benefits. 8e to the high levels of polyphenol and anthocyanins in colored rice, it is regarded as a functional food in Asia. 10 Many varieties of rice include colorful pigments, which are often concentrated in the pericarp or the bran of the rice kernel and give the grain hues like brown, red, purple, and black. 11The flavonoids anthocyanin and proanthocyanidin, which are recognized to have nutritional benefits, are responsible for these color changes.However, their efficacy varies depending on rice color or variety. 12,13e presence of polyphenols, which have been shown to have antioxidant, anti-inflammatory, and anti-adipogenic potential in in vitro and in vivo investigations, 8,14 has been predominantly cited as the cause of the possible health advantages of this type of rice.[17] Thus, the aim of this study is to systematically review existing literature on the benefit of Asian bioactive compounds within pigmented rice and their implication in breast cancer.

Search strategy
Articles for the current review were acquired from two electronic databases (PubMed and Scopus), considering that they hold the most articles for biomedical and pharmaceutical studies.The database literature search was conducted from November 8 to November 10, 2022.We created the keywords for each database.For PubMed, we used the following keywords; (((((cancer) OR ("breast cancer")) OR (metastasis)) AND ((((((rice) OR ("pigmented rice")) OR ("black rice")) OR ("red rice")) OR ("purple rice")) OR ("brown ice")) AND (("cancer therapy") OR ("anti-metastasis")). Meanwhile for Scopus, the keywords were "Cancer" OR metastasis OR "MCF-7" OR "Breast cancer" OR tumor AND "Pigmented Rice" OR rice OR paddy OR "Oryza sativa" AND "Cancer Therapy" OR medicine OR pharmaceutical OR physicochemical.During literature search, only free access articles were used.

Inclusion criteria
All types of experimental and observational studies written in English language were included.All duplicate studies and literature reviews were excluded from the final selection.Study subjects focused on breast cancer, and any other objects of in vivo and in vitro studies.Study factors included in the studies were the types of pigmented rice, other interventions in the form of extracts, whole grain, bran and hull.The research results include cancer therapy, pharmaceutical, and bioactive compounds as anti-cancer.

Study selection, data extraction, and quality assessment
The aforementioned keyword search resulted in a total of 407 articles, consisting 103 and 304 articles from PubMed and Scopus, respectively.We excluded 32 manuscripts because the article were published more than 10 years ago.After excluding book chapters and papers not in English, we had 278 potential articles to be reviewed.After checking and screening carefully the title and abstract of the manuscript, the duplicate articles were eliminated, then 66 articles were obtained.The authors reviewed the full text of those studies and finally selected 10 of them which met the inclusion criteria.46 articles did not meet the criteria because duplicated, a book chapter, not accessible, not in English and no fulltext.The flow diagram of the selection of study is shown in. 26,27

Characteristics of the articles
The included studies in this review were entirely of Asian.The year of publication ranged from 2013 to 2020.Five studies used black rice extract, two used red jasmine rice extracts, and three used a mixture of Korean rice extracts (black, red and brown rice).All studies were conducted in vitro and three studies were compared with in vivo tests on female mice.The summary of the included study were: tabulated based on the results, active compounds and sample breast cancer cell lines which are presented in Table 1.

Methodological quality
We reviewed results from 10 studies, seven of which involved in vitro experiment and three of which involved both in vitro and in vivo experiment.Unfortunately, there are no specific studies that focus on in vivo experiments.In detail, we report 10 samples from in vitro studies and three samples from in vivo studies.

In vivo
Experiments in vivo using same species of mouse, naked female mice, were carried out with different cancer cells.Two studies employed 4-week-old mice, 18,21 while one used 6-7-week-old mice. 15In these experiments, several cells types were used and injected into the flank of mammary fat pad of mice to construct the breast cancer mice model.HER2-positive MDA-MB-453 cells were employed in one study. 15Besides, the previous study, 18 found MDA-MB-453 (ErbB2-positive) was employed alongside MCF-7 (ErbB2-negative) and MCF-10A (normal) cells.In the last study, 4T1 cells were used to be transplanted to the mice. 211][12] This rice variety is distinguished by its mostly red, black, or purple pericarps.Wide-color rice varieties have drawn more attention because of their many biological functions.The pigments serve as sources of phytochemicals when contrasting the nutritional value of colored rice with white rice brans.Anthocyanidins, ferulic acid, diferulates, anthocyanins, and polymeric proanthocyanidins are some of the phenolic chemicals. 10,11gmented rice residues are attractive sources of bioactive substances such as phenolic antioxidants and anticancer agents for the benefit of human health. 12,13Anthocyanin is found in the bran layers of the rice kernel, whereas phenolic acids are primarily present in the bran layers of rice in their free, conjugated, and bound forms. 16The two primary bioactive phenolic chemicals found in cereal grains, mostly found in the pericarp of colored types, are anthocyanins and proanthocyanidins. 14Anthocyanins, which are primary metabolites found in the bran layers of rice kernels, have been identified as functional dietary components that promote good health and have anticancer, antioxidant, hypoglycemic, and anti-inflammatory activities. 111][12][13][14] The anticancer effect is suggested partly through the enhancement of bioactive substances such as vitamin E, phytic acid, γ-aminobutyric acid (GABA), γ-oryzanol, and phenolics. 9

Black rice
A traditional and healthy cuisine, black rice is mostly grown in East Asia.Phytochemicals, tocopherols, polyphenols, B vitamins, and anthocyanins are only a few examples of the water-soluble bioactive substances abundant in black rice. 21hese substances might help your health and shield you against long-term conditions linked to oxidative stress and antioxidant activity. 10A significant amount of phytochemicals are present in black rice bran, giving it strong medicinal properties.Black rice extract anthocyanins dramatically decreased the metastasis of breast cancer, according to seven research that were considered.The aleurone layer of black rice is where black rice anthocyanins (BRACs) are found.Human breast cancer cells that are ErbB2-positive can be prevented from metastasizing by BRAC. 18Additionally, Liu et al. (2013) demonstrated that black rice extract includes peonidin-3-glucoside and cyanidin-3-glucoside, which can diminish the tumor size and volume. 15d rice Two studies found that red jasmine rice, which contains proanthocyanidins, inhibits breast cancer cell proliferation.Most of the phenolic chemicals in red rice, which are responsible for the red coloring of the pericarp, are proanthocyanidins and catechins. 20,22Proanthocyanidin from red rice (PRFR) contains procyanidins and prodelphinidins. 22Moreover, red rice extract also has a high concentration of γ-oryzanol and γ-tocotrienol in the Hex and DCM fractions. 20rple rice A variety of rice varieties, including glutinous rice, are referred to as purple rice and have historically been eaten throughout Eastern and Southeast Asia. 23The pigments are naturally occurring compounds belonging to the flavonoid family in which cyanidin, pelargonidin, peonidin, delphinidin, petunidin, and malvidin represent the most commonly occurring anthocyanin aglycone. 11One study found that purple rice hulls contained the highest phenolic compound. 23innamic acid and its derivatives are the primary ingredients for breast cancer cell growth suppression and cell cycle arrest. 13plication of bioactive compound in breast cancer Phenolic and flavonoid chemicals act as an antioxidant to protect cells from oxidative damage, which is a common cause of aggressive diseases like cancer. 16However, the anticancer activities were not directly correlated with total phenolic or total flavonoid content values. 16So, phenolic and flavonoid from many types of pigmented rice have also been tested for apoptotic activity revealing that cell shrinkage and nuclear condensation occur in human breast cancer cell line MCF-7. 16he antioxidant activity of rice phenolic compounds is detectable in parallel with the inhibition of proliferation of MCF-7 cells through G1 cell cycle arrest and comparable to quercetin as an antioxidant standart. 13oanthocyanidins are monomeric flavan-3-ol oligo-or polymers that are created as a byproduct of the flavonoid biosynthesis process. 20Proanthocyanidins, which are essentially concentrated tannins, are made by cytosolic multienzyme complexes acting along the phenylpropanoid route. 22By incorporating sugars, anthocyanidins are transformed into anthocyanins. 19Proanthocyanidins turn into anthocyanins when heated in an acidic medium.As byproducts of the flavonoid pathway, proanthocyanidins and anthocyanins have the same metabolic intermediates.Proanthocyanidins, in the form of procyanidin (catechin and/or epicatechin) and prodelphinidin (epigallocatechin and/or gallocatechin) showed anti-metastatic effects in cancer breast MDA-MB-231 and HT1080 cells. 22It reduces the cell invasion and migration in a dose dependent manner with IC 50 at 7.52AE1.42μg/mL and 10.6AE0.59μg/mL respectively and as a molecular mechanism of metastasis it inhibits collagenase activity. 20Suppression of breast cancer metastasis including inhibition the mRNA expression of their signaling pathway has also been known. 19e anthocyanins pigment such as cyanin-3-glucosides or peonidin-3-glucosides known to dose-dependent inhibition of cell proliferation and suppress the tumour growth in HER2-positive cancer lines which associated with breast cancer. 15nherent with the previously studied that both compounds inhibit cell human ductal breast carcinoma HS578T growth by blocking cell proliferation at the G(2)/M phase so that it cannot form a normal mitotic apparatus, lowering some cancer response proteins, and chromatin condensation leads to cell death. 23Anti-metastasis action prevents cancer cells from invading the blood or lymphatic vessel and spreading to other tissues or organs, among other benefits.The anthocyanins found in black rice are able to lower almost 40% of tumour nodules with in vivo studies and about 10% inhibits invasion of cancer breast MDA-MB-453 cells. 18Aprevious study reported a higher invasive inhibition of cells by 68% and also a decrease in the migration distance of MDA-MB-453 cells by 37% with anthocyanins compared to untreated cells after 24 hours. 24trengths and limitations of the review Several bioactive substances with the potential to operate as anti-metastatic agents, including anthocyanins, phenolics, and flavonoids found in different kinds of pigmented rice, are among the articles employed.To ensure the efficacy of each bioactive chemical, however, more in vivo research or randomized clinical trials with multicenter investigations are required as the majority of them are in vitro studies.

Significance of the findings and possible mechanism
Breast cancer is a complex and multifactorial disease that involves many cellular and molecular pathways.Weinberg and Hanahan in 2000 stated 6 hallmarks of cancer, (1) continuous proliferative signaling, (2) escaping growth suppression, (3) countering cell death, (4) sustaining replicative (5) promoting angiogenesis, and ( 6) metastasis. 25To overcome this complex phenomenon, an effective therapy needs to be found.Due to the multi-target cancer therapy, natural product consumption is currently a major problem.As a result, this study investigated the bioactive chemicals found in Asian pigmented rice that were intended to target many pathways in the treatment of cancer (Figure 1).

Conclusions
The pigmented rice covered by this study were black, red, and dark purple rice, and all contains a variety of peonidin-3glucoside, cyanidin-3-glucoside, γ-oryzanol, γ-tocotrienol, proanthocyanidin, cinnamic acid, and anthocyanins that may act as pro-apoptotic, anti-proliferative, and anti-metastasis in breast cancer cells.Therefore, choosing whole-grain red, black, or purple is an excellent choice for health.Plus, these varieties are richer in disease-fighting antioxidants.Rice being a staple food for half of the world can be a source of energy for our generations only if it is accumulated with nutrition.

Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Molecular pharmacology and therapeutics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

Mohammed Aljunaid
Faculty of Medicine, Department of Dental Medicine, Taiz University, Taiz, Taiz Governorate, Yemen I have completed my evaluation and after reading this Systematic Review carefully I am of the opinion that this manuscript should be considered for indexing.
Nonetheless, the authors need to resolve some minor difficulties such as the following: In general check the grammar.

Methods:
The risk of bias needs to be added to the study or provide information on the quality assessment process.

1.
Add the critical appraisal process to the review.2.

In the result:
It is important to strike a balance between providing enough detail to support the conclusions and maintaining readability.

1.
Are the rationale for, and objectives of, the Systematic Review clearly stated?Yes

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?

Ananto Ali Alhasyimi
Department of Orthodontics, Faculty of Dentistry, Universitas Gadjah Mada, Yogyakarta, Special Region of Yogyakarta, Indonesia Thank you for your work.The paper is well-researched and written, with profound insights into the bioactive compounds of Asian pigmented rice and their role in breast cancer.Best wishes to all the authors.I believe it has merit and should be considered for indexing.Novelty alone is sufficient and has a significant impact.
In order to improve its quality I think some minor issues should be noticed: Please add the evaluation of the risk of bias in the included studies.1.
This systematic review was well-designed in accordance with PRISMA guidelines.It was included in the Reporting guidelines.Please incorporate the PRISMA flowchart into the primary text.

2.
Since this is a review article, it is expected that you describe some of your own premises and elucidate some novel findings from your literature studies.

Are sufficient details of the methods and analysis provided to allow replication by others? Yes
Is the statistical analysis and its interpretation appropriate?

Are the conclusions drawn adequately supported by the results presented in the review? Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: Orthodontic; biomaterials; biomechanic; retention in orthodontic I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

Kok-Yong Chin
Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia In this systematic review, the authors attempted to summarise the beneficial effects of Asian pigmented rice extract on breast cancer.However, the literature-gathering and evidence synthesis processes are flawed so the results and conclusion could not be judged fairly at this point.There is also no critical appraisal process, so it is hard to call this a systematic review.
The systematic review was not constructed based on PRISMA guidelines.The authors should follow the guidelines and rewrite the manuscript for it to be considered.The authors could also refer to any published systematic review during their writing.

○
Search string: Why was the bracket removed from the search string for the search in Scopus?
○ Keywords: the inclusion of "cancer therapy" and "anti-metastasis" may restrict the search results.I recommend searching again without these terms.

○
Setting open-access article as the inclusion criteria severely limits the search results.

○
The authors need to justify setting a time frame of 10 years in the search.How would older articles not be relevant anymore?
○ Why would the authors screen out items without original data (reviews, commentaries, letters etc) at the very last stage?This could be done earlier.

○
Other necessary steps for deciding article inclusion are not illustrated: how many persons

○
The result interpretation was done according to the study approach, the type of rice and bioactive compounds role in breast cancer.This interpretation covered overall questions of this review.Applicability of the results of the review ○ This review included possible mechanism and significance of finding that will be more applicable in health or pharmaceutical practice.This article was constructed based on PRISMA guidelines and checklist.1.
This article also referred to one literature review.

Figure 1 .
Figure 1.Pigmented rice bioactive compound possible mechanism from breast cancer.28

Reviewer Report 13
April 2023 https://doi.org/10.5256/f1000research.143078.r169255© 2023 Chin K.This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 .
Seechamnanturakit V, Karrila TT, Sontimuang C, et al.: The Natural Pigments in Pigmented Rice Bran and Their Relation to Human Health: A Literature Review.KMUTNB Int.J. Appl.Sci.Technol.2018; 11(1): 3-13.Hopefully you could understand and approve this manuscript.Thank you very much.Sincerely Yours Competing Interests: nil The benefits of publishing with F1000Research: Your article is published within days, with no editorial bias • You can publish traditional articles, null/negative results, case reports, data notes and more • The peer review process is transparent and collaborative • Your article is indexed in PubMed after passing peer review • Dedicated customer support at every stage • For pre-submission enquiries, contact research@f1000.com

Table 1 .
The summary of studies discovered benefit of Asian pigmented rice physicochemical properties and its implication in breast cancer.29

Table 1 .
Continued This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes Competing Interests:
No competing interests were disclosed.

have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.
https://doi.org/10.5256/f1000research.143078.r169259© 2023 Ali Alhasyimi A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work.The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions.