LSA & Liu Jun Zi Tang: Potential Role of Chinese Herbal Medicine in Managing Canine LSA Patients

This exclusive article is part of the MettaPets Veterinary Professional Blog Series

This article is the intellectual property of Dr. Erin Bannink, March 2021.

Distribution of this article in part or entirety without written permission from Dr. Bannink is prohibited.

IN THIS ARTICLE

INTRODUCTION TO THE TCM ACTIONS OF LIU JUN ZI TANG

Liu Jun Zi Tang is a formula consisting of the two smaller formulas, Si Jun Zi Tang and Er Chen Tang, which tonify Spleen Qi and clear Phlegm respectively.

Si Jun Zi Tang is the base formula within Liu Jun Zi Tang. Si Jun Zi Tang contains Ren Shen (Ginseng), Bai Zhu (White Atractylodes), Fu Ling (Poria), Gan Cao (Licorice). It is the foundational Qi tonic formula to treat Qi deficiency, with actions to tonify Spleen and Lung Qi, drain Damp and clear Phlegm.

Er Chen Tang is a Phlegm clearing formula which is comprised of Fu Ling (Poria), Gan Cao (Licorice), Chen Pi (Orange Pell) and Ban Xia (Pinellia). Chen Pi (Orange Peel) dries Damp and transforms Phlegm and descends rebellious Stomach Qi to resolve nausea and improve gastric motility. Ban Xia (Pinellia) dries Damp and harmonizes the stomach.

Liu Jun Zi Tang is indicated for treatment of the TCM diagnoses of Spleen Qi deficiency with secondary Damp accumulation. It can also play a role in addressing chronic Blood Stasis conditions that occur due to longstanding Qi deficiency which has resulted in the inability of Qi to move Blood. It can, therefore, be a good formula for patients with Blood Stasis who are also exhibiting Spleen Qi deficiency signs.

It can also indirectly help to resolve Blood deficiency by moving Blood and restoring the normal dynamic between the Liver and Spleen that is required for generation of Blood, and can be used in combination with Blood tonic formulas to this goal. Clinical signs may include lethargy, weakness, poor appetite, diarrhea, and weak cough (Lung Qi deficient cough). Pulse is weak and may be slippery. Tongue is pale and may be lavender, moist or have a slight white coat.

WESTERN BIOMEDICAL PERSPECTIVES ON LIU JUN ZI TANG

Liu Jun Zi Tang is clearly recognized as a formula which treats nausea, improves gastric motility, improves appetite and increases ghrelin secretion in numerous clinical and in vivo studies in rats. In dogs, Liu Jun Zi Tang stimulated gastrointestinal contractions through cholinergic neurons and 5-HT type 3 receptors and increases ghrelin levels in plasma. It is, therefore, a reasonable treatment option to consider for alleviating gastrointestinal disorders via its pro-kinetic effects as well as its appetite-promoting effects via plasma ghrelin levels. Liu Jun Zi Tang may be more effective if administered on an empty stomach as one main ingredient, Atractylodin, reached lower plasma levels when given with food versus when fasting in rats.

INTRODUCTION TO THE BIOMEDICAL ACTIONS OF HERBS WITHIN LIU JUN ZI TANG RELEVANT TO THE MANAGEMENT OF PATIENTS WITH LYMPHOMA

Ren Shen/Ginseng

20(S)-protopanaxadiol (PPD) found in Ginseng (Ren shen) showed the ability to enhance cytotoxicity of Cyclophosphamide in tumor-bearing mice (Lewis lung carcinoma cells), although showed no anti-neoplastic action on it’s own. It also significantly increased the peripheral white blood cell count and bone marrow cell count in cyclophosphamide-treated tumor-bearing mice. Based on these results, this compound was proposed as a beneficial supplement during cyclophosphamide chemotherapy.

Orally administered Ginsenosode Rh(2), one of the active compounds in Ginseng, synergistically was able to enhance the antitumour activity of cyclophosphamide in mice when given at a dose of 40 mg/kg body weight. Ginsenoside Rh(2) also decreased the DNA strand breaks in white blood cells. These were dose-dependent effects, suggesting the ability to enhance the antitumor activity and decrease the bone marrow toxicity of cyclophosphamide. Ginsenoside Rh2, was shown to inhibit an NF-κB pathway that affects ABC transporter activity on the cell surface, altering cellular pharmakokinetics of doxorubicin in cancer cells. 20(S)-ginsenoside Rh2 inhibited doxorubicin-induced ABCB1 expression and increased the accumulation of doxorubicin within tumor cells in vitro and synergistically increasing the cytotoxicity of doxorubicin in human breast cancer cells. In yet another study, Ginsenoside increased drug accumulation and tumor antigen expression.

Panaxytriol, found in Ginseng (Ren Shen) was shown to exhibit cytotoxicity to a mouse lymphoma cell line in a time and dose-dependent fashion. Cell cycle arrest at the G2/M phase was also observed, and the proportion of cells in the G0/G1 and S phases decreased.

Autophagy and mitochondrial-mediated apoptosis are both induced by Ginsenoside Rh2 (GRh2) in ALL cells.

Oligosaccharides from Panax Ginseng have been shown in increase Natural Killer Cell activity in tumor-bearing mice.

Ren Shen also has activity against Multiple Myeloma. Ginsenoside Rg3, a main chemical constituent, showed the ability to inhibited proliferation and induced apoptosis in vitro. Although this is not lymphoma or a lymphoid leukemia, per se, Multiple Myeloma is a malignant plasma cell condition. Plasma cells are a type of B cell. The information is included here to illustrate a potential in effectiveness agains B cell malignancies. In addition, there are numerous studies showing activity of Ren Shen against non-lymphoid leukemia cell lines which are not included here in consideration of time and space.

Bai Zhu/White Atractylodes

A methanol extract of dried Bai Zhu induced apoptosis (condensed chromatin, fragment nuclei and apoptotic bodies) through increased intracellular ROS generation in AML, CML and Jurkat T cell lymphoma cells.

Atractylenolide-1 (ALT-1), an active constituent in Bai Zhu, showed cytotoxic activity via induction of apoptosis in human leukemia cell lines including Jurkat T lymphoma cells, which are used to study Acute T cell leukemia. These effects were related to induction of caspase-3 and caspase-9 signaling.

Gan Cao/Licorice

Various compounds from Gan Cao were shown to exhibit anti-leukemic action. Of 21 compounds evaluated, calycosin, an isoflavinoid, showed the most activity against human T-cell leukemia cells (MT-4) and (3R)-vestitol, an isoflavin, was highly effective agains CAM-13 lymphoblastoid leukemia cells, more active even than doxorubicin in vitro.32

Gan Cao/Licorice

Various compounds from Gan Cao were shown to exhibit anti-leukemic action. Of 21 compounds evaluated, calycosin, an isoflavinoid, showed the most activity against human T-cell leukemia cells (MT-4) and (3R)-vestitol, an isoflavin, was highly effective agains CAM-13 lymphoblastoid leukemia cells, more active even than doxorubicin in vitro.

REFERENCES:

Western Biomedicine Perspective

Argyle DJ, Pecceu E. Canine and feline lymphoma: challenges and opportunities for creating a paradigm shift. Vet Comp Oncol. 2016;14(1):1-7.

WESTERN BIOMEDICAL PERSPECTIVES ON LIU JUN ZI TANG

Guo XM, Li JX, Yang XF. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1997;17(6):325–327.

Fujitsuka N, Asakawa A, Amitani H, Hattori T, Inui A. Efficacy of ghrelin in cancer cachexia: clinical trials and a novel treatment by rikkunshito. Crit Rev Oncog. 2012;17(3):277–284.

Takeda H, Muto S, Nakagawa K, Ohnishi S, Asaka M. Rikkunshito and ghrelin secretion. Curr Pharm Des. 2012;18(31):4827–4838.

Takeda H, Muto S, Nakagawa K, et al. Rikkunshito as a ghrelin enhancer. Methods Enzymol. 2012;514:333–351.

Yamamoto K, Isogai Y, Ishida T, Hagihara K. Enhancement of ghrelin-signaling system by Rikkunshi-To attenuates teriparatide-induced pica in rats. J Pharmacol Sci. 2018;137(2):137–145.

Terawaki K, Kashiwase Y, Sawada Y, et al. Development of ghrelin resistance in a cancer cachexia rat model using human gastric cancer-derived 85As2 cells and the palliative effects of the Kampo medicine rikkunshito on the model. PLoS One. 2017;12(3):e0173113.

Mondal A, Takehara A, Aizawa S, et al. Rikkunshito induces gastric relaxation via the β-adrenergic pathway in Suncus murinus. Neurogastroenterol Motil. 2015;27(6):875–884.

Harada Y, Ro S, Ochiai M, et al. Ghrelin enhancer, rikkunshito, improves postprandial gastric motor dysfunction in an experimental stress model. Neurogastroenterol Motil. 2015;27(8):1089–1097.

Wang L, Mogami S, Karasawa H, et al. Preventive effect of rikkunshito on gastric motor function inhibited by L-dopa in rats. Peptides. 2014;55:136–144. doi:10.1016/j.peptides.2014.02.011

Nahata M, Saegusa Y, Sadakane C, et al. Administration of exogenous acylated ghrelin or rikkunshito, an endogenous ghrelin enhancer, improves the decrease in postprandial gastric motility in an acute restraint stress mouse model. Neurogastroenterol Motil. 2014;26(6):821–831.

Arai T, Maejima Y, Muroya S, Yada T. Rikkunshito and isoliquiritigenin counteract 5-HT-induced 2C receptor-mediated activation of pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus. Neuropeptides. 2013;47(4):225–230.

Yanai M, Mochiki E, Ogawa A, et al. Intragastric administration of rikkunshito stimulates upper gastrointestinal motility and gastric emptying in conscious dogs. J Gastroenterol. 2013;48(5):611–619.

Nahata M, Mizuhara Y, Sadakane C, Watanabe J, Fujitsuka N, Hattori T. Influence of food on the gastric motor effect of the Kampo medicine rikkunshito in rat. Neurogastroenterol Motil. 2018;30(2):10.1111/nmo.13177.

Ren Shen/ Ginseng

Lin G, Yu X, Wang J, et al. Beneficial effects of 20(S)-protopanaxadiol on antitumor activity and toxicity of cyclophosphamide in tumor-bearing mice. Exp Ther Med. 2013;5(2):443-447.

Wang Z, Zheng Q, Liu K, et al. Ginsenoside Rh(2) enhances antitumour activity and decreases genotoxic effect of cyclophosphamide. Basic Clin Pharmacol Toxicol. 2006;98(4):411-5.

Zhang J, Lu M, Zhou F, et al. Key role of nuclear factor-κB in the cellular pharmacokinetics of adriamycin in MCF-7/Adr cells: the potential mechanism for synergy with 20(S)-ginsenoside Rh2. Drug Metab Dispos. 2012;40(10):1900-8.

Zhang J, Zhou F, Wu X, et al. Cellular pharmacokinetic mechanisms of Adriamycin resistance and its modulation by 20(S)-ginsenoside Rh2 in MCF-7/Adr cells. Br J Pharmacol. 2012;165:120–134.

Molnár J, Szabó D, Pusztai R, et al. Membrane associated antitumor effects of crocine-, ginsenoside- and cannabinoid derivates. Anticancer Res. 2000;20(2A):861-7.

Kim JY, Lee KW, Kim SH, et al. Inhibitory effect of tumor cell proliferation and induction of G2/M cell cycle arrest by panaxytriol. Planta Med. 2002;68(2):119-22.

Xia T, Wang J, Wang Y, et al. Inhibition of autophagy potentiates anticancer property of 20(S)-ginsenoside Rh2 by promoting mitochondria-dependent apoptosis in human acute lymphoblastic leukaemia cells. Oncotarget. 2016;7(19):27336-49.

Xia T, Wang JC, Xu W, et al. 20S-Ginsenoside Rh2 induces apoptosis in human Leukaemia Reh cells through mitochondrial signaling pathways. Biol Pharm Bull. 2014;37(2):248-54.

Jiao L, Zhang X, Li B, et al. Anti-tumour and immunomodulatory activities of oligosaccharides isolated from Panax ginseng C.A. Meyer. Int J Biol Macromol. 2014;65:229-33.

Li Y, Yang T, Li J, et al. Inhibition of multiple myeloma cell proliferation by ginsenoside Rg3 via reduction in the secretion of IGF-1. Mol Med Rep. 2016;14(3):2222-30.

Luo Y, Zhang P, Zeng HQ, et al. Ginsenoside Rg3 induces apoptosis in human multiple myeloma cells via the activation of Bcl-2-associated X protein. Mol Med Rep. 2015;12(3):3557-62.

Bai Zhu/White Atractylodes

Huang HL, Chen CC, et al. Reactive Oxygen Species mediation of Baizhu-induced apoptosis in human leukemia cells. J of Ethnopharmacology 2005;97(1):21-9

Huang HL, Lin ZW, et al. Induction of apoptosis and differentiation by atractylenolide-1 isolate from Actractylodes macrocephala in human leukemia cells. Bioorg Med Chem Lett. 2016;26(8):1905-9.

Gan Cao/Licorice

Shults EE, Shakirov MM, Pokrovsky MA, et al. Phenolic compounds from Glycyrrhiza pallidiflora Maxim. and their cytotoxic activity. Nat Prod Res. 2017;31(4):445-452.