Synergistic and Additive Effects of Herbal Medicines in Combination with Chemotherapeutics: A Scoping Review

Abstract

Background:

Natural products are increasingly gaining interest as potential new drug candidates for cancer treatment. Herbal formula, which are combinations of several herbs, are primarily used in East Asia and have a long history of use that continues today. Recently, research exploring the combination of herbal formulas and chemotherapy for cancer treatment has been on the rise.

Methods:

This study reviewed research on the co-administration of herbal formulas and chemotherapy for cancer treatment. The databases PubMed, Embase, and Cochrane Library were used for article searches. The following keywords were employed: “Antineoplastic agents,” “Chemotherapy,” “Phytotherapy,” “Herbal medicine,” “Drug synergism,” and “Synergistic effect.” The selection process focused on studies that investigated the synergistic interaction between herbal formulas and chemotherapeutic agents.

Results:

Among the 30 studies included, 25 herbal formulas and 7 chemotherapies were used. The chemotherapy agents co-administered included cisplatin, 5-fluorouracil, docetaxel, doxorubicin, oxaliplatin, irinotecan, and gemcitabine. The types of cancer most frequently studied were lung, breast, and colon cancers. Most studies evaluating the anticancer efficacy of combined herbal formula and chemotherapy treatment were conducted in vitro or in vivo.

Discussion:

Most studies reported synergistic effects on cytotoxicity, apoptosis, and tumor growth inhibition. These effects were found to be associated with cell cycle arrest, anti-angiogenesis, and gene expression regulation. Further studies leading to clinical trials are required. Clinical experiences in East Asian countries could provide insights for future research.

Introduction

Natural products have traditionally been employed and their usage has surged in recent years as prospective drug candidates. This is large due to the complexities and challenges faced in the development of drugs through conventional methods.^1,2 The application of natural products in various cancer treatments is also an area of active research. ³ Approaches to the utilization of natural products generally fall under 3 main categories: extraction of active components from a single natural product, whole extraction from a single natural product, and compound prescriptions composed of multiple natural products, that is, herbal formulas. Among these, the focus on compound prescriptions is predominant in countries like Korea, China, and Japan.^4,5 This trend can be attributed to the active implementation of traditional medicine practices, namely traditional Korean medicine, traditional Chinese medicine, and Kampo medicine in these nations. Compound prescriptions, with their history of traditional use and accumulated experience, provide a rich source of information for new drug development derived from natural products. In contrast, research in Europe and America primarily centers on the single active components of natural products. However, in East Asia, both types of research, focusing on single active components and compound prescriptions, are being pursued.^{6 -9} Rooted in extensive experience, the exploration of herbal medicines for cancer symptom management has been intensively studied.^10,11 There is also a considerable body of research investigating herbal medicines as potential anticancer agents. According to prior studies, the anticancer properties of herbal medicines can be traced back to their ability to inhibit tumor angiogenesis, promote apoptosis, induce autophagic cell death, and alter the tumor microenvironment.^{12 -15}

Numerous investigations are currently underway to explore the potential augmentation of anticancer effects via combination therapy, utilizing a variety of anticancer drugs. ¹⁶ Concurrently, there are ongoing studies examining the co-administration of herbal medicines with anticancer drugs, some of which have yielded efficacious results. ¹⁷ However, it is important to note that the quality of studies reporting the effectiveness of this combination therapy remains, on the whole, relatively low. ¹⁷ Moreover, adverse events have been documented in patients undergoing chemotherapy as a result of herb-drug interactions. ¹⁸ Thus, a pressing need exists for more comprehensive and rigorous research into the integration of herbal medicine and chemotherapy.

In this context, our study undertakes a systematic review of extant research on the combination of herbal formulas and chemotherapeutic agents in cancer treatment. Our primary objective is to furnish a foundational dataset for future research into chemotherapy and herbal formula combinations. We achieve this by synthesizing information regarding which specific herbal formulas have been co-administered with each chemotherapeutic agent, and the corresponding outcome variables that have been assessed.

Methods

This scoping review was conducted to assess whether herbal formulas enhance the anticancer effect of chemotherapy. Our approach adhered to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for scoping reviews. ¹⁹

Inclusion and Exclusion Criteria

The criteria for inclusion comprised studies investigating anticancer effects, those utilizing whole extracts of 2 or more herbs in conjunction with chemotherapy, and those published in English. Exclusion criteria included review articles, clinical trials, conference proceedings, studies that lacked results for the chemotherapy-alone group, and studies without results for the combination treatment group.

Search Strategy

We carried out literature searches using the PubMed (https://pubmed.ncbi.nlm.nih.gov/), Embase (https://www.embase.com/), and Cochrane Library (https://www.cochranelibrary.com/) databases. The most recent search was conducted in April 2024. The free-text keywords and Medical Subject Heading terms employed were “Antineoplastic Agents,” “Phytotherapy,” and “Drug Synergism.” The search history for the PubMed database is outlined in Table 1. We employed a similar search strategy for the Embase and Cochrane Library databases.

Table 1.

Search History of PubMed.

Search number	Keywords
1	Antineoplastic Agents [MeSH Terms]
2	Anticancer agent
3	Anticancer drug
4	Chemotherapy
5	Antitumor drug
6	Antitumor agent
7	#1 or #2 or #4 or #5 or #6
8	Phytotherapy [MeSH Terms]
9	Herbal medicine
10	Botanical drug
11	Natural product
12	Herbal therapy
13	Herb therapy
14	Herbal decoction
15	Herbal formula
16	Traditional Chinese herbal formula
17	#8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16
18	Drug Synergism [MeSH Terms]
19	Synergism
20	Drug augmentation
21	Drug Potentiation
22	Synergistic effect
23	Synergistic interaction
24	#18 or #19 or #20 or #21 or #22 or #23
25	#7 and #17 and #24

Study Selection

Duplicates were initially eliminated from the search results. The original research articles were then selected based on clearly defined inclusion and exclusion criteria, which were developed to focus on non-clinical data regarding combination therapies. We specifically excluded clinical trial results to maintain a narrow focus and manage the heterogeneity of the data. Titles and abstracts were reviewed to identify studies that met these criteria, and full texts were subsequently examined for final selection. The selection process was independently conducted by 2 researchers, and any disagreements regarding the selection of literature were resolved through discussion.

Data Extraction

Two reviewers collaborated to develop a data-charting form in Excel to determine the variables to be extracted. Both reviewers independently charted the data, reviewed the results, and iteratively adjusted the data-charting form. The following data were extracted for qualitative synthesis: first author, publication year, study type, type of chemotherapy, herbal medicine, cancer type, and major findings. Study types incorporated in vitro studies, in vivo studies, and studies encompassing both. Outcomes were presented as the anticancer efficacy results of the combined administration.

Data Analysis

Given the broad range of chemotherapies and herbal formulas in our study, a qualitative analysis was performed. The characteristics of the included studies were summarized in table format, and results were categorized based on the specific chemotherapy co-administered.

Results

Selection of Sources of Evidence

Following the removal of duplicates, we identified 1463 articles from the electronic biomedical databases. Based on the evaluation of titles and the abstracts, we excluded 1096 articles. We then assessed the full texts of the remaining 367 articles for eligibility. Of these, 337 were excluded due to the following reasons: 248 did not investigate herbal formulas, 25 did not administer herbal formula and chemotherapy in combination, 35 did not report changes in anticancer efficacy, 17 did not use chemotherapy agents, 6 were not experimental studies, 3 were not written in English, and 3 were not cancer studies. Therefore, we considered 30 studies eligible for review. The selection process is depicted in Figure 1, which follows the PRISMA flow diagram.

Figure 1.

PRISMA flow diagram of the literature selection process.

Characteristics of Sources of Evidence

A total of 30 studies examined 7 types of chemotherapy: cisplatin (10 studies), 5-fluorouracil (5-FU) (8 studies), docetaxel (5 studies), doxorubicin (4 studies), oxaliplatin (3 studies), irinotecan (2 studies), and gemcitabine (one study). Twenty-five different herbal formulas were administered across these studies.

Cisplatin

Nine herbal formulas were used in combination with cisplatin across 10 studies (Table 2).

Table 2.

Studies Using Cisplatin in Combination.

First author (year)	Herbal medicine	Study design	Cancer type	Cell line/ Animal Model	Outcomes
Park (2009) 20	HemoHIM	in vivo	Melanoma	B16F0	Tumor weight, Tumor volume
Xiong (2014) 21	Ke	in vivo	Lung cancer	A549	Tumor volume, Tumor weight
Sato (2015) 22	Bojungikgi-tang	in vitro	Cervical cancer	HeLa	Cell viability
Lu (2016) 25	Jinfukang	in vitro	Lung cancer	A549, H1975, H1650, H2228	Cell viability
Yu (2017) 23	Bojungikgi-tang	in vitro	Lung cancer	A549	Cell viability
Lou (2018) 26	Yu Ping Feng San	in vitro	Lung cancer	A549	Cell viability, apoptosis
Shen (2019) 27	Yangfei Kongliu Formula	in vivo	Lung cancer	LLC	Tumor weight
Zhang (2019) 28	Wenxia Changfu	in vitro & in vivo	Lung cancer	A549	Cell viability, Tumor volume, Tumor weight
Park (2020) 29	MH-30	in vitro & in vivo	Melanoma	B16F10	Tumor weight
Zheng (2021) 30	Feiyanning	in vitro	Lung cancer	A549	Cell viability, colony number

HemoHIM, an herbal mixture of Angelica Radix, Cnidium Rhizoma, and Paeonia Radix enhanced the efficacy of cisplatin in reducing tumor size and weight in melanoma-bearing mice, seemingly due to increased activity of NK and Tc cells and increased secretion of IL-2 and IFN-γ. ²⁰ It also reduced cisplatin-induced nephrotoxicity.

The Ke formula is composed of 13 herbs: Semen Benincasae, Arisaema Cum Bile, Houttuynia Cordata, Rhizoma Fagopyri Dibotryis, Cremastra appendiculata, Agrimonia pilosa, Carthami Flos, Lignum Sappan, Rhizoma Pinelliae, Radix Ranunculi Ternati, Radix adenophorae, Radix ophiopogonis, and Rhizoma Polygonati Odorati. ²¹ When combined with cisplatin in a mouse model of lung cancer, showed a tumor volume and weight inhibitory rate similar to that of cisplatin alone. This combination also ameliorated body weight loss caused by cisplatin, without noticeable toxicity. This may be attributed to cell cycle arrest and suppression of the PI3K/AKT pathway.

Bojungikgi-tang, a traditional herbal medicine consisting of Astragalus membranaceus, Glycyrrhiza uralensis, Codonopsis pilosula, Angelica sinensis, Citrus reticulata, Cimicifuga heracleifolia, Bupleurum chinense, and Atractylodes macrocephala, was used in combination with cisplatin in 2 studies. This combination was reported to increase cisplatin-induced apoptosis in cervical cancer and lung cancer cells.^22,23

Jinfukang, an herbal medicine containing 12 herbs, Astragalus membranaceus, Glehnia littoralis, Asparagus cochinchinensis, Ligustrum lucidum, Selaginella doederleinii, Paris polyphylla, Epimedium sagittatum, Gynostemma pentaphyllum, Cornus officinalis, Salvia chinensis, Ophiopogon japonicus, and Trigonella foenum graecum, has been used for a long time in the prevention and treatment of lung cancer in China. ²⁴ It was reported to inhibit cell proliferation and increase apoptosis when combined with cisplatin in lung cancer cells. Activation of AIFM2 was found to partially mediate the synergistic pro-apoptotic effect. ²⁵

Yu Ping Feng San, a traditional herbal mixture composed of Astragali radix, Atractylodis Macrocephalae Rhizoma, and Saposhnikoviae Radix, increased cytotoxicity and apoptosis of cisplatin, with Ginkgo Folium further enhancing this effect. This may be due to the increased intracellular concentration of cisplatin caused by the increased expression and activity of WT1. ²⁶

The Yangfei Kongliu formula is composed of Astragali Radix, Panax Ginseng, Radix Glehniae, Coicis Semen, Agrimonia herba, and Herba hedyotidis according to the treatment principles of traditional medicine. ²⁷ The Yangfei Kongliu formula enhanced the ability of cisplatin to inhibit lung cancer growth and metastasis, likely due to its effect on the TGF-β1/Smad signaling pathway.

The Wenxia Changfu formula, an herbal medicine composed of Radix Aconiti Praeparatae, Panax ginseng, Angelica sinensis, Radix et Rhizoma Rhei, when co-administered with cisplatin, increased apoptosis and inhibited both tumor volume and tumor weight growth in lung cancer. This was reported to be associated with suppressed Integrin β1, FAK, PI3K, and AKT protein expression. ²⁸

The MH-30, a novel herbal formulation, demonstrated significant effects in melanoma models when combined with cisplatin. ²⁹ The formulation, containing extracts from Angelica Radix, Cnidii Rhizoma, and Paeonia Radix enhanced the anti-cancer efficacy of cisplatin, leading to decreased tumor weight in melanoma-bearing mice. This enhancement may be attributed to increased NK cell activity and IFN-gamma secretion. Furthermore, MH-30 was shown to reduce the side effects typically associated with cisplatin, suggesting dual benefit in melanoma therapy.

Feiyanning is an herbal medicine that has been used for lung cancer management for more than 20 years in clinics and consists of 10 herbs: Astragalus mongholicus, Ganoderma lucidum, Polygonatum acuminatifolium, Ligustrum lucidum, Epimedium sagittatum, Atractylis macrocephala, Cornus officinalis, Paris polyphylla, Iphigenia caricina, and Salvia chinensis. Feiyanning enhanced the cytotoxicity of cisplatin in lung cancer cells by inhibiting cisplatin-induced protective autophagy and suppressing colony formation. ³⁰

5-Fluorouracil

Table 3 presents the characteristics of the 8 studies in which formula and 5-FU were administered in combination.

Table 3.

Studies Using 5-fluorouracil in Combination.

First author (year)	Herbal medicine	Study design	Cancer type	Cell line	Outcomes
Volate (2009) 31	Bojungikgi-tang	in vitro	Breast cancer	MCF-7, MDA-MB-231	Apoptosis
Liu (2011) 32	Chong Lou Fu Fang	in vitro	Gastric cancer	SGC-7901, BGC-823	Cell proliferation
Deng (2013) 33	Teng-Long-Bu-Zhong-Tang	in vivo	Colorectal cancer	CT26	Tumor volume, Tumor weight
Yu (2015) 34	Guan Chang Fu Fang	in vitro	Colorectal cancer	LoVo	Cell proliferation
Yang (2017) 36	Abnormal Savda Munziq	in vitro & in vivo	Cervical cancer	U27	Cell proliferation, Tumor volume, Tumor weight
Liu (2018) 37	Huang-Qin-Ge-Gen-Tang	in vitro & in vivo	Colorectal cancer	HT-29, RKO, SW48	Cell viability, Tumor volume
Ankita (2020) 38	SR033	in vitro	Cervical cancer	HeLa	Apoptosis
Gong (2023) 39	Danggui Buxue Tang	in vitro & in vivo	Colorectal cancer	HT-29	Apoptosis, Tumor weight, Tumor volume

Volate et al reported that Bojungikgi-tang, when combined with 5-FU, enhanced apoptotic effects in breast cancer cells. ³¹ Bojungikgi-tang demonstrates apoptotic activity via the activation of JNK, and it has shown a synergistic effect when combined with 5-FU. Chong Lou Fu Fang, an herbal formula containing Rhizoma Paridis, Fructus Forsythiae, and Radix Codonopsis, has reported anticancer efficacy. ³² Its co-administration with 5-FU in gastric cancer cells exhibits a synergistic cytotoxic effect reportedly associated with the downregulation of chemotherapy resistance-related genes, such as TS and ERCC1.

Teng-Long-Bu-Zhong-Tang, a traditional herbal formula, was investigated for its effect in combination with 5-FU in the CT26 colon carcinoma model. ³³ Comprising Actinidia chinensis, Solanum nigrum, Duchesnea indica, Atractylodes macrocephala, Poria cocos, Coix seed, Mistletoe, and Scutellaria barbata, the formula significantly inhibited both tumor volume and tumor weight growth with 5-FU. The mechanism appears to involve enhanced cytotoxicity of 5-FU through the upregulation of caspase-3, 8 and 9 activities.

Guan Chang Fu Fang, an herbal formula used clinically as an enema, has demonstrated anticancer efficacy with ingredients of Agrimonia pilosa, Patrinia scabiosaefolia, and Solanum nigrum. ³⁴ Yu et al. reported that Guan Chang Fu Fang enhances 5-FU efficacy in colon cancer cells by enhancing cytotoxicity through regulation of the B‑cell lymphoma‑2 family of proteins.

Abnormal Savda Munziq is a traditional Uyghur medicine consisting of 10 herbs: Adiantum capillus-veneris, Alhagi pseudalhagi, Anchusa italica, Cordia dichotoma, Euphorbia humifusa, Foeniculum vulgare, Glycyrrhiza uralensis, Lavandula angustifolia, Melissa officinalis, Ziziphus jujube, Glycyrrhiza inflata, and Glycyrrhiza glabra. ³⁵ When combined with 5-FU, it has been reported to synergistically inhibit the proliferation and growth of cervical cancer cells, as well as suppress increases in both tumor volume and tumor weight. ³⁶

Huang-Qin-Ge-Gen-Tang, comprising Paeonia lactiflora, Glycyrrhiza uralensis, Pueraria lobata, Scutellaria baicalensis, and Cimicifuga foetida, reduces cell viability and suppresses tumor growth in colorectal cancer cells when combined with 5-FU. This appears to be, in part, due to the suppression of the E2F1/TS signaling pathway. ³⁷

SR033, an herbal formula composed of green tea, cinnamon, turmeric, cardamom, and cloves, has reported anti-oxidative, chemoprotective, anti-proliferative, and anti-inflammatory effects. ³⁸ Co-administration of SR033 and 5-FU has been shown to increase the apoptosis rate in cervical cancer cells.

Danggui Buxue Tang, a traditional herbal formula composed of Astragali Radix and Angelica Sinensis Radix, recorded in “Neiwaishang Bianhuo Lun” published in 1247, has been reported to significantly enhances apoptosis and reduce tumor weight and volume in colorectal cancer cells when combined with 5-FU. ³⁹ This effect seems to be associated with increased phosphorylation of JNK and C-Jun.

Docetaxel

In 5 studies, 3 herbal formulas were administered in combination with docetaxel (Table 4).

Table 4.

Studies Using Docetaxel in Combination.

First author (year)	Herbal medicine	Study design	Cancer type	Cell line	Outcomes
Liu (2011) 32	Chong Lou Fu Fang	in vitro	Gastric cancer	SGC-7901, BGC-823	Cell proliferation
Qu (2014) 40	Aneustat (OMN54)	in vitro & in vivo	Prostate cancer	C4-2	Cell proliferation, Tumor volume
Qu (2018) 41	Aneustat (OMN54)	in vitro & in vivo	Prostate cancer	C4-2	Cell proliferation Cell migration
Jeong (2021) 43	SH003	in vitro & in vivo	Lung cancer	A549, H460	Apoptosis, Tumor volume, Tumor weight
Choi (2022) 44	SH003	in vitro & in vivo	Breast cancer	BT-20, MDA-MB-231	Cell viability, Tumor volume

A synergistic effect of Chong Lou Fu Fang on gastric cancer cells was also observed when combined with docetaxel. ³²

The herbal formula Aneustat contains the herbs Ganoderma lucidum, Salvia miltiorrhiza, and Scutellaria barbata. Two studies have reported the administration of Aneustat in combination with docetaxel to prostate cancer cells, enhancing the anticancer effect by reducing cell proliferation and migration, as well as inhibiting the growth of tumor volume, without inducing toxicity.^40,41 Inhibition of androgen receptor expression and AKT phosphorylation and downregulation of the FoxM1 gene have been reported to be involved in this effect. The efficacy of Aneustat was observed without inducing major host toxicity.

SH003 is an herbal formula composed of Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii, and many anticancer-related studies have been conducted. ⁴² Among them, there were 2 studies using docetaxel in combination, one for lung cancer and one for breast cancer.^43,44 In both studies, when SH003 was administered in combination with docetaxel, it increased cytotoxicity and suppressed tumor growth by inhibiting EGFR activation. The efficacy of SH003 was observed without inducing toxicity, and it is expected to minimize the toxicity of docetaxel.

Doxorubicin

Table 5 presents the studies in which doxorubicin, oxaliplatin, irinotecan, or gemcitabine were administered in combination with herbal formulas.

Table 5.

Studies Using Doxorubicin, Oxaliplatin, Irinotecan, Gemcitabine in Combination.

First author (year)	Herbal medicine	Chemotherapy	Study design	Cancer type	Cell line	Outcomes
Sowmyalakshmi (2005) 45	Semecarpus Lehyam	doxorubicin	in vitro	Breast cancer	MDA-MB-231, MCF-7	Cell viability
Xu (2013) 46	SENL	doxorubicin	in vitro	Lung cancer	SW1573/2R120	Apoptosis
Woo (2016) 47	SH003	doxorubicin	in vitro & in vivo	Breast cancer	MDA-MB-231	Cell viability, Tumor volume
Yue (2018) 48	Unnamed	doxorubicin	in vivo	Breast cancer	4T1	Tumor volume
Liu (2011) 32	Chong Lou Fu Fang	oxaliplatin	in vitro	Gastric cancer	SGC-7901, BGC-823	Cell proliferation
Zhang (2015) 49	Chang-Wei-Qin	oxaliplatin	in vivo	Colon cancer	HCT-116	Tumor weight
Kim (2019) 50	BP10A	oxaliplatin Irinotecan	in vitro & in vivo	Colorectal cancer	HCT-116, KM12SM	Cell viability, Tumor volume
Lam (2010) 51	PHY906	Irinotecan	in vivo	Colon cancer	Colon 38	Tumor volume
Pak (2021) 52	C5E	Gemcitabine	in vitro	Pancreatic cancer	PANC-1	Apoptosis

Semecarpus lehyam is an herbal formula composed of Nux vomica, Strychnos potatorum, Semecarpus anacardium, Smilax chinensis, Plumbago zeylanica, Nigella sativa, Ghee, and cane sugar and is used to treat breast cancer in India. ⁴⁵ Semecarpus lehyam combined with doxorubicin had a synergistic effect in reducing the viability of breast cancer cells.

An herbal formula SENL, containing Glehnia, Ophiopogon, Stephania tetrandra, Solomon’s seal, Radix Astragali, Hedyotis, Five-finger fig, Raw licorice and Pseudo-ginseng showed potential in reversing multi-drug resistance in cancer treatment, notably in combination with doxorubicin. ⁴⁶ The study, focusing on lung cancer cells, demonstrated significant inhibition of cancer cell growth. The underlying mechanism was attributed to the inhibition of the expression of the multidrug resistance-associated protein gene and promotion of intracellular accumulation of Adriamycin.

A study was conducted in which SH003 was administered in combination with various anticancer drugs to breast cancer cells. ⁴⁷ It has been reported that combinations with doxorubicin have a synergistic effect on cell viability and tumor growth.

Yue et al. ⁴⁸ investigated the efficacy of an herbal formula composed of 4 herbs, Andrographis paniculata, Acanthopanax senticosus, Camellia sinensis, and Hedyotis diffusa on breast cancer following co-administration with doxorubicin. This combination inhibited tumor growth in breast cancer and increased the survival rate of mice.

Oxaliplatin

A synergistic effect of Chong Lou Fu Fang on gastric cancer cells was also observed when combined with oxaliplatin. ³²

Chang-Wei-Qin, an herbal formula used with oxaliplatin, significantly enhanced anti-tumor effects in an orthotopic model of colorectal cancer. ⁴⁹ Chang-Wei-Qin, which includes ingredients such as Radix Astragali, Rhizoma Atractylodis, Radix Codonopsis, Akebia Quinata, Polyporus, Semen Coicis, Vitis Quinquangularis and Caulis Sargentodoxae, increased efficacy of oxaliplatin by modulating the expression of hCTR1 and downregulating ATP7A and ATP7B, which are related to drug resistance mechanisms.

BP10A is an herbal formula consisting of Descurainia sophia and Peucedani praeruptorum, and has been reported to inhibit the growth of various cancer cell lines. ⁵⁰ BP10A had a synergistic effect with oxaliplatin on the inhibition of cell proliferation and tumor growth in colorectal cancer.

Irinotecan

PHY906 is an herbal medicine composed of 4 herbs: Scutellaria baicalensis, Paeonia lactiflora, Glycyrrhiza uralensis, and Ziziphus jujube. ⁵¹ This enhanced the anti-tumor activity of irinotecan, as evaluated by tumor volume in a murine colon 38 allograft model, and also decreased the weight loss of mice due to irinotecan toxicity. No toxicity linked to PHY906 was identified. PHY906 increased expression of intestinal progenitor Lgr5, ASCl2, and Olfm4.

The synergistic effect of BP10A on cell proliferation and tumor growth inhibition in colorectal cancer was also reported when combined with irinotecan. ⁵⁰

Gemcitabine

C5E is an herbal formula consisting of 10 herbs Panax ginseng, Inonotus obliquus, Pinellia ternata, Sparganium stoloniferum, Alpinia galanga, Cinnamomum cassia, Astragalus membranaceus, Psoralea corylifolia, Tetradium ruticarpum, and Melia azedarach. ⁵² When gemcitabine, which is mainly used for the treatment of pancreatic cancer, was co-administered with C5E, a synergistic effect on the apoptosis of pancreatic cancer cells was observed. The downregulation of sonic hedgehog mRNA expression has been reported to be involved in this activity.

Discussion

Chemotherapy remains the most prevalent treatment approach for cancer. Its principal aim is to eradicate cancer cells, yet this process often negatively impacts healthy normal cells, leading to a range of adverse effects including nausea, vomiting, diarrhea, and peripheral neuropathy. ⁵³ These adverse effects present substantial concerns for both patients and healthcare providers, as they can necessitate dose reduction or, in extreme cases, the discontinuation of chemotherapy. ⁵⁴

Studies have indicated that the concomitant use of herbal formula can mitigate some of these effects, specifically anorexia, diarrhea, oral mucositis, neurotoxicity, and cardiotoxicity, in patients undergoing chemotherapy.^55,56 However, the potential augmentation of the anticancer effect when herbal medicine is combined with chemotherapy has been somewhat overlooked. This study, therefore, aims to review the synergistic effect of such herbal formulas and chemotherapy combined treatments.

Our review centered around studies that investigated whether combining herbal formula with chemotherapy could enhance anticancer efficacy. The chemotherapeutic agents most frequently used in combination were cisplatin, followed by 5-FU, then docetaxel. The most common types of cancer studied were lung cancer, breast cancer, and colon cancer, respectively. Notably, the majority of studies on lung cancer focused combining herbal formula with cisplatin, while docetaxel and doxorubicin were each used in only a single study.

Herbal formulas used in combination with chemotherapy can be classified into 3 main categories. The first category comprises those with longstanding use in traditional medicine, with records available in classical literature. Exemplary formulas in this group include Bojungikgi-tang and Yu Ping Feng San.^23,26 Given than these formulas were not originally utilized for cancer treatment in traditional medicine, their initial application was for symptom management in patients with cancer. Subsequent studies on their anticancer efficacy were carried out, or they were chosen through screening process for potential anticancer effects of diverse prescriptions. Similarly, certain formulas, such as Huang-Qin-Ge-Gen-Tang, have been explored as anticancer drugs by modifying traditionally used prescriptions, either by adding or subtracting herbs.^37,51 Both these approaches can be seen as drug repurposing strategies based on traditional medicine. The second category includes formulas that have been clinically employed for several decades, crafted following the principles of traditional medicine. In this review, the formulas Feiyanning and Guan Chang Fu Fang are examples of this category.^30,34 These prescriptions are distinctive in that research into their effectiveness has been driven by experiential evidence of their efficacy in managing cancer symptoms in clinical practice. Lastly, the third category encompasses novel formulas designed specifically for the development of new anticancer drugs, a method closely mirroring current drug development procedures. Within the present study, BP10A and SH003 represent this category.^44,50 In these instances, the formulation of the herbal formula was based on traditional medical principles or usage experience, or may have been chosen following screening tests on various herbs.

Several significant findings have emerged from studies focusing on the anticancer properties of herbal formulas. Notably, some research has shown that cancer cells resistant to chemotherapy exhibited significant response when treated with a combination of herbal medicines and chemotherapy. There have been reports that demonstrating the anticancer efficacy of Bojungikgi-tang and Yu Ping Feng San when co-administered with cisplatin in cisplatin-resistant cells.^23,26 Additionally, SR033 showed anticancer efficacy in 5-FU-resistant HeLa-R cells. ³⁸ Overcoming anticancer drug resistance could potentially offer renewed therapeutic options for patients who no longer respond to chemotherapy alone. Another key finding is that some of these herbal formulas help mitigate the toxicity associated with chemotherapy. For instance, SR033 has been reported to reduce oxidative stress, a known adverse effect of chemotherapy. ³⁸ Furthermore, SH003 has been found to alleviate neuropathic pain induced by paclitaxel and docetaxel.^57,58 If such co-administration of herbal medicines and chemotherapy has similar effects in humans, patients who would otherwise need to discontinue treatment or reduce dosage due to adverse effects might be able to continue treatment. Given these promising results, continued research and attention are warranted to fully elucidate the benefits and potential of co-administration of herbal formula with chemotherapy.

Numerous herbal medicines are recognized for their antioxidant properties, and some propose that the beneficial effects of these herbal medicines may be attributed to their antioxidant efficacy. ⁵⁹ Various chemotherapeutic agents, including anthracyclines, alkylating agents, and platinum coordination complexes, are known to induce the production of reactive oxygen species (ROS) in the body. ⁶⁰ Initially, it was concern that antioxidants could interfere with these free radical mechanisms, potentially diminishing chemotherapy efficacy. ⁶¹ However, the literature presents a complex picture regarding the impact of antioxidants on chemotherapy.^{62 -64} In fact, many studies reported that antioxidants may enhance survival times or improve tumor responses although limitations included statistical power and study heterogeneity. This finding aligns with another systematic review, which also noted difficulties in conclusively determining the impact of antioxidants on chemotherapy outcomes due to the diverse nature of the studies reviewed. ⁶³ Furthermore, recent discussions have highlighted not only traditional roles of antioxidants but also their potential influence on complex cellular mechanisms such as ferroptosis—an iron-dependent form of cell death distinctly different from apoptosis.^65,66 This suggests that antioxidants might have varied effects depending on the type of cell death pathways activated by different chemotherapeutic agents. While some studies highlighted potential benefits, others caution against the indiscriminate use of antioxidants. For instance, concerns have been raised about antioxidants potentially exacerbating certain adverse reactions like myelosuppression, alopecia, and mucositis.^60,67,68 Moreover, the critical role of ROS in cancer paradox, where ROS can both promote and suppress tumor progression, adds another layer of complexity to the use of antioxidants in chemotherapy.^64,69 Given these complexities, the inclusion of a broad range of literature in our discussion provides a more comprehensive overview of the current understanding of antioxidants in cancer therapy. It underscores the need for cautious interpretation and application of antioxidants in clinical settings. Future research should focus on elucidating the specific conditions under which antioxidants could be beneficial or detrimental, ensuring that therapeutic strategies are tailored to maximize patient outcomes while minimizing potential risks.

There is still much information that needs to be researched. For instance, Chong Lou Fu Fang showed synergistic effects with 3 chemotherapy agents, but demonstrated the strongest effect with 5-FU. ³² Similarly, SH003 was initially reported to synergize with doxorubicin, but subsequent studies reported a synergistic effect with docetaxel as well.^44,47 Therefore, it appears that various herbal medicines exhibit different synergistic effects with different anticancer drugs, these effects are challenging to predict. While several mechanisms have been proposed, much remains to be understood to fully validate the effectiveness of combined administration of herbal medicines and chemotherapy. Future research should consider the unique characteristics of herbal medicine, particularly its multiple components and targets. This will help broaden our understanding of the potential for herbal medicines to complement and enhance conventional cancer treatments, thereby providing improved therapeutic options for patients.

No toxicity of herbal formulas was reported in the articles included in our review. Instead, several articles reported effectiveness with no distinct toxicity. It appears that most studies we reviewed focused on the reduction of toxicity when herbal formulas were combined with conventional chemotherapy, rather than on conducting specific cytotoxicity tests on normal cells. There could be two reasons for the minimal mention of toxic reactions in these studies. First, these results are not the outcome of toxicity tests. Most of the included studies were designed to test efficacy. While toxic reactions might have been observed in experimental animals during these efficacy tests, the primary focus of these studies was on anticancer efficacy. Given that their design differs from a toxicity test, evaluating the toxicity of herbal formulas within the context of an efficacy test is inherently limited. Secondly, the actual toxicity may indeed be lower. Numerous studies have cited low toxicity as an advantage of herbal medicine, with several confirming its safety through in vivo studies and clinical trials.^70,71 There is also a view that the variety of ingredients in herbal medicine may neutralize the effects of each other, thereby reducing overall toxicity. ⁴⁵ Nevertheless, the toxicity of herbal formulas warrants further research and attention. Herbal formulas contain a multitude of ingredients and there is much that remains unknown about potential herb-drug interactions. There have been reports of adverse events caused by such interactions with commonly used herbal products. ¹⁸ Although some countries classify herb products as food, there is a perspective that given herbal medicine is not completely devoid toxicity, it should be categorized as a drug. This would mandate toxicity studies and safety management to be conducted as part of its use. ⁷²

While not part of this study, several clinical trials have been conducted where chemotherapy and herbal medicine were co-administered to cancer patients. Most of these clinical trials evaluated the improvement of symptoms experienced by cancer patients. One study reported that the combined use of herbal medicine improved pain and constipation in patients with cancer, and the number of adverse events was not significantly different from the group receiving conventional treatment alone, with most events being mild. ⁷³ There is also a report suggesting that several herbal medicines improved chemotherapy-induced anorexia, nausea, and vomiting. ⁷⁴ Numerous clinical trials have evaluated the anticancer effects of herbal medicine. However, in most of these studies, there was only the herbal medicine alone group or only the combination treatment group. Consequently, it was not possible to assess whether the anticancer effect was enhanced by combining the herbal medicine with chemotherapy.^71,75,76 There are two reasons why it has been challenging to find results comparing the chemotherapy alone group and the herbal medicine combination group. One is that clinical trials of herbal medicines being developed as anticancer drugs were often phase I studies, which do not usually involve a comparison group. The other reason is that Simon’s design, which evaluates only one group, is frequently used in phase II clinical trials that aim to explore the effectiveness of anticancer drugs. ⁷⁷ While many clinical trials involving the co-administration of chemotherapy and herbal medicine have focused on alleviating cancer symptoms or reducing the side effects of anticancer treatments, an increasing number of studies are now also examining the direct anticancer efficacy of these combinations. ⁷⁸ This shift reflects a growing interest in the potential of herbal medicines to not only support symptom management but also enhance anticancer outcomes. For instance, several clinical trials and emerging systematic reviews and meta-analyses have provided substantial evidence of these effects. A notable meta-analysis evaluated the efficacy and safety of adding herbal medicines to capecitabine-based regimens for colorectal cancer, which reported improvements in objective response rate, disease control rate, and quality of life, alongside reduced risks of adverse events. ⁷⁹ Another meta-analysis emphasized the benefits of combining herbal medicine with neoadjuvant chemotherapy for breast cancer treatment, showing significant improvements in the objective curative effect, performance status score effectiveness, and reductions in gastrointestinal adverse reactions post-chemotherapy. ⁸⁰

In this review, it is noteworthy that hematological cancers were not represented among the included studies. This absence may be attributed partly to our search strategy, which did not specifically target hematological malignancies. However, it also reflects a broader trend in the current body of research, where the focus of studies investigating the synergistic effects of herbal formulas and chemotherapy has predominantly been on solid tumors. This observation suggests a gap in the literature regarding the application of these combination therapies to hematological cancers. Given the potential benefits of herbal formulas in enhancing the efficacy of chemotherapy while possibly mitigating side effects, future research should endeavor to explore these effects in the context of hematological malignancies. This area of study could provide valuable insights into new therapeutic strategies for treating these cancers, emphasizing the need for a more inclusive research approach that spans various cancer types.

Most studies included in this review mention the presence of synergistic effects when herbal formulas are combined with chemotherapeutics. However, it is important to clarify that these references to synergy were not substantiated using mathematical models like the Chou-Talalay method; ⁸¹ rather, they likely describe what are technically additive effects. Recognizing even additive effects is significant, as it highlights the potential benefits of integrating herbal medicines with standard chemotherapy treatments. Our scoping review thus serves to catalog and discuss these reported benefits. Nonetheless, there remains a crucial need for more rigorous investigations into these interactions. Future research should focus not only on confirming true synergistic effects through appropriate quantitative models but also on elucidating the mechanisms underlying these interactions. This approach will enhance our understanding of how herbal medicines can be optimally combined with chemotherapeutics to improve cancer treatment outcomes.

This study presents several limitations. Firstly, despite our comprehensive search, there may be studies we have overlooked that evaluated the combined effects of herbal formulas and chemotherapy due to the wide range of interventions and diseases targeted. Future research should focus on specific cancers or specific anticancer drugs. Additionally, due to the linguistic limitations of the authors, only literature written in English was reviewed. Considering that herbal medicine is globally used, reviewing literature in multiple languages is necessary. Secondly, only studies evaluating the increased anticancer efficacy following co-administration were included. However, since the purpose of combining herbal medicines with chemotherapy is often to alleviate the adverse effects of anticancer drugs and overcome drug resistance, future studies need to evaluate other outcomes.

Despite these limitations, this study provides meaningful insight by summarizing the anticancer drugs and cancers most effectively treated in combination with herbal formulas frequently used in clinical practice. In countries like Korea and China, traditional Korean medicine and Chinese medicine practitioners can prescribe various herbal combinations to patients in the form of decoctions. ⁸² Numerous licensed herbal extracts are prescribed to patients in several East Asian countries. ⁸² Thus, the application of co-administration study finding to clinical practice in these countries is relatively straightforward, and clinical experience can provide insights for future co-administration studies. Furthermore, the U.S. Food and Drug Administration has also developed industry guidelines creating a new category of botanical drugs that can be approved as prescription drugs. ⁸³ While a significant gap still exists between laboratory studies and clinical practice, a virtuous cycle is anticipated to develop wherein research provides the foundation for treatment and clinical experience provides insights for research on the co-administration of herbal medicines.

Conclusion

In this scoping review, various herbal formulas were shown to be effective when combined with several chemotherapies. In vitro studies are expected to lead to in vivo studies and clinical trials, and the clinical experience of co-administering herbal formulas is anticipated to provide valuable insights for further research.