Antitumor Effects of Chuanxiong (Ligusticum chuanxiong) and Tetramethylpyrazine

Chuanxiong (Ligusticum chuanxiong Hort., family Apiaceae) is one of the most commonly used Chinese medicinal herbs, with extremely broad clinical applications. Li Shizhen called it "the qi-medicine within the blood," considering it to both invigorate blood and move qi. TCM therefore uses it for various diseases due to blood stasis and qi stagnation, especially in gynecology and traumatology - such as amenorrhea, difficult labor, dysmenorrhea, abdominal masses, and traumatic injuries. Chuanxiong both invigorates blood and relieves pain, so it is also used for various pain syndromes due to blood stasis and qi stagnation, such as headache, chest and hypochondriac pain, and angina pectoris. Li Dongyuan held that Chuanxiong must be used to treat headache; although it may be combined with different herbs according to each patient's pattern, Chuanxiong is indispensable.

Tetramethylpyrazine (chuanxiongzine) is an active component extracted from Chuanxiong by distillation. Its molecular formula is C8H12N2; it is a colorless needle-like crystal with a peculiar odor, readily subliming and hygroscopic. Tetramethylpyrazine is readily soluble in hot water and petroleum ether, soluble in chloroform and dilute hydrochloric acid, slightly soluble in ether, and insoluble in cold water; the injectable form is a solution of tetramethylpyrazine hydrochloride. In recent years it has been widely used to treat coronary heart disease, angina pectoris, ischemic cerebrovascular disease, and pulmonary embolism.

There are many clinical studies on tetramethylpyrazine; the following effects have been found.

First, effects on the cardiovascular and cerebrovascular systems: 1. Animal experiments show a cardiotonic effect, significantly increasing heart rate in anesthetized animals, though at excessive doses it inhibits heart rate and myocardial contraction. This is a common feature of many biological drugs, which have a biphasic action, just as Sanqi (Panax notoginseng) both stops bleeding and invigorates blood. 2. Tetramethylpyrazine has a certain antihypertensive effect. 3. It can significantly increase coronary blood flow in experimental animals, and is therefore used for coronary heart disease. 4. It can reduce the injury to myocardium under low-pressure hypoxia in myocardial-ischemia animals. 5. It markedly improves cerebral circulation and cerebral ischemia. 6. It improves human microcirculation.

Tetramethylpyrazine also has marked effects on the blood system: it inhibits platelet aggregation, is antithrombotic, lowers whole-blood viscosity, and improves erythrocyte deformability. Thus the traditional TCM view that Chuanxiong both invigorates and tonifies blood has a scientific basis. Tetramethylpyrazine raises erythrocyte SOD activity in aged rats with pulmonary edema, strongly inhibits neutrophil accumulation in the lung, and inhibits platelet aggregation and release in guinea pigs with allergic asthma. Hence in recent years many academic studies have explored tetramethylpyrazine for respiratory diseases.

Tetramethylpyrazine also acts on the urinary system: it markedly increases renal blood flow in experimental animals and has a significant diuretic effect, dose-dependent. It has a preventive effect on glycerol-induced renal failure in experimental animals.

In addition, tetramethylpyrazine can enhance immunity in experimental animals, increasing phagocytosis of mouse monocyte-macrophages and raising lymphocyte transformation rate in rats. It also has preventive and therapeutic effects on pancreatitis.

Chuanxiong has very low toxicity. The LD50 of intravenous tetramethylpyrazine in mice is 239 mg/kg, and intraperitoneal perfusion is essentially non-toxic. This agrees with the traditional TCM view that Chuanxiong is "warm in nature and non-toxic." The usual dose in decoction is 3-10 g, which is safe and non-toxic.

Chuanxiong also has antitumor and anti-radiation effects. Its constituents are complex, but ferulic acid and tetramethylpyrazine are considered the two main antitumor components; in addition, protocatechuic acid and ligustilide found in Chuanxiong also have antitumor effects.

Ferulate complexes show marked growth inhibition in vitro against multiple tumor cell lines including human breast cancer, lung cancer, gastric cancer, colon cancer, and central nervous system tumors (e.g., neuroblastoma), and also markedly inhibit cyclooxygenase COX-1 and COX-2.

Animal experiments show ferulic acid has some inhibitory effect on AOM-induced rat colon carcinogenesis in F334 rats and can induce apoptosis in mouse cancer cells. Other experiments show that ferulic acid and other phenolic acids can induce apoptosis in human breast cancer T47D cells and hepatoma HepG-2 cell lines.

Besides its antitumor action, ferulic acid also protects neurons. It reduces neuronal injury caused by excitatory amino acids and markedly improves cell viability, with a dose-dependent protective effect on injured cells. Thus some patients with elevated (neuronal markers) may show a reduction after using Chuanxiong or tetramethylpyrazine.

Research on tetramethylpyrazine's antitumor action is even richer. In animal experiments it inhibits transplanted colon tumors in mice. Studies of the mechanism suggest tetramethylpyrazine may inhibit HIF-1α expression, thereby lowering vascular endothelial growth factor expression, suppressing tumor angiogenesis and delaying tumor progression.

Animal experiments show that tetramethylpyrazine significantly reduces the volume, weight, and number of pulmonary metastases of Lewis lung carcinoma in mice, inhibits tumor VEGF expression, and lowers intratumoral microvessel density in solid tumors. It also inhibits distant metastasis formation in human lung cancer A549 cells, possibly by inhibiting COX-2 enzyme activity in those cells.

Tetramethylpyrazine also markedly inhibits human poorly differentiated gastric adenocarcinoma and human acute promyelocytic leukemia; its anti-gastric-cancer effect is related to inhibiting tumor angiogenesis, and its antileukemic effect to reducing telomerase activity in leukemia cells.

In TCM classics, the effects of Chuanxiong are very broad, including the treatment of swellings and ulcers. For example, Rihuazi Bencao records that Chuanxiong treats "all wind, all qi, all overstrain, all blood; tonifies the five strains, strengthens sinew and bone, harmonizes the various vessels, breaks up concretions and static blood, generates new blood, promotes flesh growth, and treats epistaxis, vomiting blood and hematuria, hemorrhoids and fistulae, brain abscess and back carbuncle, scrofula and goiter, sores and scabies, as well as expelling pus and resolving stasis." Here "concretions and static blood" and "brain abscess, back carbuncle, scrofula and goiter" all relate to some extent to modern benign and malignant tumors.

Successive generations of TCM physicians also identified Chuanxiong's contraindications: patients with yin deficiency and flourishing fire (manifested as heat in the five centers, dry mouth and tongue, fine rapid pulse), menorrhagia, and bleeding disorders should use it cautiously; it has also been found that for patients with qi counterflow and phlegm-wheezing, Chuanxiong does more harm than good. All these may serve as clinical references.