Anti-hepatocellular carcinoma activity and mechanism of chemopreventive compounds: ursolic acid derivatives
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Context: Hepatocellular carcinoma (HCC) is a common cancer around the world, with high mortality rate. Currently, there is no effective drug for the therapy of HCC. Ursolic acid (UA) is a natural product which exists in various medicinal herbs and fruits, exhibiting multiple biological effects such as its outstanding anticancer and hepatoprotective activity, which has drawn many pharmacists' attention.Objective: This paper summarizes the current status of the hepatoprotective activity of UA analogues and explains the related mechanism, providing a clear direction for the development of novel anti-HCC drugs.Methods: All of the data resources were derived from PubMed. By comparing the IC50 values and analyzing the structure–activity relationships, we listed compounds with good pharmacological activity from the relevant literature, and summarized their anti-HCC mechanism.Results: From the database, 58 new UA derivatives possessing wonderful anticancer and hepatoprotective effects were listed, and the relevant anti-HCC mechanism were discussed.Conclusion: UA's anti-HCC effect is the result of combined action of many mechanisms. These 58 new UA derivatives, particularly compounds 45 and 53, can be used as potential drugs for the treatment of liver cancer.Keywords:
Ursolic acid
Mechanism of Action
Liver Cancer
Natural product
본 연구에서는 ursolic acid의 위의 보호효과를 위한 실험을 실시하였다. 위장 질병에 대한 ursolic acid의 효과를 확인하기 위해서 급성, 만성위염은 각각의 HCl·ethanol과 indomethacin에 의해 유도된 위염 동물 모델을 사용하여 관찰하였다. 대표적인 공격인자인 위산에 관해서는 PPI activity를 통해서 확인하였고, 위의 손상에 대한 보호인자에 관해서는, PGE2를 정량적으로 분석하였다. 항균활성 실험은 만성위염, 위궤양, 위암에 원인인자로 잘 알려진 H. pylori로 실험하였다. AGS cell를 이용하여 DAPI 염색, Flow cytometry assay를 통하여 ursolic acid가 위암세포의 apoptosis에 관여하는지를 확인하였다. 그 결과 ursolic acid 는 HCl·ethanol과 indomethacin에 의해 유도된 급성, 만성에 대한 위손상을 억제하였다. Ursolic acid는 위산분비의 마지막 단계인 위염분비효소인 proton pump를 억제시킴으 로써 산의 분비를 억제하였다. 그리고 ursolic acid는 위 점막의 보호인자인 PGE2의 농도가 증가함으로써 위 점막 보호 효과를 확인하였다. 또한 ursolic acid는 공격인자인 H. pylori colonization을 억제하였다. DAPI를 이용한 핵 염색에서, 대조군과는 달리, 핵 형상의 변형과 함께 수축 된 세포 또는 염색질의 응축현상이 관찰되었다. Flow cytometry assay에서 ursolic acid에 의해 apoptosis가 증가하는 것을 확인 하였다. 이를 통하여 ursolic acid는 위 손상에 대한 방어 효과가 있음을 확인할 수 있었다.
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This paper reports preparation of four ursolic acid derivatives. Study on protective activity of ursolic acid on CCl4 hepatic damage indicated that the ursolic acid and derivatives at the doses of 60mg/kg significantly decreased the serum AST and ALT. The ursolic acid ethylic ester showed similar activity as that of ursolic acid against hepatic damage. Compared to ursolic acid, the ursolic acid diclofop ester demonstrated more potent protection on hepatic damage, even better than DGL.
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Early detection of hepatocellular carcinoma (HCC) is crucial in providing more effective therapies. As routine laboratory variables are readily accessible, this study aimed to develop a simple non-invasive model for predicting hepatocellular cancer.Two groups of patients were recruited: an estimation group (n = 300) and a validation group (n = 625). Each comprised two categories: hepatocellular cancer and liver cirrhosis. Logistic regression analyses and receiver operating characteristic (ROC) curves were used to develop and validate the HCC-Mark model comprising AFP, high-sensitivity C-reactive protein, albumin and platelet count. This model was tested in cancer patients classified by the Barcelona Clinic Liver Cancer (BCLC), Cancer of Liver Italian Program (CLIP) and Okuda systems, and was compared with other non-invasive models for predicting hepatocellular cancer.HCC-Mark produced a ROC AUC of 0.89 (95% CI 0.85-0.90) for discriminating hepatocellular carcinoma from liver cirrhosis in the estimation group and 0.90 (0.86-0.90) in the validation group (both p < 0.0001). This AUC exceeded all other models, that had AUCs from 0.41 to 0.81. AUCs of HCC-Mark for discriminating patients with a single focal lesion, absent macrovascular invasion, tumour size <2 cm, BCLC (0-A), CLIP (0-1) and Okuda (stage Ι) from cirrhotic patients were 0.88 (0.85-0.90), 0.87 (0.85-0.89), 0.89 (0.85-0.93), 0.87 (0.84-0.89), 0.85 (0.82-0.87) and 0.86 (0.83-0.89), respectively (all p < 0.0001).HCC-Mark is an accurate and validated model for the detection of hepatocellular cancer and certain of its clinical features.
Liver Cancer
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188. The occurrence of ursolic acid in Escallonia tortuosa. Conversion of ursolic acid into α-amyrin
J. A. Goodson, J. Chem. Soc., 1938, 999 DOI: 10.1039/JR9380000999
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OBJECTIVE To investigate the effects of different treatment methods on extracting ursolic acid from Loquat Leaf with the aid of ultrasonic wave.METHODS After the precipitates obtained by the treatment of Loquat Leaf with different methods,ursolic acid is extracted by using ethanol as a medium under the ultrasonic wave.The content of ursolic acid is determined with HPLC method. RESULTS The content of ursolic acid in Loquat Leaf is above 0.9%.Some of ursolic acids remain in the precipitates after the different treatments.CONCLUSION Ursolic acid is almost indissoluble in water or oil;the effect of ethanol refluxing extraction is not satisfactory,even increase the extract cycle,the yield of ursolic acid will not enhance obviously;Ursolic acid in Loquat Leaf exists mainly in dissociative form.
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[Objective] To optimize the extracting conditions of ursolic acid from FRUCTUS CHAENOMELIS and determine its content,so as to provide scientific evidence for the development,application and quality control of ursolic acid.[Method] The extraction conditions of ursolic acid were optimized by orthogonal test,and content of ursolic acid was determined by HPLC.[Result] The optimal extraction conditions were determined to be: 30 min of extraction duration,25.0 ml of ethanol amount and extraction solvent of absolute ethanol.Under the optimum process,content of ursolic acid was 0.324%.When the concentration of ursolic acid ranged from 0.650 to 3.250 μg/ml,the relationship between ursolic acid concentration and peak area was good(r=0.999 1).Mean recovery rate of ursolic acid was 99.20% with RSD value of 0.30%.[Conclusion] The optimal extraction conditions were feasible,and the established HPLC method was simple,sensitive and accurate.This study provided scientific evidence for the development,application and quality control of ursolic acid.
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Ursolic Acid is a type of pentacyclic triterpene compounds with many kinds of pharmacological activities, especially its antitumor activity. The antitumor mechanism of ursolic acid is multifaceted. In this paper, the research progress of anti-tumor mechanism of ursolic acid has been reviewed and forecasted.
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