The Role and Mechanism of Paeoniae Radix Alba in Tumor Therapy

Tumors have a huge impact on human life and are now the main cause of disease-related deaths. The main means of treatment are surgery and radiotherapy, but they are more damaging to the organism and have a poor postoperative prognosis. Therefore, we urgently need safe and effective drugs to treat tumors. In recent years, Chinese herbal medicines have been widely used in tumor therapy as complementary and alternative therapies. Medicinal and edible herbs are popular and have become a hot topic of research, which not only have excellent pharmacological effects and activities, but also have almost no side effects. Therefore, as a typical medicine and food homology, some components of Paeoniae Radix Alba (PRA, called Baishao in China) have been shown to have good efficacy and safety against cancer. Numerous studies have also shown that Paeoniae Radix Alba and its active ingredients treat cancer through various pathways and are also one of the important components of many antitumor herbal compound formulas. In this paper, we reviewed the literature on the intervention of Paeoniae Radix Alba in tumors and its mechanism of action in recent years and found that there is a large amount of literature on its effect on total glucosides of paeony (TGP) and paeoniflorin (PF), as well as an in-depth discussion of the mechanism of action of Paeoniae Radix Alba and its main constituents, with a view to promote the clinical development and application of Paeoniae Radix Alba in the field of antitumor management.


Introduction
Cancer continues to grow globally and has become the second leading cause of death worldwide [1,2].At present, the main treatment modalities are surgical resection, radiotherapy and chemotherapy [3], but these treatments are more damaging to the organism, and the treatment process is characterized by high toxicity and side effects, a poor postoperative prognosis and a high recurrence rate [4,5].The quality of patients' survival is still not effectively ensured, and their metastasis and recurrence cannot be prevented [6,7].Therefore, there is an urgent need to find non-toxic natural drugs to treat tumors [8].
With the prosperous development of Chinese medicine, Chinese herbal medicines have been widely used in tumor treatment as complementary and alternative therapies [9].They have the advantages of good therapeutic effects and low toxicity and side effects, which can ensure the quality of survival and prolong the survival rate of cancer patients [10,11].In recent years, more and more people have started to pay attention to Chinese herbs with health benefits and therapeutic effects [12].Most of the Chinese herbs can be used for both healing and dietary purposes, so they are called medicinal herbs.The concept of medicine and food homology has been around for a long time, dating back to the "Huangdi Neijing" [13], where it is mentioned that food can be used as medicine to enhance one's immunity and thus prevent or treat diseases [14,15].With the change in time, the theory of the medicine and food homology has been enriched and developed, and its core content has continued to this day.Paeoniae Radix Alba is one of these herbs, and as a natural medicine, it has been used for nearly a thousand years.
Paeoniae Radix Alba (PRA) is the dried root of Paeonia lactiflora Pall. in the buttercup family [16].PRA has a wide range of uses and has been widely used clinically for the treatment of visceral pain [17,18], cancerous pain [19], chronic gastritis [20,21], chronic hepatitis B [22], rheumatoid arthritis, etc. [23].It also has a high frequency of use in the prevention and treatment of tumors [24].With the in-depth development of chemical technology, there have been many reports on the pharmacological effects and mechanisms of PRA and its active ingredients, confirming that it has a wide range of pharmacological effects, including analgesic [25], anti-inflammatory [26], antidepressant [27,28], hepatoprotective [29], immune modulation [30] and significant antitumor activity, and it plays a therapeutic role in gastric cancer, hepatocellular carcinoma, pancreatic cancer and other malignant tumors [31,32].This paper mainly introduces the main active ingredients of PRA and summarizes the mechanism of action of PRA and its active ingredients in the treatment of various malignant tumors.

Effects of the Main Active Ingredients of PRA
The chemical composition of PRA is diverse, mainly including monoterpenes and their glycosides, triterpenoids, flavonoids, tannins and polysaccharides [33,34].Among them, the ones with significant efficacy and wide application in the treatment of various tumors are total glucosides of paeony (TGP) and paeoniflorin (PF).TGP is considered to be the main bioactive component of PRA, while PF is the main component of TGP [35].The chemical structure formula is shown in Table 1.

Name Structural Formula
Total glucosides of paeony herbs with health benefits and therapeutic effects [12].Most of the Chinese herbs can be used for both healing and dietary purposes, so they are called medicinal herbs.The concept of medicine and food homology has been around for a long time, dating back to the "Huangdi Neijing" [13], where it is mentioned that food can be used as medicine to enhance one's immunity and thus prevent or treat diseases [14,15].With the change in time, the theory of the medicine and food homology has been enriched and developed, and its core content has continued to this day.Paeoniae Radix Alba is one of these herbs, and as a natural medicine, it has been used for nearly a thousand years.Paeoniae Radix Alba (PRA) is the dried root of Paeonia lactiflora Pall. in the buttercup family [16].PRA has a wide range of uses and has been widely used clinically for the treatment of visceral pain [17,18], cancerous pain [19], chronic gastritis [20,21], chronic hepatitis B [22], rheumatoid arthritis, etc. [23].It also has a high frequency of use in the prevention and treatment of tumors [24].With the in-depth development of chemical technology, there have been many reports on the pharmacological effects and mechanisms of PRA and its active ingredients, confirming that it has a wide range of pharmacological effects, including analgesic [25], anti-inflammatory [26], antidepressant [27,28], hepatoprotective [29], immune modulation [30] and significant antitumor activity, and it plays a therapeutic role in gastric cancer, hepatocellular carcinoma, pancreatic cancer and other malignant tumors [31,32].This paper mainly introduces the main active ingredients of PRA and summarizes the mechanism of action of PRA and its active ingredients in the treatment of various malignant tumors.

Effects of the Main Active Ingredients of PRA
The chemical composition of PRA is diverse, mainly including monoterpenes and their glycosides, triterpenoids, flavonoids, tannins and polysaccharides [33,34].Among them, the ones with significant efficacy and wide application in the treatment of various tumors are total glucosides of paeony (TGP) and paeoniflorin (PF).TGP is considered to be the main bioactive component of PRA, while PF is the main component of TGP [35].The chemical structure formula is shown in Table 1.

Name Structural Formula
Total glucosides of paeony Paeoniflorin

Total Glucosides of Paeony (TGP)
Total glucosides of paeony (TGP) is a group of glycosides in the Chinese herb PRA [36], including paeoniflorin, paeonin [37], albiflorin [38,39], hydroxy-paeoniflorin [40], benzoyl-paeoniflorin [41], etc. [42,43].Modern pharmacological studies have found that TGP not only has immunomodulatory, anti-inflammatory and hepatoprotective effects, Paeoniflorin herbs with health benefits and therapeutic effects [12].Most of the Chinese herbs can be used for both healing and dietary purposes, so they are called medicinal herbs.The concept of medicine and food homology has been around for a long time, dating back to the "Huangdi Neijing" [13], where it is mentioned that food can be used as medicine to enhance one's immunity and thus prevent or treat diseases [14,15].With the change in time, the theory of the medicine and food homology has been enriched and developed, and its core content has continued to this day.Paeoniae Radix Alba is one of these herbs, and as a natural medicine, it has been used for nearly a thousand years.
Paeoniae Radix Alba (PRA) is the dried root of Paeonia lactiflora Pall. in the buttercup family [16].PRA has a wide range of uses and has been widely used clinically for the treatment of visceral pain [17,18], cancerous pain [19], chronic gastritis [20,21], chronic hepatitis B [22], rheumatoid arthritis, etc. [23].It also has a high frequency of use in the prevention and treatment of tumors [24].With the in-depth development of chemical technology, there have been many reports on the pharmacological effects and mechanisms of PRA and its active ingredients, confirming that it has a wide range of pharmacological effects, including analgesic [25], anti-inflammatory [26], antidepressant [27,28], hepatoprotective [29], immune modulation [30] and significant antitumor activity, and it plays a therapeutic role in gastric cancer, hepatocellular carcinoma, pancreatic cancer and other malignant tumors [31,32].This paper mainly introduces the main active ingredients of PRA and summarizes the mechanism of action of PRA and its active ingredients in the treatment of various malignant tumors.

Effects of the Main Active Ingredients of PRA
The chemical composition of PRA is diverse, mainly including monoterpenes and their glycosides, triterpenoids, flavonoids, tannins and polysaccharides [33,34].Among them, the ones with significant efficacy and wide application in the treatment of various tumors are total glucosides of paeony (TGP) and paeoniflorin (PF).TGP is considered to be the main bioactive component of PRA, while PF is the main component of TGP [35].The chemical structure formula is shown in Table 1.

Name Structural Formula
Total glucosides of paeony Paeoniflorin

Paeoniflorin (PF)
Paeoniflorin (PF), the main active ingredient of PRA, is a naturally occurring pharmacologically active ingredient that is highly valued for its low toxicity, high efficiency and safety, as well as for its association with a variety of antitumor, inflammatory, depressive and oxidative stress pharmacological effects [46,47].In recent years, scholars at home and abroad have conducted in-depth studies on the antitumor effects of PF and found that PF has a good inhibitory effect for hepatocellular carcinoma, gastric carcinoma, intestinal carcinoma, lung carcinoma, leukemia [48] as well as skin carcinoma [49], and its mechanism of action is related to apoptosis induced by different signaling pathways, preventing the proliferation of cancer cells and inhibiting metastasis [50,51].

Others
In addition to TGP and PF, PRA contains various active ingredients such as albiflorin, oxypaeoniflorin, 6 ′ -O-galloylpaeoniflorin and paeoniflorigenone [52].However, TGP and PF are more well-studied for tumor therapeutic purposes, and therefore, the focus of this paper is on TGP and PF.

Antitumor Therapy Mechanisms
Inhibition of tumor cell proliferation, induction of apoptosis, inhibition of cell metastasis, anti-inflammation and immunomodulation are the main pathways and phenotypes of the antitumor effects of PRA [53,54], as shown in Table 2.

Inhibits Tumor Cell Proliferation
The most basic characteristics of a cancer cell include its ability to proliferate persistently and over a long period of time [55].The coordinated action between out-of-control cell metabolism, growth and proliferation is essential for tumorigenesis [56].Cancer cells interfere with normal signals in the body that autonomously control cell growth [57,58].These signaling pathways are able to regulate the entire process through the cell cycle and cell growth, also known as cell size increase.PF derived from PRA was found to be a potential novel therapeutic agent for gastric cancer.PF acted on gastric cancer MGC803 cells and could inhibit cell viability and induced apoptosis by up-regulating miR-124 and inhibiting PI3K/Akt and STAT3 signaling [59].PF also inhibited the proliferation and invasion of breast cancer cells in the Notch-1 signaling pathway by interfering with breast cancer MDA-MB-231 and MCF-7 cells [60].In addition, TGP extracted from PRA inhibited the proliferation, invasion and migration ability of laryngeal cancer Hep-2 cells in a concentration-dependent manner, a process that may be related to the inhibition of the activation of the PI3K/Akt/GSK3β signaling pathway [61].Thus, PF and TGP can inhibit cancer cell proliferation through signaling pathway regulation.

Induces Apoptosis in Tumor Cells
Apoptosis is a fundamental biological phenomenon of the cell and is a tightly controlled polygenic process [62].If there is a problem with this process, apoptosis does not occur in cells that are supposed to die, and damaged cells can survive and develop into cancer cells [63,64].In the case of cancer cells, an interruption of the apoptotic process means the development and spread of cancer [65,66].Therefore, balancing the process of cellular metabolism in the body can combat the onset and development of cancer [67].It was found that PF intervention in gastric cancer SGC7901 cells significantly inhibited NF-kappaB activity and enhanced 5-fluorouracil-induced apoptosis in gastric cancer cells by preventing I kappaB alpha phosphorylation and reducing the nuclear translocation of NF-kappaB [68].Further, apoptosis was significantly induced in human cervical cancer cell line HeLa cells after PF treatment, which could result in the down-regulation of the anti-apoptotic gene Bcl-2 and the up-regulation of the pro-apoptotic genes Bax and caspase-3 [69].In addition, PF enhances the expression of caspase-9 and -3 proteins as well as Bax proteins in prolactinoma MMQ cells, whereas it inhibits the expression of Bcl-2 proteins and induces apoptosis mediated by the mitochondrial pathway [70].The apoptosis-inducing effect is seen in a variety of cancers.

Inhibits Tumor Metastasis
Malignant tumor cells have the ability to invade surrounding tissues and metastasize to distant tissues [71], and in some cases, they can penetrate the body's barriers and destroy surrounding tissues after invading the environment [72,73].Once the cancer metastasizes, it is difficult to control and will spread step-by-step in the body.Secondly, early tumors are difficult to detect, and by the time obvious symptoms appear, the tumor is likely to be in the middle or late stage of malignant transformation, so the process of controlling metastasis is particularly urgent [74].It was found that PF acted on gastric cancer AGS cells and inhibited the migration and invasion-promoting ability of gastric cancer-associated fibroblasts (GCAFs) by targeting microRNA-149 and IL-6 [75].PF also decreased the expression of MMP-9 and ERK in hepatocellular carcinoma HepG2 and Bel-7402 cells and increased the expression of E-cadherin in both cell lines [76].PF also significantly decreased the expression of Vimentin in colorectal cancer cells while increasing the expression of E-cadherin, which in turn reversed the EMT process [77,78].It can be seen that PF can inhibit metastasis by regulating matrix metalloproteinases and EMT-related proteins [79,80].In addition, TGP could inhibit the metastasis of pancreatic cancer ASPC-1 cells, and the expression levels of MMP-2 and MMP-9 proteins in the cells of the TGP group were significantly reduced compared with those of the blank control group [81].Therefore, both PF and TGP are involved in regulating the anticancer microenvironment [82], which inhibits the growth of cancer cells while suppressing their metastasis.

Anti-Inflammatory and Immunomodulatory
Inflammation has been shown to be closely associated with the stage of development of action and malignant progression of most types of tumors, as well as with the efficacy of anticancer therapies [83,84].Specifically, long-term chronic inflammation is associated with immunosuppression and would provide a favorable microenvironment for tumorigenesis, progression and metastasis [85,86].Therefore, anti-inflammation and immunomodulation have unique advantages in regulating the tumor microenvironment, and immunotherapy is becoming more and more important in the treatment of tumors [87,88].PRA, as a kind of traditional Chinese medicine, overcomes the characteristics of western medicines, which have high side effects and lower immunity, and has a natural advantage in antiinflammation and immunomodulation therapy [89][90][91].In a mouse model, PF improved survival and reduced the number and size of colon tumors.Medicinal plants and their extracts with anti-inflammatory and immunomodulatory properties may be an effective strategy for the treatment and prevention of chronic inflammation in colitis-associated colorectal cancer by mechanisms that may be related to the inhibition of the IL-6/STAT3 signaling pathway and IL-17 levels [92,93].Controlling inflammation will open new possibilities for long-term, multilevel tumor control [94].In general, PRA and its active ingredients or derivatives mainly produce antitumor effects on cell proliferation, apoptosis and metastasis and anti-inflammation and immunomodulation through signaling pathways, mitochondrial apoptotic pathway, EMT, MMPs, etc., as shown in Figure 1.In general, PRA and its active ingredients or derivatives mainly produce antitumor effects on cell proliferation, apoptosis and metastasis and anti-inflammation and immunomodulation through signaling pathways, mitochondrial apoptotic pathway, EMT, MMPs, etc., as shown in Figure 1.

Preventive Effect
PRA is found in many foods and medicines and not only has antitumor activity, but also has auxiliary therapeutic and preventive effects in many diseases [115].Postoperative patients with low immunity can take soup with PRA to improve their physical condition and enhance their immunity [116,117].In the late stage of various diseases, it helps patients having a loss of appetite to open the stomach and replenish nutrition in time [118].Long-term illnesses, bedridden conditions, all kinds of chronic diseases and the patients' long-term medication will damage the spleen and stomach, and a medicinal diet made of PRA can be very good to protect the patient's spleen and stomach, without harming the organism, but also to achieve the role of treatment of the disease [119,120].Therefore, we can consume medicinal meals with PRA for a long time to regulate the body.As shown in Table 3, we add PRA to many nutritious porridges, medicinal diets and other foods, which play a key role in preventing diseases.

Preventive Effect
PRA is found in many foods and medicines and not only has antitumor activity, but also has auxiliary therapeutic and preventive effects in many diseases [115].Postoperative patients with low immunity can take soup with PRA to improve their physical condition and enhance their immunity [116,117].In the late stage of various diseases, it helps patients having a loss of appetite to open the stomach and replenish nutrition in time [118].Long-term illnesses, bedridden conditions, all kinds of chronic diseases and the patients' long-term medication will damage the spleen and stomach, and a medicinal diet made of PRA can be very good to protect the patient's spleen and stomach, without harming the organism, but also to achieve the role of treatment of the disease [119,120].Therefore, we can consume medicinal meals with PRA for a long time to regulate the body.As shown in Table 3, we add PRA to many nutritious porridges, medicinal diets and other foods, which play a key role in preventing diseases.

Conclusions and Outlook
The current treatment of tumors is still conventional Western medicine, which can quickly kill tumor cells and reduce the tumor load, but it also inevitably brings a series of toxic side effects and adverse reactions [130].Traditional Chinese medicine and its long-term clinical experience have shown that PRA has a tonic effect and has therapeutic and preventive effects on a variety of diseases [131].Among them, it has a remarkable pain-relieving effect, which can significantly relieve cancer pain and alleviate patients' suffering.Modern pharmacological studies have shown that PRA has a wide range of anticancer activity, with obvious inhibitory effect on tumor cells, which can reduce the invasion and migration of cancer cells and inhibit the spread of cancer cells.In addition, PRA can enhance human immunity, making cancer patients more resistant to cancer cells.The concept of medicine and food homology is based on the advantage of boosting one's immunity, thus achieving the effect of preventing and treating diseases [132,133].PRA has a long history of medicinal use, and as a dual-purpose herb, it has great development and application value in clinical application, health food and diet [134].
We searched PubMed, Google Scholar, and China national knowledge infrastructure (CNKI) with the keywords "Paeoniae Radix Alba", "cancer", "carcinoma", "tumor" and so on and found that there are no reviews on the treatment of tumors by PRA in the past five years.More attention was paid to PRA and its active ingredients for the treatment of single cancers such as breast cancer and colorectal cancer.We retrieved a review of paeoniflorin for tumor therapy published in 2022 [135], which focused only on paeoniflorin's tumorsuppressing effects through various mechanisms and modulation of signaling pathways, but it talked little about paeoniflorin derived from the traditional Chinese medicine PRA, which is of little reference value to the advantages of traditional Chinese medicine.
In summary, this paper reviewed the application of PRA and its active ingredients, TGP and PF, in tumor therapy, focusing on the antitumor mechanism of action, medicinal food and treatment of disease and other advantages of PRA, which can inhibit the occurrence and malignant progression of tumors.

Table 1 .
Active ingredients and structural formula of Paeoniae Radix Alba.

Table 2 .
The therapeutic mechanism of Paeoniae Radix Alba and its active ingredients in antitumor therapy.