In vitro and vivo anti-tumor activity and mechanisms of the new cryptotanshinone derivative 11 against hepatocellular carcinoma.

Global burden of hepatocellular carcinoma (HCC) is increasing. Chemotherapy and immunotherapy are the prevailing options for therapy. Developing new therapeutic strategies for HCC patients is still highly desirable. Recent studies demonstrate that cryptotanshinone is capable of inhibiting tumor growth in HCC and induces antitumor immunity in vitro. In our previous research, we discovered a new cryptotanshinone derivative 11 as an effective immunoregulatory enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) inhibitor. This study aims to evaluate its in vitro and in vivo antitumor activity against hepatocellular carcinoma. 11 displayed robust anti-proliferative activity against HCC cell lines and promoted apoptosis of HCC cell line through the mitochondrial-mediated apoptotic pathway. In H22 tumor-bearing mice models, 11 exhibited significant in vivo anti-tumor activity with different administration routes. And no obvious toxicity was observed. RNA-seq analysis demonstrated the differential expressed genes and alteration of key pathways associated with immune responses after administration of 11. Up-regulation of anti-tumor cytokines and down-regulation of cytokines that promote tumor growth were indicated and further validated. Our study demonstrates that 11 exhibits promising anti-tumor activity both in vitro and in vivo against hepatocellular carcinoma cancer. It is a lead compound for HCC immunotherapy and is worthy for further development.

Design, synthesis and biological evaluation of a new class of Hsp90 inhibitors vibsanin C derivatives.

Hsp90, an ATP-dependent chaperone that is essential for a wide range of protein assembly and folding processes, has long been recognized as a potential target for cancer. Hsp90 has more recently been identified as having a significant pathogenic role in viral infection, neurodegenerative disease, and inflammation, therefore, the development of the agents to inhibit the chaperone could potentially treat such intractable diseases. Here, on the basis of primary structure-activity relationships and docking analysis, a series of novel vibsanin C analogues with an emphasis on the C18 position was first designed, synthesized and biologically evaluated. The most effective Hsp90 inhibitory activity among these analogues was demonstrated by 29 and 31, with IC50 values of 0.39 and 0.27 µM respectively. Direct interaction between Hsp90 and its inhibitors were further confirmed. Mechanism studies indicated that 29 promoted HL-60 cell apoptosis by mitochondrial-mediated apoptosis pathway. In addition, 29 suppressed tumor growth in the H22 tumor-bearing mice model and revealed low acute toxicity in mice (LD50 > 500 mg/kg), suggesting its potential for further investigations.

Transgelin-2 contributes to proliferation and progression of hepatocellular carcinoma via regulating Annexin A2.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, but its pathogenesis is not clear. This study found that the expression of TAGLN2 mRNA and protein in HCC was higher than that in adjacent tissues. TCGA database analysis further confirmed this result, and found that the expression of TAGLN2 was positively correlated with the prognosis of HCC, suggesting that TAGLN2 may be a tumor promoter gene. Then the TAGLN2-Annexin A2 (ANXA2) interaction and NF-κB signaling pathway were further clarified during the invasion and metastasis of HCC. This mechanism provides a theoretical basis for further finding molecular targets and drug targets related to HCC metastasis.