A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells.

["Yan Y", "Shi K", "Teng F", "Chen J", "Che J", "Dong X", "Lin N", "Zhang B"]

Acta pharmacologica Sinica 2020

Natural compound valepotriate exhibits inhibitory activity against a number of cancers, but the effect of valepotriate against pancreatic cancer is unclear, and the structure-activity relationship of valepotriate has not been characterized. In this study, we performed a structure-based similarity search and found 16 hit compounds. Among the 16 hits, (1S,6S,7R)-6-(acetyloxy)-1-[(3-methylbutanoyl)oxy]-4a,5,6,7a-tetrahydro-1H-spiro[cyclopenta[c]pyran-7,2'-oxiran]-4-ylmethyl 3-methylbutanoate (denoted as Amcp) exhibited superior anticancer activity against human pancreatic cancer BxPC-3 and SW1990 cells. The anti-proliferation activity of Amcp was validated in human pancreatic cancer BxPC-3 and SW1990 cells in vitro. Amcp more effectively induced apoptosis in BxPC-3 and SW1990 cells than gemcitabine. At a concentration of 15 μM, Amcp significantly suppressed the PI3K/AKT pathway and disrupted the mitochondrial membrane equilibrium through modulation of Noxa and Mcl-1 balance in both cell lines. Meanwhile, knockdown of Noxa substantially attenuated Amcp-induced reduction of cell viability and anti-apoptotic protein Mcl-1 level in BxPC-3 cells. In addition, Amcp showed synergistic anticancer effects when combined with gemcitabine in BxPC-3 cells. To conclude, this work not only suggests that Amcp possesses a dual-inhibitory activity towards PI3K/AKT pathway and Mcl-1, but also enlightens further development of bioactive valepotriate derivatives.

6 Figures Extracted

Fig. 1 PMC

Chemical structures of valepotriate and 5 hit compounds. Examples of five hit compounds obtained through a similarity search using (1R)-2,6,7,7a-tetr...

Fig. 2 PMC

Amcp inhibited the proliferation of human pancreatic cancer cells. a The chemical structure of Amcp. b The time- and dose-dependent inhibitory effe...

Fig. 3 PMC

Amcp induced apoptosis in pancreatic cancer cells. a Amcp induced apoptosis in BxPC-3 and SW1990 cells. Cells were treated with Amcp for 24 h before ...

Fig. 4 PMC

Amcp activated PI3K/AKT-regulated apoptotic proteins. a Cells were pretreated with the indicated concentrations of Z-VAD-FMK for 4 h and then culture...

Fig. 5 PMC

Amcp disrupted the mitochondrial membrane potential and affected mitochondrial proteins. a BxPC-3 and SW1990 cells were seeded into six-well plates a...

Fig. 6 PMC

The combination of Amcp and gemcitabine synergistically induced apoptosis in BxPC-3 cells. a BxPC-3 cells were treated with 0.625, 1.25, 2.5, or 5 µM...