National reimbursement listing determinants of new cancer drugs: a retrospective analysis of 58 cancer treatment appraisals in 2007–2016 in South Korea

<p><b>Background:</b> Since the positive-list system was introduced, concerns have been raised over restricting access to new cancer drugs in Korea. Policy changes in the decision-making process, such as risk-sharing agreement and the waiver of pharmacoeconomic data submission, were implemented to improve access to oncology medicines, and other factors are also involved in the reimbursement for cancer drugs. The aim of this study is to investigate the reimbursement listing determinants of new cancer drugs in Korea.</p> <p><b>Methods:</b> All cancer treatment appraisals of Health Insurance Review and Assessment during 2007–2016 were analyzed based on 13 independent variables (comparative effectiveness, cost-effectiveness, drug-price comparison, oncology-specific policy, and innovation such as new mode of action). Univariate and multivariate logistic analyses were conducted.</p> <p><b>Results:</b> Of 58 analyzed submissions, 40% were listed in the national reimbursement formulary. In univariate analysis, four variables were related to listing: comparative effectiveness, drug-price comparison, new mode of action, and risk-sharing agreement. In multivariate logistic analysis, three variables significantly increased the likelihood of listing: clinical improvement, below alternative’s price, and risk-sharing arrangement. Cancer drug’s listing increased from 17% to 47% after risk-sharing agreement implementation.</p> <p><b>Conclusion:</b> Clinical improvement, cost-effectiveness, and RSA application are critical to successful national reimbursement listing.</p

Inhibitory effects of water and methanol extracts of <i>N</i>. <i>nucifera</i> leaves on VEGF-induced ROS generation in HUVECs.

<p><b>(a)</b> Serum-starved cells were pretreated with extracts for 30 min and then treated with VEGF (20 ng ml⁻¹) for 15 min. ROS generation was determined by measuring DCF-DA fluorescence. The fluorescence intensity was determined by analyzing the captured images with the Image Inside program. <b>(b)</b> Data are mean ± SD values from four independent experiments. *: p<0.05 compared with untreated control; ^#: p<0.05 compared with VEGF-treated CAM samples. All tested concentrations (10, 50, and 100 μg ml⁻¹) of the water as well as the methanol extract display statistically significant difference with respect to each other.</p

Inhibitory effects of water and methanol extracts of <i>N</i>. <i>nucifera</i> leaves on tube formation in HUVECs.

<p><b>(a)</b> HUVECs (5 x 10⁴ cells) were plated on wells that had been previously coated with 40 μL of growth factor-reduced Matrigel basement membrane matrix. Cells were then treated with extracts in the presence of VEGF (20 ng ml⁻¹). After 14 h, cells were photographed with a digital camera under a phase contrast microscope at 40x magnification. <b>(b)</b>The bar graph represents the relative area covered by the tube network, and data are shown as the mean ± SD. *: p<0.05 compared with untreated control; ^#: p<0.05 compared with VEGF-treated group.</p

Inhibitory effects of water and methanol extracts of <i>N</i>. <i>nucifera</i> leaves on VEGF-induced angiogenesis.

<p><b>(a)</b> The CAM of a 10-d-old chick embryo was separately exposed to PBS (control) and VEGF (20 ng ml⁻¹) by means of filter disks. After 30 min, extracts were introduced on top of the CAMs. After 72 h of incubation, the CAM tissue directly beneath each filter disk was resected, and digital images of the CAM sections were captured. <b>(b)</b> The bar graph represents the number of new branches formed from existing blood vessels. Photographs were imported into an image software program to visualize the new vessel branch points. Data are shown as the mean ± SD. *: p<0.05 compared with untreated control; ^#: p<0.05 compared with VEGF-treated CAM samples. None of the tested concentrations (10, 50, and 100 μg ml⁻¹) of the water as well as the methanol extract display statistically significant differences with respect to each other.</p

Synthesis, Anticancer and Antioxidant Activity of Novel Carbazole-based Thiazole Derivatives

<div><p>GRAPHICAL ABSTRACT</p><p></p></div

Additional file 1 of siRNA treatment targeting integrin α11 overexpressed via EZH2-driven axis inhibits drug-resistant breast cancer progression

Supplementary Material

The Anti-Tumor Activity of Succinyl Macrolactin A Is Mediated through the β-Catenin Destruction Complex via the Suppression of Tankyrase and PI3K/Akt

<div><p>Accumulated gene mutations in cancer suggest that multi-targeted suppression of affected signaling networks is a promising strategy for cancer treatment. In the present study, we report that 7-<i>O</i>-succinyl macrolactin A (SMA) suppresses tumor growth by stabilizing the β-catenin destruction complex, which was achieved through inhibition of regulatory components associated with the complex. SMA significantly reduced the activities of PI3K/Akt, which corresponded with a decrease in GSK3β phosphorylation, an increase in β-catenin phosphorylation, and a reduction in nuclear β-catenin content in HT29 human colon cancer cells. At the same time, the activity of tankyrase, which inhibits the β-catenin destruction complex by destabilizing the axin level, was suppressed by SMA. Despite the low potency of SMA against tankyrase activity (IC₅₀ of 50.1 μM and 15.5 μM for tankyrase 1 and 2, respectively) compared to XAV939 (IC₅₀ of 11 nM for tankyrase 1), a selective and potent tankyrase inhibitor, SMA had strong inhibitory effects on β-catenin-dependent TCF/LEF1 transcriptional activity (IC₅₀ of 39.8 nM), which were similar to that of XAV939 (IC₅₀ of 28.1 nM). In addition to suppressing the colony forming ability of colon cancer cells <i>in vitro</i>, SMA significantly inhibited tumor growth in CT26 syngenic and HT29 xenograft mouse tumor models. Furthermore, treating mice with SMA in combination with 5-FU in a colon cancer xenograft model or with cisplatin in an A549 lung cancer xenograft model resulted in greater anti-tumor activity than did treatment with the drugs alone. In the xenograft tumor tissues, SMA dose-dependently inhibited nuclear β-catenin along with reductions in GSK3β phosphorylation and increases in axin levels. These results suggest that SMA is a possible candidate as an effective anti-cancer agent alone or in combination with cytotoxic chemotherapeutic drugs, such as 5-FU and cisplatin, and that the mode of action for SMA involves stabilization of the β-catenin destruction complex through inhibition of tankyrase and the PI3K/Akt signaling pathway.</p></div

Anti-tumor effect of SMA alone and in combination with cisplatin in the A549 human non-small cell lung cancer xenograft model.

<p>(A) Tumor-bearing BALB/c nude mice were treated intraperitoneally with SMA, cisplatin, or both, for 7 consecutive days following a 3-day intermission as one cycle. Six mice per group were used. (B) Tumor growth was monitored by measuring tumor size. (C) Twenty eight days after commencing three cycles of treatment, tumor tissues were isolated and the tumor weights were measured. (D-F) Western blotting of tumor tissues on signaling molecule activation (D), nuclear localization of β-catenin (E), and protein expression of target genes (F). C and N in (E) represent cytosol and nucleus, respectively. ^*<i>P</i><0.05 vs. vehicle-treated controls. ^#<i>P</i><0.05 vs. cisplatin alone-treated animals. ^$<i>P</i><0.05 vs. SMA alone-treated animals.</p

SMA facilitated GSK3β activity by inhibiting PI3K/Akt and tankyrase in HT29 colon cancer cells.

<p>(A) Western blot analyses of phosphorylation of PI3K, Akt, GSK3β, and β-catenin and the expression level of axin in SMA- or XAV939-treated HT29 cells. ^*<i>P</i><0.05 vs. vehicle-treated controls. (B) Tankyrase activity was measured using the Tankyrase 1 Colorimetric Activity Assay Kit and TNKS2 Histone Ribosylation Colorimetric Assay Kit. XAV939 was used as a positive control. ^*<i>P</i><0.05 vs. vehicle-treated control cells. (C) HT29 cells transfected with TCF/LEF-1-Luc reporter gene were pretreated with vehicle or SMA 1 hour prior to being treated with serum.</p

SMA inhibited nuclear translocation of β-catenin and TCF/LEF1 transcriptional activity in HT29 human colon cancer cells.

<p>(A-B) Immunofluorescence confocal images of β-catenin in HT29 cells treated with serum (A) or Wnt3α (B). β-Catenin and cell nuclei are stained green and blue, respectively. The images are representative of three independent experiments. (C) Western blots showing the levels of β-catenin in the cytosolic, nuclear, and total fractions of HT29 cells. The bar graph shows the relative band intensities of β-catenin. (D) HT29 cells were transfected with TCF/LEF-1-Luc reporter gene and pretreated with vehicle or SMA 1 hour prior to treatment with serum or Wnt3. ^*<i>P</i><0.05 vs. vehicle-treated control cells. ^#<i>P</i><0.05 vs. serum- or Wnt3α-treated cells. (E) The nuclear protein expressions of cyclin D1 and c-myc were inhibited in HT29 cells by SMA in a concentration-dependent manner. ^*<i>P</i><0.05 vs. vehicle-treated control cells. ^#<i>P</i><0.05 vs. serum-treated cells (n = 3).</p