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Marsdenia tenacissima (Roxb.) Moon, (M. tenacissima) a traditional herbal medicine, has been used for thousands of years. It is noted in Dian Nan Ben Cao that M. tenacissima is bitter in flavor and cold in property, and extracts possess diverse pharmacological effects, including immunomodulation and anti-tumor activities.The anti-tumor effects of M. tenacissima extracts (MTE) have been repeatedly confirmed, and this medicine has also been extensively applied in cancer treatment or prognostic adjuvant therapy, with significant curative effect. This study aims to comprehensively analyze the anti-tumor mechanism of M. tenacissima starting from the key features of traditional Chinese medicine and by studying the main active components individually to identify anti-tumor targets in the context of hepatocellular carcinoma.Molecular network profiling and multi-omic joint analyses were conducted using an H22 mouse model of hepatocellular carcinoma to determine the main active ingredients in MTE and the underlying anti-tumor mechanisms.Tenacissosides I, H, and G (TI,TH and TG) were found to be the likely active ingredients of MTE in the treatment of hepatocellular carcinoma. These compounds were shown to promote apoptosis, inhibit angiogenesis and improve immune function through targeting P53, JAK-1 and HIF1α, respectively.For the first time, based on the theory that multiple components and multiple targets synergistically exert the beneficial effects of a traditional Chinese medicine, this paper comprehensively analyzes the mechanisms of action of M. tenacissima and provides a novel strategy for the subsequent development of anti-tumor therapies.

Marsdenia tenacissima (Roxb.) Wight et Arn. (M. tenacissima) is considered as an anti-cancer medicine in the traditional Chinese medicine (TCM), which is extensively adopted in clinical application since it has great therapeutic effects. Currently, although a number of articles have examined M. tenacissima in terms of its pharmacology and quality control, few of them investigated the in vivo process of the M. tenacissima active ingredients. Previously, we have studied the pharmacokinetics of 8 active ingredients after oral administration of M. tenacissima extracts in rats plasma. This study constructed a new scientific ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) approach to simultaneously quantify the contents of Tenacissosides B, G, H, I, cryptochlorogenic acid, chlorogenic acid, neochlorogenic acid and caffeic acid in rats administered with M. tenacissima extract orally. Thereafter, the proposed approach was used successfully for investigating the distributions of those 8 analytes in rat tissues, with digoxin being used as an internal control. The Eclipse Plus C18 RRHD column was used for determination at the 30°C column temperature. The mobile phase system consisted of acetonitrile and water (supplemented with 0.1% formic acid) at optimal gradient elution conditions. Afterwards, this approach was validated according to the requirements for the analysis of biological samples developed by the US Food and Drug Administration (FDA), including precision, accuracy, stability and matrix effects. Based on tissue distribution analysis, those eight analytes showed rapid distribution within all the tested tissues. With regard to organic acid distribution, it followed the order below, stomach> liver> kidney> small intestine >lung> spleen > heart, whereas for the four steroids, they followed the order below, stomach >lung> spleen> small intestine > liver > kidney > heart. Moreover, the present study can lay theoretical foundation for the use and development of M. tenacissima in clinical practice.