Pulsatilla saponin D regulates ras-related C3 botulinum toxin substrate 3 (RAC3) to overcome resistance to paclitaxel in lung adenocarcinoma cells.

BACKGROUND: Paclitaxel, a tubulin-binding agent, is a Food and Drug Administration-approved first-line drug for the treatment of non-small cell lung cancer (NSCLC), for both squamous and non-squamous cell lung carcinoma, with paclitaxel/carboplatin + bevacizumab a common chemotherapy regimen for stage IV non-squamous NSCLC; however, primary or acquired resistance to paclitaxel is gradually increasing, leading to treatment failure. METHODS: Our results show that Ras-related C3 botulinum toxin substrate 3 (RAC3) is overexpressed in cultured paclitaxel-resistant cells and that RAC3 expression levels are negatively correlated with sensitivity of lung adenocarcinoma cells to paclitaxel. Pulsatilla saponin D could inhibit RAC3 expression, and we hypothesize that it may block paclitaxel resistance. Further, we found that treatment with paclitaxel combined with Pulsatilla saponin D, can overcome lung adenocarcinoma cell resistance to paclitaxel alone in cell culture and mouse xenograft models.

[Effect of Met kinase inhibitor BMS-777607 on proliferation and apoptosis of tongue cell line CAL 27 squamous cell carcinoma].

PURPOSE: To investigate the effect of Met kinase inhibitor BMS-777607 on proliferation and apoptosis of tongue squamous cell carcinoma cell line CAL27. METHODS: The effect of BMS-777607 on proliferation of CAL27 was detected by MTT method, clone formation assay and EdU cell imaging. Morphological changes of apoptosis of CAL27 cells induced by BMS-777607 were observed by Heochst33342 staining. JC-1 staining was used to detect the changes of mitochondrial membrane potential of CAL27 cells treated with BMS-777607. Western blot was used to detect the effect of BMS-777607 on the expression of proliferation protein Akt, p-Akt and apoptosis-related proteins Bcl-2, Cleaved caspase-3, Bax and Parp in CAL27 cells. The data were analyzed using SPSS 22.0 software package. RESULTS: BMS-777607 inhibited proliferation and promoted apoptosis of CAL27 cells in a concentration-dependent manner（P＜0.05）. It also inhibited the expression of Bcl-2 and p-Akt and promoted the expression of Bax, Cleaved caspase-3 and Parp protein (P＜0.05). CONCLUSIONS: BMS-777607 can inhibit proliferation and promote apoptosis of CAL27 cells.

Artesunate Regulates Neurite Outgrowth Inhibitor Protein B Receptor to Overcome Resistance to Sorafenib in Hepatocellular Carcinoma Cells.

The multireceptor tyrosine kinase inhibitor sorafenib is a Food and Drug Administration-approved first-line drug for the treatment of advanced liver cancer that can reportedly extend overall survival in patients with advanced hepatocellular carcinoma (HCC). Primary and acquired resistance to sorafenib are gradually increasing however, leading to failure of HCC treatment with sorafenib. It is therefore crucial to study the potential mechanism of sorafenib resistance. The results of the current study indicate that neurite outgrowth inhibitor protein B receptor (NgBR) is overexpressed in cultured sorafenib-resistant cells, and that its expression is negatively correlated with the sensitivity of liver cancer cells to sorafenib. Artesunate can inhibit the expression of NgBR, and it may block sorafenib resistance. Herein we report that sorafenib treatment in combination with artesunate overcomes HCC resistance to sorafenib alone in a cell culture model.

Long non-coding RNA LINC00152 promotes tumorigenesis via sponging miR-193b-3p in osteosarcoma.

The majority of the human genome has been revealed to be non-protein-coding, which are transcribed into noncoding RNAs (ncRNA), RNAs which are not translated into protein. Long non-coding RNAs (lncRNAs), including LINC00152, may be associated with the pathogenesis of different types of cancer. LINC00152 serves as an endogenous sponge by binding to micro-RNAs (miRNAs) and inhibiting their activity. The current study revealed that LINC00152 is overexpressed in osteosarcoma cells, leading to increased cell proliferation, and decreased G0/G1 cell cycle arrest and apoptosis. The binding of miR-193b-3p to LINC00152 was demonstrated by dual-luciferase assay, and led to miR-193b-3p downregulation in osteosarcoma cells. Knockdown of LINC00152 revealed an antitumorigenic effect by reducing cell proliferation and increasing G0/G1 arrest and apoptosis. Inhibiting miR-193b-3p reversed the effects of LINC00152 knockdown. These results suggested that LINC00152 binds to miR-193b-3p and reduces its expression level, leading to increased cell proliferation and decreased G0/G1 cell cycle arrest and apoptosis in osteosarcoma cells.

Experimental research on preventing mechanical phlebitis arising from indwelling needles in intravenous therapy by external application of mirabilite.

Various types of complications arising from intravenous indwelling needles have become a challenge in clinical care. It is urgent to seek a simple and cost-effective method for prevention and treatment of phlebitis. We investigated the roles of mirabilite in preventing and treating phlebitis caused by intravenous indwelling needles and provide guidance for prevention and treatment of mechanical phlebitis caused by intravenous indwelling needles. A total of 57 healthy congeneric big-eared New Zealand rabbits were randomly divided into 3 groups: blank control, indwelling needle, and group with external application of mirabilite. The ear vein of each rabbit was punctured with an intravenous indwelling needle. The ear vein specimens were taken at 3, 5, and 7 days after indwelling. The hematoxylin and eosin stained pathological tissue sections of the ear veins of the rabbits in each group were observed. The expression levels of IL-1 and IL-6, and tumour necrosis factor-α (TNF-α) in the vascular tissue of the ear veins of the rabbits in each group were detected with the immunofluorescence method. In the blank control group, there was no inflammatory cellular infiltration and no proliferation of fibrous tissue around the vascular wall. With the increase of the indwelling time, proliferation of fibrous tissue in vascular wall, increased inflammatory cellular infiltration and organized thrombus in the vascular tissue occurred in the ear veins of the rabbits in the indwelling needle group and group with external application of mirabilite. Compared with the indwelling needle group, the group with external application of mirabilite had significantly decreased fibrous tissue in the vascular wall and significantly decreased inflammatory cellular infiltration. At the same point in indwelling time, the expression levels of IL-1, IL-6, and TNF-α in the indwelling needle and group with external application of mirabilite were significantly higher than that in the blank control group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α in the group with external application of mirabilite were lower than that in the indwelling needle group (P<0.05). The expression levels of IL-1, IL-6, and TNF-α are positively correlated with the indwelling time within the same group at different points in time. In conclusion, external application of mirabilite can significantly decrease infiltration of venous inflammatory cells of the rabbit ear margin, proliferation of fibrous tissue and thrombosis in the vascular wall, significant decrease the expression levels of IL-1, IL-6, and TNF-α in the mechanical phlebitis caused by intravenous indwelling needles, and decrease the inflammatory responses of the ear veins of rabbits.

Genetic polymorphisms in the TERT-CLPTM1L region and lung cancer susceptibility in Chinese males.

The objective of the present study was to analyze the relationship between genetic polymorphisms of the rs2736098 locus of the telomerase reverse transcriptase (TERT) gene and the rs401681 locus of the cleft lip and palate transmembrane protein 1 (CLPTM1L) gene and the risk of developing lung cancer in males in Jinzhou. A total of 214 lung cancer patients who were admitted in Jinzhou Medical University were analyzed, and 216 healthy males were selected as controls. Venous blood from all subjects and data on relevant risk factors were collected. DNA was extracted from peripheral blood by the phenol-chloroform method. Real-time fluorescent quantitative PCR (TaqMan real-time PCR) was used for DNA amplification. The genotyping results of the genetic polymorphisms of the TERT rs2736098 and CLPTM1L rs401681 loci were detected. The risk of developing lung cancer in the population with the TERT rs2736098 locus carrying the T allele was 1.614 times that with the TERT rs2736098 locus carrying the C allele after adjustment of the age factor. The risk of developing lung cancer in the population carrying the TT mutant genotype and the CT genotype increased significantly compared with that carrying the CC wild genotype [odds ratio (OR)=1.815, 95% CI=1.132-2.957; OR=2.417, 95% CI=1.158-4.943]. Based on a comparison between the combination of the two mutant genotypes (CT+TT) and the wild homozygous genotype (CC), the mutant genotype increased the risk of developing lung cancer (OR=1.955, 95% CI=1.213-3.157). The risk of developing lung cancer in the population with the CLPTM1L rs401681 locus carrying the T allele was 1.399 times that carrying the C allele (OR=1.343, 95% CI=1.035-1.978). The population with the TERT rs2736098 locus carrying the mutant genotype (CT+TT) was associated with the number of tumors (OR=0.553, 95% CI=0.236-0.928). In conclusion, in males, the TERT rs2736098 and CLPTM1L rs401681 T alleles are the susceptibility factors for developing lung cancer. Individuals, including the smoking population, who carry both the TERT rs2736098 and CLPTM1L rs401681 T alleles are more likely to develop lung cancer.

GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS axis in hepatocellular carcinoma.

5-FU is a common first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma. However the development of acquired resistance to 5-FU confines its clinical usages. Although this phenomenon has been the subject of intense investigation, the exact mechanism of acquired resistance to 5-FU remains elusive. Here, we report that over-expression of GRP78 contributes to acquired resistance to 5-FU in HCC by up-regulating the c-Src/LSF/TS axis. Moreover, we found that the resistance to 5-FU conferred by GRP78 is mediated by its ATPase domain. The ATPase domain differentially increased the expression of LSF, TS and promoted the phosphorylation of ERK and Akt. We further identified that GRP78 interacts physically with c-Src through its ATPase domain and promotes the phosphorylation of c-Src, which in turn increases the expression of LSF in the nucleus. Together, GRP78 confers the resistance to 5-FU by up-regulating the c-Src/LSF/TS axis via its ATPase domain.