Oxymatrine and cancer therapy

Abstract

Oxymatrine is a kind of alkaloid extracted from traditional Chinese herb Sophora flavescens Ait. It has been proved to exert various biological activities such as anti-angiogenesis, proliferation-inhibiting, apoptosis-promoting, analgesic-strengthening, and anti-metastasis. The biological activities are related with inhibition of angiogenesis-associated factors, regulation of related signaling pathway and protein expression, synergistic effects with chemotherapy drug, cell cycle arrest and inhibition of voltage-activated K+ channel. In this review, we summarize the recent investigations of oxymatrine in cancer therapy so as to provide references for further study and clinical therapy.

Introduction

Traditional Chinese Medicine has a long history in China and is widely used for various diseases including cancer. Oxymatrine is a kind of alkaloid extracted from traditional Chinese herb Sophora flavescens Ait and its chemical structure is shown in Figure 1. ¹ Oxymatrine has been traditionally used for therapy of hepatitis B virus (HBV), inflammatory diseases, and various cancers due to its few side effects and low cost. The present review provides an up-to-date and comprehensive knowledge of traditional uses and scientific evidence of oxymatrine.

Figure 1.

The chemical structure of oxymatrine.

Pharmacological functions and traditional uses

Anti-inflammatory properties

Studies show that oxymatrine exhibits great anti-inflammatory effects and protects tissue from inflammatory infiltration, whose molecular mechanism is related to inhibition of phosphorylation of nuclear factor κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signal pathways, ² reduction of NF-κB nuclear translocation and independent activity of inhibitor κBα (IκBα) status, blockade of inflammatory signaling, ³ and release of pro-inflammatory factors.^4–6 Oxymatrine significantly ameliorates L-arginine-induced acute pancreatitis by the reduction of plasma amylase, D-lactic acid, tumor necrosis factor alpha concentration, serum diamine oxidase, lipase activity, and pancreatic myeloperoxidase activity. ⁷ The administration of oxymatrine can significantly inhibit inflammatory responses. Combined with sodium ferulate, oxymatrine shows synergistic anti-inflammatory effects. ⁴ Therefore, oxymatrine plays an important role in anti-inflammatory effects.

Anti-fibrosis properties

Oxymatrine is effective and safe in treatment of hepatic fibrosis. ⁸ The possible mechanism is summarized as follows: (1) Enhancing the mesenchymal stem cell therapy and increasing serum levels of interleukin-4 (IL-4) and interleukin-10 (IL-10); ⁹ (2) Reducing serum alkaline phosphatase, attenuating liver injury and collagen deposits, and inhibiting fibrosis-related gene expression, such as matrix metalloproteinases (MMP-2), tissue inhibitor of metalloproteinase-1 (TIMP-1), and type 1 procollagen; ¹⁰ (3) Reducing the production and deposit of collagen in the liver tissue via modulating the fibrogenic transduction of p38 MAPKs signaling ¹¹ and protecting against myocardial from fibrosis by transforming growth factor -β1-Smads (TGF-β1-Smads) signal pathway. ¹²

Anti-viral properties

Hepatitis B is a worldwide public health problem, especially in China. Although several anti-viral drugs have been approved, they cause significant side effects and drug resistance. Safe and potent anti-hepatitis B virus drugs are urgently needed. Oxymatrine is an effective and safe agent for the treatment of chronic hepatitis B. ¹³ It inhibits HBV replication and antigen expression and exerts a similar efficacy to interferon-α-2b without adverse effects. ¹⁴ Its possible anti-viral mechanism is surveyed as follows: (1) Downregulating peripheral blood HBV-specific cytotoxic T lymphocyte (CTL) surface PD-1 expression, increasing HBV-specific CTL level ¹⁵ and inhibiting HBV in chronic hepatitis B patients; (2) Destabilizing or downregulating the expression of heat-stress cognate 70 (HSC70), a host protein required for HBV DNA replication ¹⁶ and preventing HBV from developing drug resistance when combined with lamivudine; ¹⁷ (3) Interfering the process of packaging pregenomic RNA into the nucleocapsid, and inhibiting the activity of the viral DNA polymerase; ¹⁸ (4) Triggering the change of immune response to hepatitis B infection by increasing T Helper Type 1 (Th1) cytokines, decreasing Th2 cytokines, and improving anti-HBV activities. ¹⁹ Combined with lamivudine, oxymatrine improves the curative effect against HBV infection. ²⁰ We anticipate that oxymatrine has potential as an application in the treatment of clinical hepatitis B.

Cardiovascular protective effect

Accumulating evidence indicates that oxymatrine plays various protective roles in the cardiovas-cular system. It ameliorates the experimental ventricular remodeling by reducing serum content of asymmetric dimethylarginine (ADMA), increasing double methyl arginine hydrolase 2 antibodies (DDAH2) expression, ²¹ and inhibiting the expression of angiotensin-converting enzyme (ACE) and TGF-β1 and activation of extracellular signal-regulated kinase 1/2 (ERK 1/2), Jun N-terminal kinase (JNK), and p38 MAPK signaling pathways. ²² Oxymatrine acts against excessive aldosterone-induced cardiotoxicity through inhibition of calpain/apoptosis-inducing factor signaling pathways, ²³ improves heart failure by upregulation of sarcoplasmic reticulum Ca2+ ATPase and dihydropyridine receptor, ²⁴ protects arrhythmias through inhibition of sodium and calcium currents, ²⁵ and shortens the action potential duration through reduction of L-type calcium current, enhances transient outward potassium current, and inhibits inward rectifier potassium current. ²⁶

Protective effect on diabetes and hyperlipidemia

Oxymatrine has effective protection in glucose and lipid metabolism. It guards islet and liver architecture and ameliorates insulin secretion and sensitivity via increase of the mRNA and protein levels of peroxisome proliferator-activated receptor-α (PPARα), carnitine palmitoyltransferase 1A (CPT1A), and microsomal triglyceride transfer protein (MTTP), and decrease of Srebf1, contributing to the reduction of insulin resistance and alleviation of overweight, hyperglycemia, and hyperlipemia.^27,28 Oxymatrine defends oxidative stress and reduces the contents of renal advanced glycation end products, TGF-β1, connective tissue growth factor and inflammatory cytokines in diabetic rats, ²⁹ implicated in diabetes and hyperlipidemia.

Protective effect on ischemia reperfusion injury

Oxymatrine protects nervous system from ischemic damage through downregulation of 12/15-lipoxygenase, phospho-p38MAPK, cytosolic phospholipase A2, Toll-like receptor, myeloid differentiation factor 88, NF-Κb, and B-cell lymphoma 2 (Bcl-2) family.^30,31 It significantly inhibits inflammatory responses, oxidative injury, and neuronal cell apoptosis in intracerebral hemorrhage rats. ³² Oxymatrine protects against lung ischemia reperfusion injury ³³ and improves intestinal barrier function, ¹ preventing pulmonary hypertension. ³⁴

Anti-tumor properties

Rapid increases in incidence and mortality of human cancer are observed worldwide, and development of new effective chemicals with low cost and toxicity is urgently needed. Oxymatrine has aroused the scholars’ attention to its multiple biological activities.

Anti-angiogenesis

Angiogenesis is necessary for tumor growth. Anti-angiogenesis is now widely accepted as a method for cancer therapy through suppression of tumor growth by disrupting oxygen and nutrient supply from blood to the tumor. ³⁵ Oxymatrine decreases the expression of angiogenesis-associated factors, including NF-κB and vascular endothelial growth factor (VEGF). ³⁶ When combined with angiogenesis inhibitor or low-dose chemotherapy drug, oxymatrine inhibits the expression of VEGF and CXC Chemokine Receptor-4 and exerts synergistic inhibitory effects on the growth of gastric cancer cells. ³⁷

Anti-proliferation

One notable feature of tumor cells is the uncontrolled growth. Many anti-cancer drugs exert anti-tumor activity via controlling tumor growth. Oxymatrine markedly and dose-dependently inhibits the proliferation of cancer cells ³⁸ by inhibiting the expression of β-catenin, ³⁹ blocking cell cycle in G2/M and S phase, and regulating Bcl-2 and p53 expression. ⁴⁰

Apoptosis-promoting

Oxymatrine induces cell apoptosis in a dose- and time-dependent manner. It appears to exert anti-tumor action by stimulating the caspase-triggered signaling pathway. ³⁸ It downregulates anti-apoptotic Bcl-2 and inhibitor of apoptosis protein (IAP) families, upregulates pro-apoptotic Bax expression, releases mitochondrial cytochrome c, and activates caspase-3/-9 in human cancer cells.^41,42 Livin and Survivin are members of IAPs, which can play important roles in inhibiting apoptosis by exerting their negative action on caspases. ⁴³ Overexpression of Livin and Survivin is found associated with poor prognosis in primary and cultured tumors, but oxymatrine obviously downregulates Livin and Survivin expression, thus promoting an apoptosis effect. ⁴⁴

Analgesic effect

Cancer-induced pain is a severe chronic pain, and relief of pain is a preferential strategy for improving quality of life. Wide use of opioid drugs in cancer pain is associated with complications such as analgesic tolerance, dependence, and opioid abuse. Li et al. ⁴⁵ have found that a high dose of oxymatrine significantly inhibits the expression of morphine-induced P-glycoprotein and the development of morphine tolerance, leading to the analgesic effect. Molecular mechanisms are related with the regulation of N-methyl-D-aspartate (NMDA) Receptor 2b (NR2B)-containing NMDA receptor-ERK/ CAMP-response element binding protein (CREB) signaling ⁴⁶ and inhibition of voltage-activated K(+) channel. ⁴⁷ Combined with sodium ferulate, oxymatrine causes significant analgesic effect via the synergistic inhibition of transient receptor potential vanilloid-1. ⁴⁸

Anti-metastasis

The human Ether-à-go-go-Related Gene (hERG) is associated with aggressive tumors and plays a role in mediating tumor invasion. Oxymatrine carries the common molecular structure of O=C=N-C-C-C-N that possesses positive ionotropic effect and hERG blocking activity, thus suppressing cancer cell invasion and metastasis. ⁴⁹

Other benefits for cancer patients

Oxymatrine regulates the body’s immune system and enhances the ability to fight against cancer. It is especially suitable for patients who are inoperable, in intermittent periods of chemotherapy, and in a postoperative recovery period, but until now, the relative research is rare.

Conclusions and future perspectives

Obviously, oxymatrine is a natural product which has many potential clinical applications with low toxicity, low cost, and well-established traditional use. It has great advantages in terms of suppressing tumor progression, helping analgesia, regulating the body’s function, and enhancing the ability to fight against cancer. More specific mechanisms are still unclear, especially in regulating immune system and treating cancer. Therefore, profound researches about anti-tumor effects of oxymatrine are needed to be further explored. We expect that oxymatrine may be a potential candidate for cancer treatment.