Advances of antitumor drug discovery in traditional Chinese medicine and natural active products by using multi-active components combination.

The antitumor efficacy of Chinese herbal medicines has been widely recognized. Leading compounds such as sterols, glycosides, flavonoids, alkaloids, terpenoids, phenylpropanoids, and polyketides constitute their complex active components. The antitumor monomers derived from Chinese medicine possess an attractive anticancer activity. However, their use was limited by low bioavailability, significant toxicity, and side effects, hindering their clinical applications. Recently, new chemical entities have been designed and synthesized by combining natural drugs with other small drug molecules or active moieties to improve the antitumor activity and selectivity, and reduce side effects. Such a novel conjugated drug that can interact with several vital biological targets in cells may have a more significant or synergistic anticancer activity than a single-molecule drug. In addition, antitumor conjugates could be obtained by combining pharmacophores containing two or more known drugs or leading compounds. Based on these studies, the new drug research and development could be greatly shortened. This study reviews the research progress of conjugates with antitumor activity based on Chinese herbal medicine. It is expected to serve as a valuable reference to antitumor drug research and clinical application of traditional Chinese medicine.

Conjugating 4ß-NH-(5-Aminoindazole)-podophyllotoxin and Galectin-1-Targeted Aptamer for Synergistic Chemo-Immunotherapy of Hepatocellular Carcinoma.

By conjugating a chemotherapeutic candidate drug 4ß-NH-(5-aminoindazole)-podophyllotoxin (ßIZP) and an immunosuppressive protein galectin-1 targeted aptamer AP74, a chemo-immunotherapy molecule (AP74-ßIZP) is developed against liver cancer. AP74-ßIZP can target galectin-1 and enrich the tumor microenvironment to improve the tumor inhibition ratio by 6.3%, higher than that of ßIZP in a HepG2 xenograft model. In safety evaluation, ßIZP cannot be released from AP74-ßIZP in normal tissues with low glutathione level. Therefore, the degrees of organs injury and myelosuppression after the treatment with AP74-ßIZP are lower than those with ßIZP. After 21 d treatment at a drug dose of 5 mg kg-1 , AP74-ßIZP does not cause weight loss in mice, while the weight is significantly reduced by 24% and 14% from oxaliplatin and ßIZP, respectively. In immune synergy, AP74-IZP enhances CD4/CD8 cell infiltration to promote the expression of cell factor (i.e., IL-2, TNF-α, and IFN-γ), which further improves the antitumor activity. The tumor inhibition ratio of AP74-ßIZP is 70.2%, which is higher than that of AP74 (35.2%) and ßIZP (48.8%). Because of the dual effects of chemotherapy and immunotherapy, AP74-ßIZP exhibits superior activity and lower toxicity. The approach developed in this work could be applicable to other chemotherapy drugs.