Natural Product Interventions for Chemotherapy and Radiotherapy-Induced Side Effects

1Cancer is one of the most common causes of death worldwide (Mcguire, ). Chemotherapy and radiotherapy are the most effective and extensive approaches for cancer management. However, chemotherapy, and radiotherapy-induced adverse effects including oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity, hinder the clinical uses. Subsequently, these harmful effects often reduce the quality of life in cancer patients, and may lead to therapy discontinuation (Shapiro,; Turcotte et al., ). Therefore, it is important to develop effective management strategies against chemotherapy and radiotherapy-induced side effects.

2Natural products including crude extracts, bioactive components-enriched fractions, and pure compounds derived from herbs as well as herbal formulas have been proved to prevent and treat cancers (Sanders et al., ). Clinical trials and preclinical studies show that some natural products can reduce chemotherapy and radiotherapy-induced oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity. Natural dietary supplements containing some ingredients such as Ginseng extract, Grape seed extract, and curcumin promote the recovery from severe illness, and relieve chemotherapy and radiotherapy-induced side effects. Gut microbiota plays the role in the modulation of drug action (Curro, ), possibly could evaluate the risk of severe gastrointestinal toxicity. Herb medicine has potential to improve digestive health (Peterson et al., ). The aim of this review is to summarize the recent evidence in detail for the effectiveness of natural products, and describe the possible mechanisms of the actions in reducing chemotherapy and radiotherapy-induced side effects. This review also draws particular attention to recent advances in the efficacy of natural dietary supplements, and the modulation of natural products on gut microbiotan for the protection against cancer therapy-induced toxicity.

3Oral mucositis is a common complication in patients undergoing chemotherapy and radiotherapy, which is initiated partly by oxidative stress and inflammation. Plant-derived and other natural medicines with anti-inflammation are recently demonstrated to manage chemotherapy-induced oral mucositis (Panahi et al.,; Mahendran et al., ). Plantago major is a most abundant herbaceous perennial plant that has been traditionally used for hundreds of years, and is effective as a wound healer with anti-ulcerative, anti-inflammatory, anti-bacterial, anti-viral, and anti-oxidant activities (Adom et al., ). Moreover, its extract is reported to have anticancer effect in Ehrlich ascites tumor bearing Balb/C mice (Ozaslan et al., ). A feasibility randomized triple-blind phase III clinical trial shows that P. major extract, chlorhexidine 0.12% and sodium bicarbonate 5% solution can effectively manage oral mucositis in cancer patients with grade II-III mucositis (Cabrera-Jaime et al., ).

4Severe stomatitis may interrupt or discontinue cancer therapeutics, and increase the risk of local and systemic infection. Japanese traditional medicine (Kampo) Hangeshashinto (TJ-14) effectively relieves chemotherapy-induced oral mucositis in gastric cancer and colorectal cancer patients by anti-oxidation and anti-inflammation (Matsumoto et al.,; Nishikawa et al., ) or suppression of inflammatory cell chemotaxis and cyclooxygenase-2 (COX2) expression (Kamide et al., ). Chamomile (Matricaria recutita) is a medicinal plant widely used in traditional medicine for its anti-oxidant, anti-microbial, and anti-inflammatory actions (Gomes et al., ), which seems to be a promising alternative for the treatment of 5-fluorouracil-induced oral mucositis and recurrent aphthous stomatitis (Seyyedi et al.,; Gomes et al., ). Aznol mouthwash combined with chamomile extract and Hangeshashinto, alleviates stomatitis in a small cohort of lung cancer patients treated with afatinib (Kato et al., ). Aloe vera, an herbal medicine in tropical area, has been used to treat skin disorders with anti-bacterial and wound-healing effects. Its mouthwash significantly reduces the intensity of chemotherapy-induced stomatitis and pain in clients with lymphoma and leukemia, and possibly improves the nutritional status of cancer patients (Mansouri et al., ).

5Natural nutritional products are also investigated to reduce chemotherapy and radiotherapy-induced oral mucositis. Turmeric (the rhizome of Curcuma longa) is a traditional spice and herb with many health benefits. Turmeric and its active ingredient curcumin have anti-oxidant and anti-inflammatory properties. Anticancer effects of curcumin have been demonstrated in a number of preclinical studies as well as in phase I/II clinical trials (Hatcher et al., ). Curcumin mouthwash is observed to be better than chlorhexidine mouthwash in terms of rapid wound healing in adult patients with chemotherapy and radiotherapy-induced oral mucositis (Patil et al., ). The rhizome of Zingiber officinale (ginger) is also used as traditional medicine with health benefits to treat muscular aches and pains worldwide. Its main ingredients 6-gingerol and 6-shogaol are reported to relief 5-fluorouracil-induced oral ulcerative mucositis and pain by regulating Na+ channels, playing an essential role in ginger-associated analgesia of pain (Hitomi et al., ). Tocotrienols are natural compounds existed in vegetable oil, which are a promising analogs of vitamin E for cancer therapeutics by sensitizing cancer cells to chemotherapeutic agents (Sailo et al., ). γ-Tocotrienol can prevent 5-fluorouracil-induced reactive oxygen species (ROS) generation in human oral keratinocytes by stabilizing the activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a redox-sensitive master regulatory transcription factor (Takano et al., ). Quercetin, a natural flavonoid enriched in common vegetables and herbs, has anti-oxidative and anti-inflammatory effects. Administered 250 mg quercetin capsules twice daily for 4 weeks, can reduce the incidence of oral mucositis in patients who undergo high dose chemotherapy for blood malignancy (Kooshyar et al., ).

6Honey produced by bees from flower nectar, is a folk medicine since ancient times in many countries. A meta-analysis indicates that honey can effectively reduce the incidence of chemotherapy and radiotherapy-induced oral mucositis (Xu et al., ). Further clinical evidence demonstrates its effectiveness as a preventative and therapeutic measure for chemotherapy-associated oral mucositis in pediatric oncology patients (Friend et al., ). There is potential interaction between oral microenvironment and mucositis development. Honey treatment produces the significant reduction of oral mucositis associated Candida and aerobic pathogenic bacterial infection, and increases body weight, delays the onset of oral mucositis, and decreases the severity of pain (Al Jaouni et al., ). In Turkey, black mulberry molasses is a foodstuff widely used as traditional intervention for the treatment of mucositis. Recently, black mulberry molasses usage is demonstrated to be an effective intervention in the prevention of radiation-induced oral mucositis in head and neck cancer patients (Demir Dogan et al., ). Propolis is a natural product collected by honeybee worker, and contains flavonoids with anti-ulcer, anti-bacterial, anti-fungal, healing and anti-inflammatory effects (Dodwad and Kukreja, ). Its water extract mouthwash efficiently prevents and heals chemotherapy or radiotherapy-induced oral mucositis in patients with head and neck cancers, or leukemia (Javadzadeh Bolouri et al.,; Eslami et al., ). However, early report of a double blind randomized placebo controlled trial shows that propolis cannot be recommended for severe oral mucositis in chemotherapy-treated pediatric patients (Tomazevic and Jazbec, ). The natural products in this part together with relevant characteristics of the respective studies are summarized in Table 1.

7The most common gastrointestinal toxicities induced by chemotherapy and radiotherapy include nausea, vomiting and diarrhea. In 2016, Chen et al. conduct a systematic review and meta-analysis (from 2005 to 2013) and show that Atractylodes macrocephala, Poria cocos, Coix lacryma-jobi, Astragalus membranaceus, Glycyrrhiza uralensis, and Panax ginseng can significantly reduce oxaliplatin-induced nausea and vomiting in colorectal cancer (Chen M. H. et al., ). Bacopa monnieri is used in several traditional systems of medicines for the management of epilepsy, depression, and neuropathic pain. Its bacoside-rich n-butanol fraction antagonizes cisplatin-induced retching and vomiting response (Ullah et al., ). Red Ginseng, a product with a steaming and drying process of the fresh ginseng, contains the majority of ginsenosides. Its anticancer mechanisms mainly include cell cycle arrest, apoptosis/paraptosis induction, and angiogenesis inhibition (Wang et al., ). Recently, a randomized double blind placebo-controlled trial demonstrates that Red Ginseng decreases symptom of nausea, vomiting, dyspnea and fatigue, and its efficacy and safety can improve life quality in patients receiving six cycles of adjuvant taxane- and platinum-based chemotherapy after cytoreductive surgery (Kim H. S. et al., ). A phase II randomized double-blind placebo-controlled study shows that safe and well-tolerated 6-gingerol improves the overall complete response rate in nausea and vomiting, appetite as well as quality of life in cancer patients with surgical resection of primary tumor and moderately to highly emetogenic adjuvant chemotherapy (Konmun et al., ), further demonstrating that ginger supplementation can significantly reduce the severity of chemotherapy-induced nausea in adult cancer patients (Ryan et al., ). Rhus coriaria, a flowering shrub, possesses anticancer effect against human colorectal cancer cells and triple-negative breast cancer cells (El Hasasna et al.,,; Athamneh et al., ). Its resin extract also attenuates angiogenesis and is used in treatment and management of cancer in Kenya (Ochwang'i et al.,; Mirian et al., ). Bunium persicum is a perennial plant in Iran. A randomized, double blind, crossover clinical trial shows that Persumac, a combination of R. coriaria and B. persicum, may be helpful in patients with refractory chemotherapy-induced nausea and vomiting (Nazari et al., ).

8Huang-Qin decoction is first described in Chinese canonical medicine about 1800 years ago for the treatment of different gastrointestinal symptoms, including nausea, vomiting and diarrhea. This decoction attenuates irinotecan-induced gastrointestinal toxicity and diarrhea in rats possibly via regulating glycine, serine and threonine pathway as well as bile acid metabolism homeostasis. Scutelleria baicalensis may play a crucial role in the therapeutic effect of this decoction on irinotecan-induced diarrhea (Cui et al.,; Wang X. et al., ).

9Of note, nutrient absorption and digestion of gastrointestinal tract may be compromised during chemotherapy and radiotherapy-induced damage to non-cancerous gastrointestinal mucosa. In 2018, Mahendran et al. review and show that plant-derived and some natural medicines with anti-inflammation manage chemotherapy-caused gastrointestinal mucositis (Mahendran et al., ). Other animal experiments confirm the efficacy of herbal medicines on intestinal mucositis. Wei-Chang-An pill, a traditional Chinese pharmaceutical preparation, possesses anti-inflammatory advantage and gastrointestinal regulation in digestive diseases. This pill promotes the recovery of intestinal function in 5-fluorouracil-induced intestinal mucositis in mice via relieving severe diarrhea and inhibiting gastric emptying and gastrointestinal transit in intestinal homeostasis (Chen Y. et al., ). Bu-Zhong-Yi-Qi decoction, a Chinese traditional herbal medicine, is widely used in Asia as an alternative treatment to reduce side effects of chemotherapy. This decoction protects against 5-fluorouracil-induced intestinal mucositis in mice (Gou et al., ). Saireito (TJ-114) is often used to treat inflammatory diseases such rheumatoid arthritis, systemic lupus erythematodes, and nephrotic syndrome. TJ-114 can reduce 5-fluorouracil-induced intestinal mucositis in mice by inhibiting cytokine-mediated apoptosis in intestinal crypt cells (Kato et al., ). The root of Rehmannia glutinosa is one of the commonly used Chinese herbal medicines. Its steamed products alleviate methotrexate-induced rat gut mucositis by inhibiting oxidative stress and inflammation (Shi et al., ). Licorice (G. uralensis) is reported to possess anti-tumor activity, and effectively treats peptic ulcer. Its pentacyclic triterpenoid derivative 18β-glycyrrhetinic acid has anti-inflammatory, hepatoprotective and anti-oxidant effects. This compound prevents against cisplatin-induced oxidative intestinal damage in rats possibly by inhibiting nuclear factor-kappa B (NF-κB) and caspases (Rashid et al., ). Rutin with free radical scavenging and anti-inflammatory actions also significantly protects against methotrexate-induced intestinal lesion damage in rats (Gautam et al., ). Nigella sativa seed is a traditional herbal medicine throughout the world. Its oil is beneficial in a wide range of gastrointestinal disorders, and significantly attenuates cisplatin-induced alteration of brush border membrane enzymes, carbohydrate metabolism and antioxidant system in the intestine of rats (Shahid et al., ). Thymoquinone, a major principle active ingredient derived from this seed oil, improves gastrointestinal function as well as the redox and metabolic status of intestinal mucosal tissue in rat model of cisplatin-induced intestinal injury (Shahid et al., ).

10Radiotherapy-induced esophagitis and enteropathy are the major issues for long-term cancer survivors (Kim J. S. et al., ). Chinese herbal medicine Zhu-Ye-Shi-Gao granule can treat recurrent oral ulcer and chronic pharyngitis. A randomized controlled trial shows that this granule decreases the incidence and grade of acute radiation-induced esophagitis, demonstrating its efficacy and safety in patients with lung, esophagus or mediastinal cancer (Wang L. J. et al., ). A. vera also effectively treats acute radiation proctitis in patients after external-beam radiation therapy of pelvic malignancy (Sahebnasagh et al., ). Oroxylin is a natural flavonoid isolated from S. baicalensis, and shows its anticancer effect on human primary hepatocellular carcinoma cells and patient-derived tumor xenograft model for hepatoma (Wei et al., ). This compound could be a promising radiosensitizer by inducing G2/M phase and activating cell apoptosis in esophageal squamous cell carcinoma exposed to radiotherapy (Tan et al., ). Grape seed extracts and its proanthocyanidins are commonly utilized as dietary supplements for anti-oxidant property in cancer patients (Bagchi et al., ). A systematic review of preclinical studies shows that grape seed extracts may alleviate chemotherapy and radiotherapy-induced toxicity (Olaku et al., ). Grape seed proanthocyanidins have radioprotective action (Katiyar et al.,; Yang et al., ). Green tea contains a high content of catechins. Compared with placebo group, its tablet shows less frequency and severity of radiotherapy-induced diarrhea but not vomiting in patients with abdomen and pelvic malignancy after receiving radiotherapy (Emami et al., ). Therefore, an extract mixture of green tea and grape seed is considered to be a good radioprotector and immune modulator, indicating its possible use as an adjuvant during radiotherapy (El-Desouky et al., ).

11Silymarin, a complex of flavonolignans extracted from milk thistle (Silybum marianum), has been used for centuries as the treatment of different diseases with anti-oxidant and anti-inflammatory activities. Its major constituent silibinin is reported to radiosensitize prostate cancer by inhibiting DNA repair signaling (Nambiar et al., ) and improving the response to radiotherapy in invasive bladder cancer (Prack Mc Cormick et al., ). Nephelium lappaceum is an importantly commercial crop with nutrients and bioactive constituents. Its hydrolysable polyphenol geraniin possesses good anti-oxidant property, and protects intestinal crypt cells from γ-irradiation-induced cell death in mice by suppressing DNA damage, being considered as a radioprotective agent (Bing et al., ). Clerodendrum infortunatum rich in flavonoids and saponins is used in Ayurvedic and Siddha traditional medicine. Its hydro-alcoholic extract reduces radiation-induced damage to intestinal crypt cells and suppress BCL2-associated X protein (Bax)/B-cell lymphoma (Bcl-2) ratio, DNA repair gene ataxia telangiectasia mutated (ATM) and COX-2 gene in mice exposed to whole-body γ-radiation (Chacko et al., ).

12The gut microbiota is a vast community of synergistic bacterial species providing health benefits to the host (Westfall et al., ). Gastrointestinal tract forms the targets of chemotherapy and radiotherapy-induced toxicity, causing imbalance in the gut microbiota (dysbiosis) (Serban,; Wardill and Tissing,; Bruneau et al.,; Curro, ). Fucoidans, a group of certain fucose-containing sulfated polysaccharides, are naturally occurring components of certain edible seaweeds and echinoderms in Japan and Korea. Fucoidan intervention can relieve cyclophosphamide-induced intestinal mucosal injury by decreasing inflammation and increasing tight junction protein expression in mice. Low molecular weight of fucoidan (50 kDa) remarkably increases the abundance of short chain fatty acids (SCFAs) producer Coprococcus, Rikenella, and Butyricicoccus species within the intestinal mucosa compared with the cyclophosphamide group, possibly as an effective supplement to protect against intestinal mucosal barrier damage during chemotherapy via gut microbiota (Shi et al., ). PHY906 is derived from Huang-Qin-Tang, as a modulator of irinotecan-based chemotherapy in patients with advanced colorectal cancer (Kummar et al., ). Of note, intestinal bacteria can metabolize irinotecan and PHY906. In murine Colon-38 tumor-bearing mice, alteration in the population of intestinal bacteria can not affect the ability of PHY906 to enhance irinotecan anti-tumor activity or reduce irinotecan-induced intestinal toxicity, indicating that the major species of intestinal bacteria may not appear to have a role in the enhancement of the therapeutic index of irinotecan in tumor-bearing mice treated with PHY906 (Lam et al., ). SN-38-glucuronide is an active metabolite of irinotecan hydrochloride to be responsible for gastrointestinal toxicity. Interestingly, baicalin, a main constituent in PHY906, is found to reduce intestinal transporter organic anion transporting polypeptide (OATP)1B1-mediated uptake of SN-38, showing its ability to prevent gastrointestinal toxicity (Fujita et al., ). Sheng-Jiang-Xie-Xin decoction, a classic traditional Chinese medical formula in Shang Han Lun, has been applied to treat gastroenteritis, ulcerative colitis, and diarrheais, as well as irinotecan-induced gastrointestinal toxicity. Recently, this decoction is reported to alter the pharmacokinetics of irinotecan and its metabolites (SN-38 and SN-38G) to alleviate irinotecan-induced diarrhea in rats, partly by altering carboxylesterase 2 (CES2) and jejunal uridine diphosphate-glucuronosyltransferase 1A1(UGT1A1) activity (Guan et al., ). These observations indicate that cancer patients with different gut microbiota profiles may benefit from natural product treatment alongside chemotherapy and radiotherapy. The natural products in this part together with relevant characteristics of the respective studies are summarized in Table 2.

13Radioembolization-induced liver injury is an uncommon but relevant complication. Lycopene is an anti-oxidant substance in plants and micro-organisms. Its treatment significantly decreases radiotherapy-induced hepatic toxicity with oxidative stress in rats (Meydan et al., ). A perennial plant Ashwagandha (Withania somnifera), a perennial plant used in Ayurvedic medicine, shows hepatoprotective and anti-oxidant effects against radiation-induced hepatotoxicity in rats (Hosny Mansour and Farouk Hafez, ). N. sativa oil also alleviates irradiation-induced liver injury in rats (Radwan and Mohamed, ).

14Chemotherapeutic agents commonly cause hepatic injury in cancer patients. Some Indian natural products have promise in relieving chemotherapy-induced hepatotoxicity (Metri et al., ). Recently, clinical trials show that milk thistle (main hepatoprotective ingredient silymarin) can effectively reduce hepatotoxicity in oncology patients (Frassova and Ruda-Kucerova, ). A edible mushroom mycelium product containing active hexose-correlated compound, can reduce hematotoxicity and hepatotoxicity, and improve the quality of life in patients with advanced cancer during chemotherapy (Ito et al., ).

15In animals of chemotherapy-induced hepatotoxicity, Pine bark extract (Pycnogenol®), a standardized proprietary mixture of bioflavonoids extracted from the bark of Pinus pinaster, has protective effect due to its anti-oxidation (Ko et al., ). Pomegranate (Punica granatum) is mentioned in the Ebers papyrus of Egypt written in about 1550 BC. Its seed extract containing robust polyphenolic flavonoid can ameliorate cisplatin-induced liver damage in rabbits (Yildirim et al., ). Grape seed extract prevents against dexamethasone-induced liver histopathological change in rats (Hasona and Morsi, ). Ginsenoside Rg1, a main compound of Ginseng, effectively alleviates cisplatin-induced liver histological lesion in mice possibly by Nrf2 pathway (Gao et al., ). Turmeric and curcumin are known to have hepatoprotective action. They antagonize chemotherapy-induced hepatotoxicity (Mohamad et al.,; Waseem et al., ). Pre-treatment with a combination of curcumin and α-tocopherol regulates liver enzyme and lipid peroxidation biomarker, and alleviates liver histopathology change in rats, showing the protection against cisplatin-induced hepatotoxicity via abrogating oxidative stress (Palipoch et al., ). Phyllanthus fraternus has long been used in folk medicine to treat liver disturbance and painful disorder. P. fraternus attenuates cisplatin and cyclophosphamide-induced mitochondrial damage in rats with hepatotoxicity (Kumari and Setty, ). Thus, mitochondria may be considered as the target for the hepatoprotection (Waseem et al., ).

16Of note, herbs are responsible for 24.2% of drug-induced liver injury cases (Li et al., ). Systematic review shows that a comprehensive list of herbs can cause a high risk of hepatotoxicity in Korea (Lee et al., ). S. baicalensis is reported to induce autoimmune hepatitis in mice through modulating immune response (Wang et al., ). Thus, natural products-induced liver injury is a hot topic. In a recent case report, Turmeric interaction with paclitaxel induces an acute toxic hepatitis in Caucasian male with lung cancer probably by altering pharmacokinetic of paclitaxel in association with a contaminated Chlorella supplement (Costa et al., ). These observations indicate that some natural products may evoke acute hepatotoxicity possibly via the interaction with chemotherapeutic agents. Although the hepatotoxicity of some natural products remains speculative, the associated liver injury address the need to clarify and investigate the potential harmful effects. The natural products in this part together with relevant characteristics of the respective studies are summarized in Table 3.

17Nephrotoxicity is one of the most serious problem that hinders cisplatin-based chemotherapy (Mahmoodnia et al., ). In 2016, Shreesh Ojha et al. provide a review summarized plant-derived natural products for counteracting cisplatin-induced nephrotoxicity (Ojha et al., ). Of note, oxidative stress is significantly related to cisplatin-induced nephrotoxicity in head and neck cancer patients (Quintanilha et al., ). Lycopene has anti-oxidative effect. The results from a double-blind, randomized clinical trial show that lycopene is a useful adjuvant therapy, because its oral administration from 24 to 72 h after cisplatin administration can relief the complication of nephrotoxicity in cancer patients (Mahmoodnia et al., ). Hesperetin, a naturally-occurring bioflavonoid, protects against hydrogen peroxide-triggered oxidative damage via upregulation of Keap1-Nrf2/HO-1 pathway in ARPE-19 cells (Zhu et al., ). It normalizes renal function by attenuating cisplatin-induced oxidative stress, lipid peroxidation, inflammatory cytokine, and histopathological alteration in rats (Budhani et al., ). Fruits of Withania coagulans contain several bioactive compounds as curative agents for various clinical conditions. This fruit extract prevents against cisplatin-induced kidney damage, primarily through its free radical scavenging and anti-inflammatory activity (Sharma et al., ). Pine bark extract with potent anti-oxidant activity attenuates cisplatin-induced kidney injury of rats (Lee et al., ). Silybin (a main flavonoid of S. marianum) as a pharmacological activator of SIRT3, has capable of protection against cisplatin-induced tubular cell apoptosis and acute kidney injury by improving mitochondrial function (Li et al., ). Origanum majorana is commonly known as marjoram in traditional medicine, which possesses anti-oxidant, anti-microbial and anti-inflammatory activities (Leyva-Lopez et al., ). Its anti-proliferative effect is observed in human hepatocarcinoma cells (Fathy et al., ). Moreover, O. majorana and its polyphenol carnosol have anti-metastatic and antitumor effects in breast cancer cells (Al Dhaheri et al.,, ). Its ethanol extract significantly reduces cisplatin-induced nephrotoxicity in rats, possibly through enhancing free radical scavenging activity (Soliman et al., ).

18Other chemotherapy agents such as adriamycin, 5-fluorouracil, methotrexate, ifosfamide and doxorubicin also cause nephrotoxicity. Traditional Chinese medicine Qi-Lu-Xiao-Bai decoction can inhibit connective tissue growth factor, fibronectin and α-smooth muscle actin expression, and improve glomerular sclerosis in adriamycin-induced nephropathy in rats (Su et al., ). Multi-glycoside of Tripterygium wilfordii, a Chinese herbal medicine, is clinically effective in improving glomerulosclerosis in chronic kidney disease. It effectively and safely relieves the prolonged glomerulosclerosis in adriamycin-induced nephropathy in rats, possibly via the reduction of extracellular matrix components and suppression of TGF-β1/Smad signaling (Wan et al., ). N. sativa and its constituent thymoquinone have potential renoprotective effect on chemotherapy-associated kidney complication, possibly via decreasing lipid peroxidation and increasing anti-oxidant enzyme activity (Cascella et al., ). Traditional herbal medicine Thymus vulgaris has anti-oxidant property (Heidari et al., ). Its anticancer effect is observed in human leukemia THP-1 cells and colorectal cancer cells (Ayesh et al.,; Al-Menhali et al., ). Naringenin, a natural flavanone isolated from T. vulgaris, has growth inhibitory and chemo-sensitization effects on human breast and colorectal cancer (Abaza et al., ). Naringenin can ameliorate daunorubicin-induced nephrotoxicity in rats by mitigating inflammation (Karuppagounder et al., ).

19Kidney is a radiosensitive organ. Acorus calamus is a well-known plant in Asia traditional medicine for centuries. Its extract significantly increases major enzyme activity of the antioxidant defense system and decreases DNA strand breaks in liver and kidney of irradiated mice (Sandeep and Nair, ). The dried fruit of Xylopia aethiopica is used in folk medicines and widely consumed as a spice in Nigeria, with anti-plasmodial, anti-oxidant, hypotensive and diuretic effects (Tatsadjieu et al.,; Karioti et al., ). It increases the anti-oxidant defense system in liver and kidney of irradiated rats (Adaramoye et al., ). Quercetin also attenuates irradiation-induced kidney injury via its anti-oxidant activity (Ozyurt et al., ). Genistein, found in soybean products, has anti-oxidant and anti-inflammatory properties with low toxicity. Genistein is suggested be a chemotherapeutic agent against different types of cancer, mainly by changing apoptosis, cell cycle and angiogenesis and inhibiting metastasis (Spagnuolo et al., ). Melatonin is a potent free radical scavenger with anti-inflammation. The supplementation of genistein and melatonin prior to irradiation protects against nephrotoxicity in mice (Canyilmaz et al., ).

20Nutritional supplement ingredients have attracted the attention for the ability to prevent and treat kidney injury. Honey and royal jelly are effective in reducing cisplatin-induced acute kidney injury in cancer patients (Osama et al., ). Ginger extract shows renoprotective effects on radiotherapy-induced renal histological and biochemical alteration in rats (Saberi et al., ). Purslane (Portulaca oleracea), widely distributed around the globe in traditional medicine, significantly attenuates lipid alteration, liver, and kidney function as well as oxidative stress in irradiated rats (Abd El-Azime et al., ). American ginseng berry extract also has nephroprotective effect against cisplatin-evoked nephrotoxicity in mice through ROS-mediated mitogen activated protein kinase (MAPK) and NF-κB signaling pathway (Ma et al., ). Curcumin and its analog difluorinated curcumin potentially reduce cisplatin-induced nephrotoxicity, thereby enhance the therapeutic window of cisplatin, the latter also decreases inflammatory factors NF-κB and COX-2, oxidative stress as well as multi-drug resistance markers (Sahin et al.,; Ugur et al., ). A Se-polysaccharide from Se-enriched G. frondosa (Se-GFP-22) significantly enhances the anti-oxidant and immunomodulatory activities in kidney of cyclophosphamide-treated mice (Li et al., ). Grape seed extract is found to reduce severe acute tubular necrosis and improve kidney function in cisplatin-treated rabbits, partially showing its protective effect against nephrotoxicity (Benzer et al., ). Recently, grape seed proanthocyanidin extract reduces thalidomide and carboplatin combination-induced renal damage in rats by reducing oxidative stress, inflammation, p53 change, and apoptosis (Yousef et al., ), as well as attenuates arsenic-induced renal inflammatory injury in mice by inhibiting NF-κB signaling activation and inflammatory cytokine production (Wang C. et al., ). Up to 2,500 mg of this extract administration for 4 weeks is found to be generally safe and well-tolerated in humans (Sano, ). These observations may offer a promising chance for clinically meaningful prevention of chemotherapy and radiotherapy-induced nephrotoxicity by natural products. The natural products in this part together with relevant characteristics of the respective studies are summarized in Table 4.

21Myelosuppression with leukocytopenia, erythrocytopenia, and thrombocytopenia, are serious and common side effects during cancer treatment. A systematic review and meta-analysis of randomized controlled trials show that Chinese herbal medicine as an adjuvant can alleviate chemotherapy or radiotherapy-induced myelosuppression, and maintain therapeutic dose and treatment cycle by reducing grade III-IV toxicity, (Hou et al., ). A Chinese herbal medicine Shuang-Huang-Sheng-Bai granule approved by the Food and Drug Administration of China, can effectively treat cancer. Recently, this granule is observed to elevate white blood cell count, and reduce the incidence of chemotherapy-caused myelosuppression in cancer patients compared with control group taken with Leucogon tablet, demonstrating its protection against bone marrow suppression and alleviation of clinical symptoms (Wang L. F. et al., ).

22Cyclophosphamide is of great interest in the clinic due to its relatively high oncotoxic specificity. Sheng-Mai injection is derived from Sheng-Mai-San, a well-known traditional Chinese herbal prescription. This injection has therapeutic potential in reducing chemotherapy-induced adverse effects and improving life quality in patients with non-small cell lung cancer. Recently, a meta-analysis shows that combination of Sheng-Mai injection with chemotherapy significantly reduces grade 3/4 myelosuppression compared with the chemotherapy alone in cancer patients (Duan et al., ). Chinese Ginseng is well-known to strengthen the body resistance to eliminate pathogenic factors, and reduce side effects of chemotherapy drugs. Panaxadiol saponins, a biologically active fraction derived from Ginseng, possess hematopoietic growth factor-like activity that promotes proliferation and differentiation of HPCs in cyclophosphamide-induced myelosuppressive mice, probably by regulating MAPK/ERK kinase (MEK) and extracellular signal-regulated kinase (ERK) protein kinases, C-kit, and GATA-1 transcription factors (Sun X. et al., ). Ginsenoside Rg3 is used as a potent anticancer agent to induce apoptosis, inhibit proliferation, metastasis and angiogenesis, as well as promote immunity during conventional cancer therapy (Sun et al., ). A multicenter, large-sample, randomized clinical trial shows that ginsenoside Rg3 improves the median survival time and reduces myelosuppression in advanced non-small cell lung cancer patients during the standard first-line chemotherapy (Zhang et al., ). Dang-Gui-Bu-Xue decoction, a classical formula of traditional Chinese medicine, has an impact on promoting hematopoiesis, and prevents myelosuppression in breast cancer patients treated with adjuvant chemotherapy. However, a phase II randomized prospective controlled clinical study is conducted from December 2013 to February 2015, and shows that this decoction fails to prevent myelosuppression in breast cancer patients treated with adjuvant chemotherapy (Hong et al., ). Further studies are warranted to validate the efficacy of Dang-Gui-Bu-Xue decoction in selected patients.

23Infection and inflammation are observed in chemotherapy and radiotherapy patients with myelosuppression. A traditional medicinal formula Dang-Gui-Si-Ni decoction has been clinically used for infectious diseases that are complicated with hemodynamic instability (Yao et al., ). This decoction significantly elevates the level of bone marrow hematopoietic stem progenitor cells in myelosuppression model of mice (Chen et al., ). Herba Epimedii, one of most popular Chinese herbs, is used for the treatment of osteoporosis and inflammation. H. Epimedii and its main constituent icariin can improve immune function after cyclophosphamide-induced myelosuppression (Zhao et al., ). Icaritin, hydrolyzed by icariin, prevents cyclophosphamide-induced myelosuppression in mice by improving bone marrow hematopoietic microenvironment, promoting the proliferation and differentiation of HSCs, inhibiting the apoptosis of HSCs and stimulating granulocyte colony-stimulating factor and thyroperoxidase (Sun C. et al., ). A herbal medicine Radix Sanguisorbae used to treat diarrhea, enteritis, duodenal ulcers, and internal hemorrhage, is clinically effective against myelosuppression induced by chemotherapy and/or radiotherapy (Seo et al., ). Its main ingredients saponins show hematopoietic effect mediated by focal adhesion kinase (FAK) and ERK1/2 activation as well as cytokine inhibition in the bone marrow (Chen X. et al., ). Paeoniflorin and albiflorin, two active constituents identified from the root of P. lactiflora, can increase the white blood cell counts, reverse the atrophy of thymus, and suppress cyclophosphamide and radiotherapy-induced myelosuppression in animals, showing hematopoietic effect (Zhu Y. et al.,; Zhu Y.-L. et al., ).

24Anti-oxidant natural products can prevent excessive ROS produced by chemotherapy and radiotherapy from killing white blood cells and inhibiting bone marrow suppression. Chinese medicine Yi-Qi-Yang-Yin formula can ameliorate hematopoietic system injury by reducing intracellular ROS levels in hematopoietic cells of mice after total body irradiation (Zhang et al., ). San-Yang-Xue-Dai mixture is a natural medicine originating from an ancient prescription of the Dai nationality in Southwest China. It attenuates doxorubicin-induced myelosuppression by inhibiting ROS-mediated apoptosis (Chen T. et al., ). Coriander (Coriandrum sativum) is an annual herb used as a flavoring agent and traditional remedy. Its extract can scavenge ROS and up-regulate endogenous cellular antioxidant system (Velaga et al.,; Zielniok et al., ). Recently, rutin-enriched coriander extract is found to ameliorate ionizing radiation-induced myelosuppression with improvement of the proliferation and differentiation ability of hematopoietic stem and progenitor cells in mice, probably by inhibiting apoptosis and DNA damage attributed to its scavenging ROS and activating antioxidant enzyme ability (Han et al., ). Theaflavin, one of the tea pigments from black tea, prevents the progression of inflammatory disorder, cancer, bacterial and viral infection, and ameliorates ionizing radiation-induced HSC injury in mice by regulating Nrf2 pathway to reduce oxidative stress (Han et al., ). Astaxanthin, predominantly found in marine organisms, can improve radiation-induced skewed differentiation of peripheral blood cells and accelerate hematopoietic self-renewal and regeneration in mice. This radio-protective effect is probably mediated by scavenging of ROS, activation of Nrf2 and downstream anti-oxidative proteins (Xue et al., ). The natural products in this part together with relevant characteristics of the respective studies are summarized in Table 5.

25Energy metabolism imbalance and oxidative stress mediate chemotherapeutic agents-induced cardiotoxicity. Doxorubicin has cumulative and dose-related cardiotoxicity. In 2017, Sahebkar et al. review the attenuation of doxorubicin-induced cardiotoxicity by plant extracts and phytochemicals (Hosseini and Sahebkar, ). In 2018, Yu et al. also review the protective effects of natural products on doxorubicin-caused cardiotoxicity without affecting its anticancer efficacy (Yu et al., ). A Chinese medicine Dan-Hong injection is demonstrated to alleviate ischemic myocardial injury and improve heart function. Recently, this injection is reported to restore doxorubicin-induced cardiotoxicity in H9c2 cells by improving energy metabolism and reducing oxidative stress (Yi et al., ). San-Yang-Xue-Dai mixture alleviates doxorubicin-induced cardiotoxicity and apoptosis by inhibiting p53 and MAPK signaling activation (Chen et al., ). Fermented Cordyceps sinensis is reported to attenuate doxorubicin-induced cardiotoxicity by inhibiting myocardial hypertrophy and myocardial damage, regulating systolic function, and antioxidant enzyme system and improving cardiac energy metabolism (Wu et al., ). Chinese herb Salvia miltiorrhiza is used as an empiric treatment for cardiovascular disorders (Zhou et al., ). Its main compound diethyl blechnic inhibits doxorubicin-induced apoptosis by inhibiting ROS in H9c2 cells and primary rat cardiomyocytes (Yu et al., ). Curcumin also protects the myocardium against doxorubicin-induced cardiotoxicity in mouse hearts and primary cardiomyocytes, probably via upregulating 14-3-3γ expression (He et al., ). Natural steroid saponin dioscin found abundantly in legumes and yams, alleviates doxorubicin-induced cardiotoxicity by regulating miR-140-5p-mediated myocardial oxidative stress (Zhao et al., ).

26Anthracycline also causes cardiotoxicity in cancer patients. Modified Zhi-Gan-Cao-Tang relieves anthracycline-induced congestive heart failure in an 18-year-old adolescent male (Wu et al., ). Platycodon grandiflorum is used in traditional Chinese medicine for centuries to treat cardiovascular disease. It can nourish Qi and relieve symptoms such as palpitations, shortness of breath, and chest pain. A randomized controlled trial reveals that P. grandiflorum has cardioprotective effect in early breast cancer patients undergoing anthracycline-based chemotherapy (Hao et al., ). Flaxseed oil (containing α-linolenic acid) reduces arsenic-induced cardiac toxicity in rats (Varghese et al., ). Parsley oil with anti-oxidant, anti-inflammatory and anti-apoptotic actions is reported to ameliorate cisplatin-induced hepatic and cardiac injury in rats (Abdellatief et al., ). Blueberry anthocyanins-enriched extract with anti-inflammatory and anti-oxidant activities attenuates cyclophosphamide-induced cardiotoxicity of rats (Liu et al., ). Rubia cordifolia is a valuable medicinal herb in the Ayurvedic system. Its extract can protect cyclophosphamide-induced cardiac tissue injury of rats by modulating anti-oxidant markers (Chandrashekar et al., ).

27Radiotherapy-driven heart injury remains a major issue for cancer survivors. A traditional Chinese medicine Sheng-Mai-San is used to improve the syndrome of Qi and Yin deficiency, and has the ability to treat patients with cardiac diseases, fatigue and cancer. It also enhances heart function and improves the quality of life in cancer patients undergoing chemotherapy or radiotherapy (Lo et al., ). Black grape juice protects against whole body γ-irradiation-induced heart toxicity of rats with the alteration of metabolites from lipid peroxidation and lactate dehydrogenase (de Freitas et al., ). A natural polyphenol zingerone due to its anti-oxidative and anti-inflammatory properties can prevent against cisplatin- or γ-radiation-induced cardiotoxicity in rats by decreasing caspase-3 expression and the prominent nuclear DNA fragmentation as well as increasing mitochondrial complexes' activities (Soliman et al., ). A citrus flavanoglycone hesperidin also restores whole body γ-irradiation-induced cardiocellular damage and oxidative stress in rats (Pradeep et al., ). These observations suggest that natural products may be the effective agents used as an adjunct/dietary supplement for the cancer patients receiving chemotherapy and radiotherapy. The natural products in this part together with relevant characteristics of the respective studies are summarized in Table 6.

28Neurotoxicity is a frequent adverse effect of cancer chemotherapy and radiotherapy, and causes excruciating pain to cancer patients. A network meta-analysis shows that Ai-Di, Shen-Qi-Fu-Zheng, and Matrine injections approved by the Food and Drug Administration of China, improve the overall response rate and quality of life, and reduce the incidence of peripheral neurotoxicity (III-IV) for advanced colorectal cancer treated with oxaliplatin, 5-fluorouracil, and leucovorin (Ge et al., ). Traditional Japanese medicine Goshajinkigan (TJ107) is used to alleviate neuropathy and general pain. Shakuyakukanzoto (TJ68) effectively treats muscle cramps and crampy pain. A multicenter retrospective study shows that TJ107 and TJ68 reduce neurotoxicity without negatively affecting tumor response in patients with colorectal cancer who undergo 5-fluorouracil/folinic acid plus oxaliplatin therapy (Hosokawa et al., ). A systematic review and meta-analysis shows that Radix Astragali intervention may be beneficial in reducing oxaliplatin-induced peripheral neuropathy (Deng et al., ). Recently, its hydroalcoholic extract (containing astragalosides) is reported to relieve pain and promote the rescue mechanisms for the protection of nervous tissue in oxaliplatin-induced neuropathy of rats (Mannelli et al., ) as well as prevents against oxaliplatin-induced lipid peroxidation and DNA oxidation in astrocytes (Mannelli et al., ), further demonstrating the anti-neuropathic profile of Radix Astragali.

29Currently, chemotherapy and radiotherapy-induced peripheral neuropathy is focused on the treatment with anti-convulsants, anti-depressants, opioids, and non-opioid analgesics. A traditional Chinese medicine Wen-Luo-Tong, has been used to alleviate oxaliplatin-induced neuropathic pain for many years. Recently, Wen-Luo-Tong is found to prevent glial activation and nociceptive sensitization in a rat model of oxaliplatin-induced neuropathic pain (Deng et al., ). Its ingredients including hydroxysafflor yellow A, icariin, epimedin B, and 4-dihydroxybenzoic acid increase the viability of Schwann cells injured by oxaliplatin. Microemulsion formulation containing these ingredients also decreases oxaliplatin-induced mechanical hyperalgesia responses in rat model (Lin et al., ). Liu-Jun-Zi-Tang is a traditional herbal medicine widely used in East Asia and clinically applied to treat functional dyspepsia and depression. Recently, it is reported to attenuate cisplatin-induced thermal hyperalgesia in mice and apoptosis in human neuroblastoma SH-SY5Y cells, showing its prevention of cisplatin-induced neurotoxicity, possibly through anti-oxidation and mitochondrial function regulation (Chiou et al., ). A Mexican medicinal plant Tithonia tubaeformis is used for the treatment of rheumatism and stomachache. Its hydromethanolic extract is effective in attenuating vincristine-induced allodynia and thermal hyperalgesia in mice, relieving chemotherapy-induced peripheral neuropathy (Nawaz et al., ). Hypericum perforatum (St. John's Wort) is used for centuries as a natural remedy for the treatment of a variety of disorders including depression (Asgary et al.,; Abtahi Froushani et al., ). It can reduce oxaliplatin-induced caspase-3 activity in rat astrocytes, but its alone produces a cytotoxic effect and fails to reduce the cytotoxicity of oxaliplatin in HT-29 cancer cells (Cinci et al., ). Its main constituent hypericin is a potent inhibitor of glioma growth in vitro. In patients with documented recurrent or progressive malignant gliomas who have received standard radiation therapy with or without chemotherapy, oral hypericin is well-tolerated (Couldwell et al., ), suggesting that H. perforatum is used as a therapeutic strategy for counteracting chemotherapy and radiotherapy-induced neuropathy. Natural bicyclic sesquiterpenes, β-caryophyllene and β-caryophyllene oxide are found in a large number of plants worldwide. They possess neuropharmacological effects as chemo-sensitizing agents for doxorubicin chemotherapy and re-sensitize cancer-resistant cells (Di Giacomo et al., ). A therapeutic plant Lithospermi radix (the root of Lithospermum erythrorhizon) is used to treat septic shock, eczema, and burns. Its water extract restores oxaliplatin-induced neurotoxicity in nerve growth factor-stimulated neurite outgrowth in PC12 cells and animals with enhanced nociceptive sensitivity to mechanical stimuli along with spinal activation of microglias and astrocytes as well as loss of intraepidermal nerve fibers of footpads (Cho et al., ). β-Caryophyllene also effectively attenuates paclitaxel-induced peripheral neuropathy in mice, possibly through CB2-activation in the central nervous system and posterior inhibition of p38 MAPK/NF-κB activation (Segat et al., ). Curcumin also has neuroprotective action. In 2017, Rezaee et al. provide a summary of the studies done to show the protective effects of curcumin against cisplatin-induced neurotoxicity, nephrotoxicity and ototoxicity (Rezaee et al., ). Its natural derivative demethoxycurcumin exhibits neuroprotective effect in rotenone-induced neurotoxicity in SH-SY5Y neuroblastoma cells (Ramkumar et al., ). 5, 7-Dihydroxyflavone (Chrysin), a natural plant flavonoid, has neuroprotective effect against γ-irradiation induced-neurotoxicity in rats (Mansour et al., ). Shikonin, a natural naphthoquinone compound, is one of the main chemicals isolated from Lithospermi radix. Shikonin and its derivatives suppress the epidermal growth factor receptor signaling and synergistically kill glioblastoma cells in combination with erlotinib, possibly being a potential strategy to overcome drug resistance to erlotinib (Zhao et al., ). Oxidative damage contributes to cisplatin-induced neurotoxicity. As an apoptotic inhibitor, natural flavonoid compound cyanidin effectively restores cisplatin-induced neurotoxicity through inhibition of ROS-mediated DNA damage and apoptosis (Li et al., ).

30Dietary supplement OPERA® containing α-lipoic acid, Boswellia Serrata, methylsulfonylmethane and bromelain, is able to improve chemotherapy-induced peripheral neuropathy symptoms in a prospective series of patients treated with neurotoxic chemotherapy, without significant toxicity or interaction (Desideri et al., ). A systematic review of preclinical studies demonstrate that grape seed extract can treat chemotherapy and radiotherapy-induced neurotoxicity (Olaku et al., ). Clinical trial demonstrates that green tea consumption with neuroprotective effect has anticancer action via regulation of intra-tumoural lymph-angiogenesis and COX-2 expression (Najaf Najafi et al., ). These diet supplements may be effective in the prevention or treatment of chemotherapy and radiotherapy-induced neurotoxicity.

31However, in 2017, Schloss et al. provide review that there is no solid beneficial evidence for herb medicine which is recommended for the prevention or treatment of chemotherapy-induced peripheral neuropathy (Schloss et al., ). In fact, in 2015, Oki et al. conduct a placebo-controlled, double-blind, randomized phase III study and observe no effects of Goshajinkigan on oxaliplatin-associated peripheral neuropathy in patients with colorectal cancer (Oki et al., ). Consistently, in 2017, Kuriyama et al. conduct a systematic review and meta-analysis, and further demonstrate that Goshajinkigan is impossible to prevent peripheral neuropathy in patients receiving neurotoxic chemotherapy. Next, Hoshino et al. also conduct a systematic review and show that Goshajinkigan tends to prevent persistence but not severity of chemotherapy-induced peripheral neuropathy (Hoshino et al., ). Given the low quality and insufficient amount of the evidence, use of Goshajinkigan as standard of care is not currently recommended (Kuriyama and Endo, ). On the other hand, although phytochemicals, medicinal herbs, and their formulas may be considered for prophylaxis of chemotherapy-induced peripheral neuropathy, the curative usability as well as the reciprocal effect with other drug should be examined in well-designed clinical trials (Lee and Kim, ). The natural products in this part together with relevant characteristics of the respective studies are summarized in Table 7.

32Recent efforts to prevent chemotherapy and radiotherapy-induced side effects have used natural products with biochemical and pharmacological properties. However, there are multiple limitations. These include:

33Lack of high quality trials using multiple measures to assess the various aspects of chemotherapy and radiotherapy-induced side effects, as well as to clarify the preventive effects of natural products.

34Preclinical models of chemotherapy and radiotherapy-induced side effects are not sufficiently to verify the prevention of natural products.

35Need an imaged-based high-content screening platform with a protocol to find innovative natural products against chemotherapy and radiotherapy-induced side effects.

36Unknown molecular mechanisms of the attenuations of some natural products on chemotherapy and radiotherapy-induced side effects.

37No strategy of the modulation of gut microbiota by natural products to control chemotherapy and radiotherapy-induced side effects.

38Unknown the biological mechanisms of interaction between chemotherapy drugs and natural products.

39Need to ascertain natural products-evoked toxicity.

40There is the evidence that natural products can reduce chemotherapy and radiotherapy-induced side effects such as oral mucositis, gastrointestinal toxicity, hepatotoxicity, nephrotoxicity, hematopoietic system injury, cardiotoxicity, and neurotoxicity (Figure 1). The summarized data have also highlighted the efficacy of natural dietary supplements to counteract these side effects. Thus, these products including dietary supplements should be used as an alternative therapeutic strategy for the prophylaxis and treatment of chemotherapy and radiotherapy-induced side effects in cancer patients.

41However, this issue is still controversial in underlying the efficacy conducted by different analysis and clinical trials in selected cancer patients. The difficulty in the revealing the molecular mechanisms has so far hampered the understanding of the attenuation of chemotherapy and radiotherapy-induced side effects in clinical use of natural products (Anwar et al., ).

42Of note, new therapies in clinical validation phases are investigating gut microbiota fighting against many diseases, and forming the targets of chemotherapy and radiotherapy-induced toxicity. These studies may help to shed light upon the preventive process of chemotherapy and radiotherapy-induced side effects by natural products and develop the available intervention for cancer patients for the managements.

43LD-K conceived and designed the review. L-DK, Q-YZ, F-XW, and K-KJ performed the literature search. L-DK, F-XW, and Q-YZ analyzed and wrote the paper.

44The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.