Edited by: Stephen Cho Wing SZE, Hong Kong Baptist University, Hong Kong
Reviewed by: Shuai Ji, Xuzhou Medical University, China; William Chi-Shing Tai, Hong Kong Polytechnic University, Hong Kong
This article was submitted to Ethnopharmacology, a section of the journal Frontiers in Pharmacology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Side effects, including nausea, vomiting, mucositis, peripheral neuropathy, and diarrhea, have been frequently reported in colorectal cancer (CRC) patients undergoing chemotherapy. Chinese Herbal Medicines (CHMs) display distinct clinical outcomes, as a result, they have been increasingly used as an adjuvant therapy to manage chemotherapy-induced side effects. In this review, we aim to intensively explore the molecular mechanisms of CHMs, underline the significance of CHMs in mitigating the side effects induced by chemotherapy, and examine the necessary studies required to understand the role of CHMs in alleviating chemotherapy-induced side effects. Specifically, ginger,
Colorectal cancer (CRC) is one of the most common malignancies, with incidence ranking the third among males and females worldwide. In terms of mortality, CRC is in the third place and the fourth place in males and females, respectively (Siegel Rebecca et al.,
Despite the advancement in various treatment strategies in managing chemotherapy-induced side effects, such as 5-HT3 receptor antagonist and dexamethasone for nausea and vomiting, calcium gluconate, magnesium sulfate and glutathione for attenuating peripheral neurotoxicity, and loperamide for irinotecan-induced diarrhea, these can hardly satisfy the requirements of patients undergoing chemotherapy (Mustian et al.,
Chinese Herbal Medicines (CHMs) are combinations of herbs or a single herb. Most of them originate from ancient Chinese medical classics, for instance, “
Oxaliplatin, a third-generation derivative of platinum, is demonstrated to restrain tumor growth through its alkylating activity. It has been wildly used to treat various solid tumors and is often used to manage locally advanced and metastatic colon or rectal cancer (de Gramont et al.,
Curcumin is the main phenolic compound of turmeric (
Guilong Tongluo Decoction is a formula constituted by
Niuche Shenqi Wan is a frequently used prescription in Asia. It is comprised of 10 different herbs, including
Wenluotong Decoction is a prescription composed of
Guizhi Jiazhufu Decoction is composed of
Shaoyao Gancao Decoction, a prescription composed of
Huangqi Guizhi Wuwu Decoction is composed of
It's interesting that herbal decoctions mentioned above are composed of different herbs and some of them may contain the same single herb. The function of the same single herb in different herbal decoctions may vary based on the “Jun-Chen-Zuo-Shi” theory of CHMs. In an herbal decoction, herbs regarded as “Jun” (emperor) is applied to treat the main cause of the disease. “Chen” (minister) is usually utilized to enhance the function of “Jun.” “Zuo” (adjuvant) plays a role in reducing the toxicity of other herbs and treating accompanying symptoms. “Shi” (courier) helps to guide or deliver the other herbs to the target organ. For instance, both Huangqi Guizhi Wuwu Decoction and Guilong Tongluo Decoction contain
Chemotherapeutics contribute to killing the rapidly proliferated cancer cells. However, most of them show no selectivity, leading to damage to rapidly regenerated normal tissues, such as gastrointestinal and immune cells (Kwon,
Banxia Xiexin Decoction has been widely used to attenuate chemotherapy-induced gastrointestinal toxicity, which is composed of
Moreover, other Chinese prescriptions, such as Yinqiaosan Powder, Yunujian Decoction, and Qingying Decoction, have also been proven to be partially beneficial to chemotherapy-induced oral mucositis (Meyer-Hamme et al.,
Irinotecan is one of the most frequently used agents in advanced CRC patients (Bosch et al.,
Banxia Xiexin Decoction, a prescription effective in relieving the above-mentioned oral mucositis, is also recognized to slow down the enterohepatic circulation of SN-38. On this account, Banxia Xiexin Decoction has been illustrated to exhibit protective effects against irinotecan-caused intestinal toxicity, which was achieved through inhibiting β-glucuronidase activity and prostaglandin E2 synthesis (Takasuna et al.,
Shengjiang Xiexin Decoction, a CHM prescription derived from Banxia Xiexin Decoction, contains one additional herb:
Huangqin Decoction, or PHY906, is a prescription made up of
Intestinal mucositis is one of the most frequently encountered side effects in CRC patients undergoing chemotherapy regimens, such as 5-Fu and irinotecan. 50%-80% of patients developed intestinal mucositis when undergoing 5-Fu-based chemotherapy (Longley et al.,
The main ingredients of Pianzaihuang include
Buzhong Yiqi Decoction is composed of 8 herbs, including
TJ-114 is a combination of Xiaochaihu Decoction and Wulingsan Powder composing of
Nausea and vomiting are the most commonly experienced side effects in patients receiving chemotherapy. Briefly, chemotherapy can trigger serotonin secretion from the enterochromaffin cells lining the gastrointestinal tract. Serotonin can then stimulate the type-3 vagal afferent serotonin receptors (5-HT3) located in the gastrointestinal tract, as well as the nucleus tractus of the medulla oblongata and the chemoreceptor trigger zone located outside the blood-brain barrier. Serotonin can also send impulses to the vomiting center upon stimulation by an emetogenic substance P (Janelsins et al.,
Liujunzi Decoction is composed of
Ginger is the most extensively applied supplement for preventing and/or reducing CINV. It has long been used by practitioners in the management of gastrointestinal discomforts, such as nausea and excessive flatulence (Shukla and Singh,
Furthermore, other CHMs, such as
Even though investigators have been studying CHMs and chemotherapy-induced side effects for years, there is still growing interest in defining the mechanisms and effects of CHMs in preventing or attenuating chemotherapy-induced side effects. A summary of the main herbs and decoctions for treating chemotherapy-induced side effects is listed in Table
Summary of the effect of CHMs against chemotherapy-induced side effects.
Neurotoxicity | Pre-clinical: Reduce oxaliplatin-induced cold hypersensitivity, block the onset of the pro-allodynia effect, and relieve neuro-damage-induced; Down-regulate the expression of the activating transcription factor 3 in the dorsal root ganglia. | ||
Curcumin | Pre-clinical: Reducing the high plasma neurotensin and platinum accumulation in the sciatic nerve. | ||
Guilong Tongluo Decoction (Liu et al., |
Clinical: alleviate the development of grades 1-2 neurotoxicity after 6 cycles of adjuvant oxaliplatin-based chemotherapy in CRC patients, and delayed the onset time of grades 1-4 neurotoxicity. | ||
Niuche Shenqi Wan (Kono et al., |
Pre-clinical: Increase peripheral blood flow, stimulate spinal kappa-opioid receptors, and inhibit oxidative stress or activation of the C fiber. Clinical: Decrease the incidence and delay the development of grade 2 and above oxaliplatin-induced neurotoxicity in CRC after 8 cycles of oxaliplatin-based chemotherapy. | ||
Wenluotong Decoction (Deng et al., |
Pre-clinical: Reverse both glial activation in the spinal dorsal horn and nociceptive sensitization of oxaliplatin-resultant chronic neuropathic pain in rats. | ||
Guizhi Jiazhufu Decoction (Hosokawa et al., |
Clinical: Reduce neuropathy in metastatic CRC patients undergoing the FOLFOX regimen. | ||
Shaoyao Gancao Decoction (Hosokawa et al., |
Pre-clinical: Suppress transient receptor melastatin 8 mRNA expression in the mouse dorsal root ganglia. Clinical: Response rate was reported to be 65% in advanced CRC patients with oxaliplatin-related neuropathy. | ||
Huangqi Guizhi Wuwu Decoction (Jun et al., |
Pre-clinical: Down-regulate inflammation and immune responses. Clinical: Lower the incidence and relieve the severity of neurotoxicity in patients undergoing the FOLFOX regimen. | ||
Oral mucositis | Banxia Xiexin Decoction (Matsuda et al., |
Clinical: Reduce the severity grade (≥2) and the duration of chemotherapy-induced oral mucositis in gastric cancer and CRC patients. | |
Pre-clinical: Suppress the expression of COX-2, IL-1 and IL-6. | |||
Delayed onset of diarrhea | Banxia Xiexin Decoction (Takasuna et al., |
Pre-clinical: Inhibit β-glucuronidase activity and prostaglandin E2 synthesis. Clinical: Delay the onset of diarrhea in patients treated with cisplatin and irinotecan. Reduce the frequency of severe diarrhea (grade 3 or 4). | |
Shengjiang Xiexin Decoction (Deng et al., |
Pre-clinical: Inhibit intestinal cell apoptosis, as well as triggering intestinal injury repair by promoting intestinal stem cell proliferation and inhibiting β-glucuronidase activity. | ||
Huangqin Decoction (Farrell and Kummar, |
Pre-clinical: Restore intestinal epithelial damage through enhancing intestinal progenitor or stem cell regeneration; Induce anti-inflammatory activity in mice by down-regulating the expression of TNF-α, NF-κB and COX-2 in neutrophils and macrophages; potentiate Wnt3a activity. | ||
Clinical: Alleviate nausea and diarrhea in metastatic CRC patients undergoing irinotecan, 5-Fu, and LV (5-Fu/LV) regimens. | |||
Intestinal mucositis | Pre-clinical: Alleviate 5-Fu induced diarrhea and hemafecia, maintain the intestinal length, reduce villus shortening, and inhibit apoptosis and inflammation in the small intestine. | ||
Pianzaihuang (Fu et al., |
Pre-clinical: Reduce 5-Fu-induced intestinal crypt damage through inhibiting the expression of apoptotic proteins. | ||
Buzhong Yiqi Decoction (Jeong et al., |
Pre-clinical: Restore villi shortening, crypt destruction, reduce apoptosis and necrosis, alleviate neutrophil infiltration in intestinal mucosal epithelia, and inhibit up-regulated inflammatory factors, such as TNF-α and IL-1β. | ||
TJ-114 (Coates et al., |
Pre-clinical: Lower the diarrhea score and alleviated villi shortening and crypt destruction. Also, it can inhibit apoptosis and lower the secretion of pro-inflammatory cytokines, such as TNF-α and IL-1β. | ||
Nausea and vomiting | Liujunzi Decoction (Takeda et al., |
Pre-clinical: Antagonize the 5-HT3 receptor, the 5-hydroxytryptamine receptor 2B and 5-hydroxytryptamine receptor 2C to avoid the cisplatin-induced reduction in ghrelin levels. Clinical: Alleviate CNIV in patients undergoing cisplatin and paclitaxel regimen. | |
Ginger (Ernst and Pittler, |
Clinical: Ginger combined with standard 5-HT3 receptor antagonists and dexamethasone can reduce acute CINV compared with the application of placebo in combination with the standard 5-HT3 receptor antagonists and dexamethasone. |
WC provided the idea and designed the theoretical framework. DC and JZ searched literature. WC and DC wrote the article.
The 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.
The authors are thankful to Dr. Yan Jiang for helpful suggestions on the abstract.