No abstract

The Tithonia diversifolia methanolic extract (TDM), which showed antiproliferative activity against human glioblastoma U373 cells, with an IC50 value of 59.2±3.7 μg mL(-1), was passed through silica gel chromatography and successively eluted with different percentages of EtOAc/hexane. The 10-60% EtOAc/hexane subfractions, which exhibited a comparatively higher antiproliferative activity, were isolated, and then structural identification was proceeded with 1H nuclear magnetic resonance. The isolated compound was tagitinin C, a kind of sesquiterpenoid. The IC50 value was 6.1±0.1 μg mL(-1) in U373 treated with tagitinin C. In flow cytometric analysis and inhibition of pan-caspase, the results showed that the anti-glioblastoma effect was apoptosis-independent. In PARP, p-p38, ULK1, and LC3-II expression, the anti-glioblastoma induced by tagitinin C was likely via autophagy. In the ULK1 siRNA transfection experiment, autophagy blockade counteracted the suppression induced by tagitinin C. The result suggested that tagitinin C induces U373 cell death dependent upon autophagy under certain conditions.

Tagitinin C, a major sesquiterpenoid, was isolated from the leaves of Tithonia diversifolia. The high morbidity and mortality rate of hepatoma in Taiwan motivated our interest in the investigation of tagitinin C's mechanism against the human hepatocellular carcinoma. The methanolic extract of leaves of T. diversifolia (TDM) and tagitinin C were found to have cytotoxic activities against human hepatoma Hep-G2 cells in the MTT assay with IC(50) values of 40.0 ± 2.0 and 2.0 ± 0.1 μg/mL, respectively. This compound induced population increase in the sub-G(1) phase and S phase arrest. Treatment with tagitinin C isolated from TDM resulted in activation of both caspase 3 and caspase 8 which suggested that the antiproliferative effect of this compound was caspase-dependent apoptosis. Magnetic resonance techniques indicated that the tumorigenisity of xenografts derived from Hep-G2 cells was retarded by the delivery of tagitinin C (15 μg/mouse/day) relative to the control counterparts.

Chemotherapy efficacy is limited by intrinsic and acquired resistance in glioblastoma (GBM); hence, novel tactics are crucial. Survivin has been demonstrated as a key resistant factor in GBM because of its function in inhibiting apoptosis, regulating autophagy, and in promoting G₂/M cell cycle transition. Parthenolide has been reported to be an effective antitumor agent in a variety of tumor cells and decreases survivin level in leukemia cells. But the effect of parthenolide on survivin and the cell death process in GBM is still unknown. The aim of this study was to examine whether parthenolide had the potential to inhibit cell proliferation in the GBM cell line U373. The parthenolide-induced effects in relation to survivin suppression and cell death were further investigated. Our results showed that parthenolide substantially inhibited cell viability with IC₅₀ values of approximate 16 μM. Treatment with parthenolide at the dose of 16 μM led to considerable downregulation of survivin, G₂/M cell cycle arrest and Chk2 upregulation in cells. Parthenolide induced apoptosis in only a few cells and a slight increase in activated caspases 3 levels. By contrast, parthenolide induced a significant increase of intracellular autophagosomes and the expression of autophagy related proteins, including ULK1 and LC3 I/LC3 II, in the treated cells. These results suggested that parthenolide induced survivin inhibition, G₂/M cell cycle arrest, and triggered cell death through autophagic cell death in the GBM cell line.

Sesquiterpenoid tagitinin C, present in Tithonia diversifolia leaves, has been known to have anti-hepatoma properties. Therefore, we investigated the anti-metastatic potential of tagitinin C in xenograft models of hepatocellular carcinoma (HCC). We isolated tagitinin C from a methanolic extract of the leaves of T. diversifolia. HepG-2 and Huh 7 hepatoma cells were treated with tagitinin C, and cell viability, migration, and matrix metalloproteinase (MPP) activity were assessed using the 3-(4,5-dimethylthiozol-2-yl)-2,5-diphenyltetrazolium bromide assay, scratch migration assay, and MMP activity assay, respectively. We used magnetic resonance spectroscopy to determine the tumorigenicity of xenografts inoculated with Hep-G2 and Huh 7 cells. Tagitinin C was cytotoxic against Hep-G2 and Huh 7 cells, with IC50 values of 2.0 ± 0.1 µg/mL and 1.2 ± 0.1 µg/mL, respectively, and it showed an anti-metastatic effect in vitro. Additionally, MRS assays revealed that tagitinin C (15 g/mouse/day) reduced the tumorigenicity of Hep-G2 and Huh 7 cell xenografts. Tagitinin C demonstrated significant antitumor and anti-metastatic activity in the two human hepatoma cell lines. Tagitinin C might be used as an alternative or auxiliary therapy for the treatment of HCC, and its effect should be further investigated in clinical settings.