Anticancer Activity of (±)-Kusunokinin Derivatives towards Cholangiocarcinoma Cells

Abstract

This study aimed to investigate the cytotoxicity and anticancer activity of (±)-kusunokinin derivatives ((±)-TTPG-A and (±)-TTPG-B). The cytotoxicity effect was performed on human cancer cells, including breast cancer, cholangiocarcinoma, colon and ovarian cancer-cells, compared with normal cells, using the MTT assay. Cell-cycle arrest and apoptosis were detected using flow-cytometry analysis. We found that (±)-TTPG-B exhibited the strongest cytotoxicity on aggressive breast-cancer (MDA-MB-468 and MDA-MB-231) and cholangiocarcinoma (KKU-M213), with an IC50 value of 0.43 ± 0.01, 1.83 ± 0.04 and 0.01 ± 0.001 µM, respectively. Interestingly, (±)-TTPG-A and (±)-TTPG-B exhibited less toxicity than (±)-kusunokinin (9.75 ± 0.39 µM) on L-929 cells (normal fibroblasts). Moreover, (±)-TTPG-A predominated the ell-cycle arrest at the S phase, while (±)-TTPG-B caused cell arrest at the G0/G1 phase, in the same way as (±)-kusunokinin in KKU-M213 cells. Both (±)-TTPG-A and (±)-TTPG-B induced apoptosis and multi-caspase activity more than (±)-kusunokinin. Taken together, we conclude that (±)-TTPG-A and (±)-TTPG-B have a strong anticancer effect on cholangiocarcinoma. Moreover, (±)-TTPG-B could be a potential candidate compound for breast cancer and cholangiocarcinoma in the future.

Trans-(±)-TTPG-B Attenuates Cell Cycle Progression and Inhibits Cell Proliferation on Cholangiocarcinoma Cells

“…(±)-TTPG-B had a greater cytotoxic and apoptotic induction effect than (±)-KU. In addition, (±)-ARC induced cell cycle arrest at the S phase, whereas (±)-TTPG-B caused cell arrest at the G0/G1 phase, which is the same as (±)-KU in KKU-M213 cells [13]. In contrast, in this study, half of the IC 50 values of (±)-TTPG-B, (±)-ARC, and (±)-KU caused cell cycle arrest at G0/G1 at 12 and 24 h. Therefore, we hypothesized that the specific target protein of these derivatives might be a protein associated with cell signaling and cell proliferation, which remains similar to (±)-KU.…”

“…Both (±)-TTPG-B and (±)-ARC were recently reported to have anticancer properties [13]. To predict the target protein of both (±)-KU compounds, molecular docking was employed similarly to previous studies [10,11].…”

“…Interestingly, (±)-TTPG-B showed a stronger cytotoxicity to CCA cells (KKU-M213) (IC 50 at 0.01 ± 0.001 µM) than (±)-KU (4.47 ± 0.04 µM) and (±)-ARC (0.07 ± 0.01 µM). Moreover, (±)-TTPG-B and (±)-ARC exhibited less toxicity than native (±)-KU on L-929 cells (normal fibroblasts) [13].…”