Review of Pharmacological Effects and Mechanisms of Crotonoside

Anqi WANG, Yannan LI, Wenbo ZUO, Yue TENG, Jiazhu LI, Qing ZHANG, Xue ZHAO, Chenghao JIN

College of Life Science and Biotechnology, Heilongjiang Bayi Agricultural University, Daqing 163319, China

Abstract Crotonoside is an important alkaloid component in Croton tiglium. It has the effects of drastic purgation, expelling water and reducing swelling, eliminating phlegm and relieving pharynx. Studies have found that crotonoside can exert a variety of pharmacological effects such as anti-cancer, anti-inflammatory, anti-arrhythmic, and anti-acute myelogenous leukemia through a variety of ways. This paper reviewed the pharmacological effects and mechanisms of crotonoside.

Key words Crotonoside, Anti-cancer, Anti-inflammation, Anti-arrhythmia, Anti-acute myeloid leukemia

1 Introduction

Crotonis Fructus is the dry mature seed ofCrotontigliumL. It is mainly produced in Southwest China, such as Fujian, Hunan, and Guangxi. TheChinesePharmacopoeia(2015) determined crotonoside as a component of croton and croton cream. Its molecular formula is C10H13N5O5[1], and it has various pharmacological activities such as anti-cancer (anti-tumor), anti-inflammatory, and anti-arrhythmia effects[2]. In this paper, we reviewed the research progress of the pharmacological effects and mechanisms of crotonoside in recent years, to provide a certain reference for the in-depth research, development and utilization of crotonoside.

2 Pharmacological effects and mechanisms

2.1 Anti-cancerCancer is a disease resulted from the loss of normal regulation and excessive proliferation of cells in the body. It seriously threatens human health and life. Studies have found that crotonoside can inhibit the proliferation of a variety of cancer cells[3]. Through the inhibitory study on the growth activity of SGC-7901 cells, Xu Dongqingetal.[4]found that crotonoside has a certain inhibitory effect on the proliferation of human gastric adenocarcinoma SGC-7901 cells, and the effect is obviously time- and dose-dependent. With the prolongation of the treatment time of crotonoside and the increase of the dose, the inhibitory effect on the growth activity of SGC-7901 cells continues to strengthen. Through the study of inhibiting histone deacetylase (HDACs), Chen Wuetal.[5]found that the abnormal expression of HDACs is related to the development of various cancers and hematological malignancies in human tumor cells. With the prolongation of the treatment time of crotonoside and the increase of the dose, HDACs are inhibited and the growth activity of AML cells is also inhibited, which eventually causes cancer cells to stop growth and differentiation. Nuclear transcription factor is an important transcription factor involved in gene regulation in various biological processes such as inflammation, immunity, stress, cell growth, and cancer. Studies have shown that crotonoside can prevent malignant transformation of cells and inhibit the metastasis of tumor cells by inhibiting a variety of oncogenic nuclear transcription factors[6]. Through studying the expression level of HDACs protein, Suarezetal.[7]found that crotonoside has a significant inhibitory effect on the proliferation of MCF-7 breast cancer cells. The above experiments have proved that crotonoside can inhibit the proliferation of cancer cells.

2.2 Anti-inflammationInflammation is the defensive response of living tissues of the vascular system to injury factors, and it is a very common and important basic pathological process. Crotonoside shows anti-inflammatory effects of inhibiting capillary permeability and ear swelling. Zhou Jinhuangetal.[8]found that crotonoside can significantly inhibit capillary permeability in the respect of anti-inflammatory effects. Sun Songsanetal.[9]studied the peritoneal vascular permeability of mice through a controlled experiment and found that the anti-inflammatory ability of crotonoside is better than other active components of crotonoside. They administered crotonoside 1.6 g/kg, prednisone 25 mg/kg and normal saline respectively, and measured the amount of Evans blue exuded from the abdominal cavity according to the usual method. Experimental results show that crotonoside has a significant inhibitory effect on the permeability of mouse abdominal capillaries. Through studying the ear swelling of mice through a controlled experiment, Sun Songsanetal.[9]selected two groups of mice weighing 19-22 g, respectively administered crotonoside 1.5 g/kg and normal saline, and measured the swelling of auricles of mice by conventional methods. The experimental results show that crotonoside has a significant inhibitory effect on mouse ear swelling induced by croton oil. Wu Xinan[10]conducted a TPA induction study. He used the method of mouse ear swelling to evaluate the anti-inflammatory activity of 95% ethanol extracts of croton leaves by intragastrical administration, and it showed certain anti-inflammatory activity at a dose of 500 mg/kg, and the swelling inhibition rate was 52%. The above experiments have demonstrated that crotonoside has a significant effect on inhibiting capillary permeability and ear swelling.

2.3 Anti-arrhythmiaArrhythmia (cardiac dysrhythmia) is a disease caused by abnormal sinus node activation, the origin of heart impulse, frequency rhythm, conduction velocity or activation sequence. Crotonoside can significantly inhibit the proliferation and differentiation of ventricular myocytes against cardiac dysrhythmia. Zhang Huaetal.[11]detected the action potential of crotonoside on rabbit ventricular myocytes. When 10, 100, and 200 μmol/L of crotonoside was used to intervene in ventricular myocytes, different concentrations of crotonoside inhibited the growth of INa.L (late sodium current) of ventricular myocytes in a concentration-dependent manner. Ren Ziqiangetal.[12]used the Hill equation to fit a dose-response relationship curve of the percentage inhibition of crotonoside on ICa.L (L-type calcium current), and theIC50value of ICa.L in ventricular myocytes was 158.99 μmol/ L. The ICa.L after repeated gavage basically recovered to the original range. The experimental results showed that the inhibitory effect of crotonoside on the proliferation of ICa.L was recoverable. Cao Zhenzhenetal.[13]found that crotonoside has a significant inhibitory effect on IKr (potassium current). The above experiments have proved that crotonoside can significantly inhibit the proliferation and differentiation of ventricular myocytes.

2.4 Anti-acute myeloid leukemiaAcute myeloid leukemia (AML) is a malignant disease of the hematopoietic system. One of the main reasons why AML is difficult to effectively cure is the strong proliferation ability of bone marrow leukocytes. In this situation, inhibiting the proliferation of MV4-11 cells in acute myeloid leukemia has become a main method for the treatment of acute myeloid leukemia. Studies have shown that crotonoside can affect the growth of acute myeloid leukemia MV4-11 cells, and has no obvious toxicity to normal cells. Through the experiment of inhibiting the expression of HDACs in MV4-11 cells, Suarezetal.[7]found that HDACs can inhibit the growth of AML cells, and after 20 h, the protein expression of HDAC3 and HDAC6 in MV4-11 cells decreased significantly, and finally inhibited the growth of MV4-11 cells.

FMS-like tyrosine kinase 3 (FLT3) can promote the proliferation and differentiation of hematopoietic stem cells, which are expressed in approximately 25% of acute myeloid leukemia cases. Through studying the JAK/STAT5 signaling pathway to regulate hematopoietic cells, Liu Xuelietal.[14]found that STAT5 is highly expressed in various cell lines and primary mouse and human FLT3-ITD-expressing leukemia cells. In particular, JAK2 is most closely related to hematopoiesis and can regulate cell growth, differentiation and apoptosis, and further inhibit the proliferation and differentiation of MV4-11 cells[15]. Xu Dongqingetal.[4]conducted a study on the inhibition of FLT3 phosphorylation in MV4-11 cells and found that crotonoside can inhibit the phosphorylation of FLT3 downstream proteins, thereby inhibiting the activation of transcription factors, and finally inhibiting the proliferation of MV4-11 cells in acute myeloid leukemia. These indicate that crotonoside is an anti-leukemia drug with good development prospects.

3 Prospects

In recent years, a large number of studies on crotonoside have shown that crotonoside has a wide range of biological activities and has no obvious side effects on the human body. In addition to the above anti-cancer, anti-inflammatory, anti-arrhythmic, anti-acute myeloid leukemia and other pharmacological effects, crotonoside also has many pharmacological effects. However, there are relatively few studies on the specific mechanism of action. Therefore, it is necessary to carry out more in-depth and comprehensive research at the cellular and molecular levels to lay a solid theoretical foundation for the development of crotonoside and the study of pharmacological effects.