Tumor-initiating cell (TIC) is a subpopulation of cells in tumors that are responsible for tumor initiation and progression. Recent studies indicate that hepatocellular carcinoma-initiating cells (HCICs) confer the high malignancy, recurrence and multi-drug resistance in hepatocellular carcinoma (HCC). In this study, we found that Icaritin, a prenylflavonoid derivative from Epimedium Genus, inhibited malignant growth of HCICs. Icaritin decreased the proportion of EpCAM-positive (a HCICs marker) cells, suppressed tumorsphere formation in vitro and tumor formation in vivo. We also found that Icaritin reduced expression of Interleukin-6 Receptors (IL-6Rs), attenuated both constitutive and IL-6-induced phosphorylation of Janus-activated kinases 2 (Jak2) and Signal transducer and activator of transcription 3 (Stat3), and inhibited Stat3 downstream genes, such as Bmi-1 and Oct4. The inhibitory activity of Icaritin in HCICs was augmented by siRNA-mediated silencing of Stat3 but attenuated by constitutive activation of Stat3. Taken together, our results indicate that Icaritin is able to inhibit malignant growth of HCICs and suggest that Icaritin may be developed into a novel therapeutic agent for effective treatment of HCC.

The transcription factor c-Myc plays critical roles in cancer development and progression through regulating expression of targeted genes. Lactate dehydrogenase A (LDHA), which catalyzes the conversion of l-lactate to pyruvate in the final step of anaerobic glycolysis, is frequently upregulated in pancreatic cancer. However, little is known about the effects of c-Myc–LDHA axis in the progression of pancreatic cancer. In this study, we found that c-Myc and LDHA are concomitantly overexpressed in pancreatic cancer cell lines and clinical specimens. c-Myc overexpression and LDHA overexpression were correlated with TNM stage and tumor size and indicated poor prognosis in patients with pancreatic cancer. Knockdown of c-Myc reduced the protein expression of LDHA, lactate production and glucose consumption, and silencing of LDHA mimicked this effect. Meanwhile, reduced c-Myc–LDHA signaling resulted in decreased tumor growth and metastasis in pancreatic cancer. Treatment with 2-Deoxy-d-glucose, an inhibitor of anaerobic glycolysis, completely blocked the oncogenic roles of c-Myc–LDHA signaling. Taken together, dysregulated c-Myc–LDHA signaling plays important roles in aerobic glycolysis and facilitates tumor progression of pancreatic cancer.

An efficient method for the rapid construction of carbo- and heterocycles has been developed using radical relay cyclizations initiated by alkoxy radicals. Linear substrates were cyclized to form a wide range of cyclopentane, pyrrolidine, tetrahydropyran, and tetrahydrofuran derivatives in excellent yields. This methodology was utilized as a key step in the synthesis of the tetrahydrofuran fragment in (-)-amphidinolide K.

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Icaritin, a hydrolytic product of icariin isolated from traditional Chinese herbal medicine genus Epimedium, has many pharmacological and biological activities. Here, we show that icaritin can effectively decrease tumor burden of murine B16F10 melanoma and MC38 colorectal tumors in a T-cell dependent manner. The treatment effects are associated with increased CD8 T-cell infiltration and increased effector memory T-cell frequency. In vivo depletion of CD8 T cell using an anti-CD8 monoclonal antibody abolished the antitumor effect, which supports the critical role of CD8 T cells during icaritin treatment. By analyzing immune cells in the tumor tissue, we found reduced frequency of CD11b + Gr1 + myeloid-derived suppression cells (MDSCs) infiltration and downregulation of PD-L1 expression on MDSCs after icaritin treatment. This was not limited to MDSCs, as icaritin also decreased the expression of PD-L1 on neutrophils. Importantly, the combination of anti-PD-1/CTLA-4 and icaritin significantly enhances antitumor ability and increases the efficacy of either treatment alone. Our findings reveal that icaritin induces antitumor immunity in a CD8 T-cell-dependent way and justify further investigation of combining immune checkpoint therapy to icaritin-based antitumor therapy.Keywords: CD8 T-cells accumulation r Combination immunotherapy r Icaritin r MDSCs r Melanoma Additional supporting information may be found online in the Supporting Information section at the end of the article.

Hydroxysafflor yellow A (HSYA) is a component of the flower Carthamus tinctorius L. The present investigation determines whether HSYA can modify the effects of hypoxia on vascular endothelial cells (EC) and its mechanisms. Human EC line (EAhy926) viability was determined using the MTT assay. EC cycle phase distribution was done with PI staining and flow cytometric analysis, and EC apoptosis was done by AnnexinV-FITC detection and the TUNEL assay. The protein levels of VEGF, Bcl-2, Bax, and HIF-1 alpha were determined by ELISA or Western blot analysis, and the mRNA expression of these genes by RT-PCR analysis. HIF-1 alpha transcriptional activity was measured using a reporter gene assay. HSYA improved cell viability under hypoxia in a concentration-dependent manner by attenuating its cycle arrest and inhibiting its apoptosis. HSYA upregulated the bcl-2/bax ratio, which is downregulated under hypoxia, increased VEGF protein concentration and VEGF mRNA expression and enhanced HIF-1 alpha protein accumulation and its transcriptional activity. In conclusion, HSAY could enhance the survival of ECs under hypoxia, which may be correlated with its effect of upregulating the bcl-2/bax ratio and promoting HIF-1 alpha protein accumulation, which increases VEGF. These findings provide evidence for the mechanisms by which HSYA maintains EC survival under hypoxia.

Radical relay cyclizations initiated by alkoxy radicals are a powerful tool for the rapid construction of substituted tetrahydrofurans. The scope of these relay cyclizations has been dramatically increased with the development of two strategies that utilize an oxygen atom in the substrate to accelerate the desired hydrogen atom transfer (HAT) over competing pathways. This has enabled a chemoselective 1,6-HAT over a competing 1,5-HAT. Furthermore, this allows for a chemoselective 1,5-HAT over competing direct cyclizations and β-fragmentations. Oxygen atom incorporation leads to a general increase in cyclization diastereoselectivity over carbon analogues. This chemoselective relay cyclization strategy was utilized in the improved synthesis of the tetrahydrofuran fragment in (−)-amphidinolide K.

Icaritin, a small molecule currently being investigated in phase III clinical trials in China (NCT03236636 and NCT03236649) for treatment of advanced hepatocellular carcinoma (HCC), is a prenylflavonoid derivative obtained from the Epimedium genus. Previously, it was found that Icaritin decreased the expression of PD‐L1, but its direct molecular targets and the underlying mechanisms have not been identified. In this study, we report the identification of IKK‐α as the protein target of Icaritin by biotin‐based affinity binding assay. The further mutagenesis assay has provided evidence that C46 and C178 in IKK‐α were essential amino acids for Icaritin binding to IKK‐α, revealing the binding sites of Icaritin to IKK‐α for the first time. Functionally, Icaritin inhibited the NF‐κB signalling pathway by blocking IKK complex formation, which led to decreased nuclear translocation of NF‐κB p65, and subsequent downregulation of PD‐L1 expression in a dose–dependent manner. More importantly, PD‐L1‐positive patients exhibited longer overall survival upon Icaritin therapy. Finally, Icaritin in combination with checkpoints antibodies, such as α‐PD‐1, has demonstrated much better efficacy than any single therapy in animal models. This is the first report that anticancer effects of Icaritin are mediated, at least in part, by impairing functions of IKK‐α.