Chemotherapy is one of the most widely used standard therapy for cancer treatment. It shows remarkable efficacy in killing cancer cells, but also harms normal cells and causes side effects like vomiting, nausea，rashes, diarrhea, hair loss, poor appetite, etc. Ginseng is a traditional medicinal herb that shows stronger anti-tumor activity against tumor cells with low toxicity to normal cells, and it is regarded as a promising drug agent used with chemotherapy drugs together to achieve synergic effectiveness.
Ginsenosides are the pharmacologically active compounds of ginseng, and there have been hundreds of ginsenoside monomers identified in the past decades. Rare ginsenoside monomers like Rg3, Rg5, Rh2, Rk1 and many more are metabolized from large-molecule-weight ginsenosides and they are show superior antitumor activities
Ginseng/Ginsenosides and Chemotherapy Combination in Cell and Animal studies
A combination of ginsenosides and chemotherapeutic drugs improved the effectiveness of chemotherapy in a variety of tumor cell lines and animal models.
A Canadian study in 2004 revealed that ginsenoside Rh2 could inhibit cell growth and induce apoptosis in various tumor cell lines. Ginsenoside Rh2 was found to enhance inhibition of chemotherapy drugs on cancer cells. In particular, it enabled hyper-sensitization of multidrug-resistant breast cancer cells to paclitaxel, a conventional chemotherapy drug.
A recent study suggested that ginsenoside Rg3 could increase gemcitabine sensitivity against pancreatic tumor. Zinc finger protein 91 homolog (ZFP91) expression is positively related to the growth of pancreatic tumor and can reduce survival of cancer patients. The study found that ginsenoside Rg3 treatment inhibited ZFP91 overexpression in a dose-dependent manner in gemcitabine-resistance pancreatic tumor cells. In the tumor-bearing mice models, ginsenoside Rg3 plus gemcitabine treatment enhanced tumor apoptosis and partly reduced FP91 overexpression-mediated tumor growth.
Another study investigated the combined effects of capecitabine chemotherapy with ginsenoside Rg3 on breast cancer in mice. The result showed that the administration of capecitabine plus ginsenoside Rg3 exerted better antiangiogenic effects. Ginsenoside Rg3 in combination with capecitabine resulted in better anti-tumor effects, less toxicity and increased sensibility to chemotherapy drugs.
In addition to ginsenosides Rg3 and Rh2, ginsenoside Rg5 was found to overcome chemotherapeutic multidrug resistance in vitro and in vivo.
Ginseng/Ginsenosides and Chemotherapy Combination in Human Studies
A number of clinical studies explored the association of ginsenosides and chemotherapy combination with improved efficacy in different cancers.
A analysis of twenty-two randomized clinical trials, including 2022 cancer patients concluded that ginsenoside Rg3 could enhance drug efficacy and reduce drug-included toxicity from first-line chemotherapy drugs among advanced non-small cell lung cancer in China.
The analysis results showed that compared to chemotherapy alone, ginsenoside Rg3 plus first-line chemotherapy improved the objective response rate, disease control rate, karnofsky performance status, one-year survival rate, two-year survival rate, and weight change; and reduced VEGF levels, incidence of gastrointestinal reactions and bone marrow suppression.
Similarly, another systematic review of 18 trials comprising 1531 patients also demonstrated that ginsenoside Rg3 in combination with chemotherapy could improve the efficacy and reduce side effects among patients with digestive system cancer.
A clinical trial of 60 patients with advanced esophageal cancer investigated the efficacy of Shenyi capsules (95%, ginsenoside Rg3) + gemcitabine + cisplatin. Compared to chemotherapy alone, ginsenoside Rg3 and chemotherapy combination significantly reduced vascular endothelia growth factor to inhibit tumor angiogenesis after treatment, resulted in higher one-year survival rate and improved quality of life, although the total respond rate was not found statistically significant during the treatment.
Ginseng use with adjuvant chemotherapy could enhance immune health. A clinical trial investigated the clinical effects of Korean red ginseng administrated with adjuvant chemotherapy on the immune function of patients with bile duct or pancreatic cancer in a Korean population. The clinical trial included 26 patients undergoing curative resection for bile duct or pancreatic cancer who administrated 5-fluorouracil/leucovorin or gemcitabine. The results showed that patients receiving Korean red ginseng plus chemotherapy had higher CD4+ T lymphocyte levels and better CD4+/CD8+ T lymphocyte ratio after chemotherapy, which indicated the immune-enhancing effects of ginseng together with chemotherapy drugs.
Myelosuppression is one of the most common adverse reactions of chemotherapy, and patients suffering from myelosuppression will have a varying degree of decreasing hemoglobin, leukocyte or thrombocytopenia. A systematic review analyzed 18 trials of 222 subjects, finding that administering ginsenoside Rg3 and radiation simultaneously was associated with decreased chemotherapy-induced leukocyte, hemoglobin, platelet, and neutrophil counts.
Conclusion
Studies supported the synergistic effects of ginseng and ginsenosides use together with chemotherapy among cancer patients, despite limited populations. Ginseng and ginsenosides are promising adjuvants to enhance the efficacy of chemotherapy in cancer treatment.
References
Jia, W. W., Bu, X., Philips, D., Yan, H., Liu, G., Chen, X., Bush, J. A., & Li, G. (2004). Rh2, a compound extracted from ginseng, hypersensitizes multidrug-resistant tumor cells to chemotherapy. Canadian journal of physiology and pharmacology, 82(7), 431–437. https://doi.org/10.1139/y04-049
Peng, Z., Wu, W. W., & Yi, P. (2021). The Efficacy of Ginsenoside Rg3 Combined with First-line Chemotherapy in the Treatment of Advanced Non-Small Cell Lung Cancer in China: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Frontiers in pharmacology, 11, 630825. https://doi.org/10.3389/fphar.2020.630825
Huang J, Sun Y, Fan Q, Zhang Y. Efficacy of Shenyi Capsule combined with gemcitabine plus cisplatin in treatment of advanced esophageal cancer: a randomized controlled trial. Journal of Chinese Integrative Medicine. 2009;7(11):1047–1051.
Zhang, Q., Kang, X., Yang, B., Wang, J., & Yang, F. (2008). Antiangiogenic effect of capecitabine combined with ginsenoside Rg3 on breast cancer in mice. Cancer biotherapy & radiopharmaceuticals, 23(5), 647–653. https://doi.org/10.1089/cbr.2008.0532
Pan L, Zhang T, Cao H, Sun H, Liu G. Ginsenoside Rg3 for Chemotherapy-Induced Myelosuppression: A Meta-Analysis and Systematic Review. Front Pharmacol. 2020 May 12;11:649. doi: 10.3389/fphar.2020.00649. PMID: 32477128; PMCID: PMC7235324.
Kim, I. K., Lee, K. Y., Kang, J., Park, J. S., & Jeong, J. (2021). Immune-modulating Effect of Korean Red Ginseng by Balancing the Ratio of Peripheral T Lymphocytes in Bile Duct or Pancreatic Cancer Patients With Adjuvant Chemotherapy. In vivo (Athens, Greece), 35(3), 1895–1900. https://doi.org/10.21873/invivo.12454
Pan, L., Zhang, T., Sun, H., & Liu, G. (2019). Ginsenoside Rg3 (Shenyi Capsule) Combined with Chemotherapy for Digestive System Cancer in China: A Meta-Analysis and Systematic Review. Evidence-based complementary and alternative medicine : eCAM, 2019, 2417418. https://doi.org/10.1155/2019/2417418
Jia WW, Bu X, Philips D, Yan H, Liu G, Chen X, Bush JA, Li G. Rh2, a compound extracted from ginseng, hypersensitizes multidrug-resistant tumor cells to chemotherapy. Can J Physiol Pharmacol. 2004 Jul;82(7):431-7. doi: 10.1139/y04-049. PMID: 15389289.