TPGS-1000 exhibits potent anticancer activity for hepatocellular carcinoma in vitro and in vivo.

D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS1000) is the most active water-soluble derivative of vitamin E and has been widely used as a carrier of solvents, plasticizers, emulsifiers, absorbent agents and refractory drug delivery systems. However, its anti-hepatocellular carcinoma (HCC) properties have not been explored. HCC cells were treated with different concentrations of TPGS1000. Cell survival was tested by CCK8 assay, and cell migration was tested by wound healing and Transwell assay. EdU staining verified cell proliferation, and signalling pathway was assayed by Western blot analysis. The BALB/c-nu mouse xenograft model was established to test HCC cell growth in vivo. In vitro TPGS1000 significantly inhibited the viability and mobility of HCC cells (HepG2, Hep3B and Huh7) in a dose-dependent manner. Cell cycle analysis indicated that TPGS1000 treatment arrested the HCC cell cycle in the G0/G1 phase, and induction of cell apoptosis was confirmed by TUNEL and Annexin V-7-AAD staining. Further pharmacological analysis indicated that collapse of the transmembrane potential of mitochondria, increased ROS generation, PARP-induced cell apoptosis and FoxM1-p21-mediated cell cycle arresting, were involved in the anti-HCC activity of TPGS1000. Moreover, treatment in vivo with TPGS1000 effectively impaired the growth of HCC xenografts in nude mice.

Radiosensitization effect of hsa-miR-138-2-3p on human laryngeal cancer stem cells.

BACKGROUND: Treatments that target cancer stem cells play an important role in the controlling and eliminating of tumor initiation as well as in development, progression, and chemotherapy/radiotherapy resistance. In our previous study, we cultured and harvested human laryngeal cancer stem cells (CSCs) and applied microRNA biochips to screen differentially expressed miRNAs that were related to radiation tolerance in irradiated human laryngeal CSCs. According to the predicted genes and pathways of differential miRNAs target, down-regulated expression of hsa-miR-138-2-3p under radiation was thought to play a key role in enhancing the radio-sensitivity in human laryngeal squamous cancer stem cells. METHOD: To investigate the radiational enhancement of hsa-miR-138-2-3p, we transfected hsa-miR-138-2-3p mimics that were synthesized based on the sequences of hsa-miR-138-2-3p in vitrointo human laryngeal CSCs (Hep-2, M2e, and TU212 cell lines) to make hsa-miR-138-2-3p overexpressed, and the tumorous specialities of CSCs, like cell proliferation, invasion, apoptosis, cell cycle arrest, and DNA damage were evaluated by CCK-8 assay, clone formation assay, invasion assay, flow cytometry, and comet assay. Furthermore, we explored the signal transduction pathways that regulated the cancer stem cell initiation, development, invasion, apoptosis and cell cycle arrest, which were controlled by hsa-miR-138-2-3p. RESULT: Overexpressed hsa-miR-138-2-3p played a key role in many anti-cancer biological processes in human laryngeal CSCs: (1) it decreased laryngeal CSCs proliferation and invasion in response to radiotherapy; (2) it increased the proportion of early and late apoptosis in laryngeal CSCs after radiation, raised G1 phase arrest in laryngeal CSCs after radiation, and decreased the proportion of S stage cells of cell cycle that were related to radio-resistance in laryngeal CSCs; (3) it down-regulated the expression of ß-catenin in Wnt signal pathway that was related to the tolerance of laryngeal CSCs to radiotherapy; (4) it down-regulated the expression of YAP1 in Hippo signal pathway that regulated cell proliferation, invasion and apoptosis; (5) it up-regulated the expression of p38 and JNK1 in MAPK signal pathway that was concerned to radio-sensitivity. CONCLUSION: In the present study, it was found that hsa-miR-138-2-3p regulated the Wnt/ß-catenin pathways, the Hippo/YAP1 pathways, and the MAPK/p38/JNK1 pathways that were involved in cell proliferation, invasion, apoptosis, cell cycle arrest, radio-resistance and radio-sensitivity in laryngeal CSCs. These results will be useful for a better understanding of the cell biology of hsa-miR-138-2-3p in laryngeal CSCs, and for serving hsa-miR-138-2-3p as a promising biomarker and as a target for diagnosis and for novel anti-cancer therapies for laryngeal cancers.

Downregulation of caveolin-1 increases the sensitivity of drug-resistant colorectal cancer HCT116 cells to 5-fluorouracil.

Colorectal cancer is the third most common type of cancer in men and women. Chemotherapy is an important treatment strategy for patients with terminal stage cancer. However, the development of drug resistance hampers the effectiveness of chemotherapy. Therefore, an effective therapeutic approach to target chemoresistance-associated cellular molecules is required. In the present study, drug-resistant human colorectal cancer HCT116 cells were developed by treating HCT116 cells with increasing concentrations of 5-fluorouracil (5-FU). The present study indicated that the drug-resistance cells (DRC) were resistant to 5-FU compared with parental HCT116 cells by detecting cell survival using an MTT assay. Additionally, the expression of the chemoresistance-associated protein caveolin-1 (Cav-1) was assessed by reverse transcription-quantitative polymerase chain reaction and western blotting. The results revealed that the Cav-1 expression level was significantly higher in DRC compared with that in the parental HCT116 cells. Next, Cav-1 was silenced by small interfering RNA (siRNA) or was inhibited with its specific inhibitor methyl ß-cyclodextrin (MCD). MTT assay demonstrated that Cav-1 siRNA and MCD resensitized DRC to 5-FU. These data reveal that Cav-1 was involved in the development of resistance, suggesting that Cav-1 is a potential target for the treatment of colorectal cancer chemoresistance. In addition, 5-FU combined with Cav-1 siRNA or its specific inhibitor may increase the effectiveness of the treatment strategy.

[To investigate the relationship of alcohol intake and hepatocellular carcinoma among patients with hepatitis B virus infection].

OBJECTIVE: To investigate the relationship of alcohol intake and hepatocellular carcinoma among patients with hepatitis B virus infection. METHODS: A total of 553 patients with HCC and 160 control subjects affected with hepatitis B virus were recruited. Serum virology, serum biochemistry, as well as demographic information were studied. Finally, risk factors were selected by stepwise Logistic regression analyse. Odds ratios (ORs) were estimated for each risk factor. According to alcohol intake, HCC patients were divided into three groups,then to observe the differences between them. RESULTS: Elevated AST, GGT, ALP and AFP levels were seen more frequently in the HCC case groups compared to control group (P < 0.05). Multivariate analysis revealed that heavy alcohol use, smoking, positive family history of liver cancer is associated with HCC development among patients with hepatitis B virus infection. Significantly increased risk was found among patients for heavy alcohol use [A = 2.66 (2.01-3.50)] and for smoking [A = 2.51 (1.66-3.80)] and for positive family history of liver cancer [A = 1.64 (1.04-2.59)]. Compared to patients who did not have alcohol use, elevated GGT and ALP were seen more frequently in patients who had alcohol use either mild or heavy (P < 0.05). CONCLUSIONS: Heavy alcohol use, smoking, positive family history of liver cancer is positive correlation with HCC development among patients with hepatitis B virus infection in China. In patients with hepatitis B virus infection who also has history of heavy alcohol, the most risk factor of HCC is hepatitis B virus infection, not alcohol.