Invivo anti-cancer activity of 10-methyl-aplog-1, a simplified analog of aplysiatoxin, and its possible signaling pathway associated with G1 arrest.

Naturally occurring protein kinase C (PKC) activators such as phorbol esters, teleocidins, and aplysiatoxins, have the potential to become anti-cancer agents, since they are anti-proliferative against specific cancer cell lines in vitro. However, their potent tumor-promoting and proinflammatory activities have hampered their clinical uses. Recently, we developed 10-methyl-aplog-1 (1), a simplified analog of tumor-promoting debromoaplysiatoxin (DAT), which retained anti-proliferative activity comparable to DAT, but induced neither tumorigenesis nor inflammation on mouse skin. Our previous study suggested that PKCα and δ were involved in the cell line-selective anti-proliferative activity of 1 , but the downstream signaling of PKC isozymes remained unknown. In this study, we confirmed that 1 inhibited the growth of three aplog-sensitive cancer cell lines (NCI–H460, HCC-2998, and HBC-4) without severe side effects in mice xenograft models. In addition, in vitro analysis using A549, one of the aplog-sensitive cell lines in vitro , revealed that PKCα induced PP2A-mediated attenuation of the Akt/S6 signaling axis. Since S6 inhibition in A549 was reported to result in G1 arrest, this pathway could be involved in the PKCα-dependent anti-proliferative activity of 1. • 10-Methyl-aplog-1 showed anti-cancer activity in vivo against NCI–H460, HCC2988, and HBC-4 cancer cell lines. • 10-Methyl-aplog-1 induced cell cycle arrest in G1 phase via PKCα activation in A549 cells. • PKCα induced PP2A-mediated attenuation of Akt/S6 signaling axis in A549 cells. • The crosstalk between PKC and Akt could be a factor that determines sensitivity to PKC ligands. [ABSTRACT FROM AUTHOR]