Activation of PKC supports the anticancer activity of tigilanol tiglate and related epoxytiglianes

Jason K Cullen,Natasa Broit,Stefan Elmlinger,Alberto Pagani,Craig M Williams,Lidia A Maslovskaya,Peter G Parsons,Pei-Yi Yap,Jacinta L Simmons,Paul Malek Mirzayans,Victoria A Gordon,Paul V Bernhardt,Jenny Johns,Blake Ferguson,Andrei I Savchenko,Giovanni Appendino,Paul W Reddell,Glen M Boyle,Achim Porzelle

doi:10.1038/s41598-020-80397-9

Abstract

The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors. To explore the hypothesis that activation, rather than inhibition, of these isoforms is critical for anticancer activity, we isolated and characterized a family of 16 novel phorboids closely-related to tigilanol tiglate (EBC-46), a PKC-activating epoxytigliane showing promising clinical safety and efficacy for intratumoral treatment of cancers. While alkyl branching features of the C12-ester influenced potency, the 6,7-epoxide structural motif and position was critical to PKC activation in vitro. A subset of the 6,7-epoxytiglianes were efficacious against established tumors in mice; which generally correlated with in vitro activation of PKC. Importantly, epoxytiglianes without evidence of PKC activation showed limited antitumor efficacy. Taken together, these findings provide a strong rationale to reassess the role of PKC isoforms in cancer, and suggest in some situations their activation can be a promising strategy for anticancer drug discovery.

Highlights

The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors
Many questions remain around the possible role of PKC in tumorigenesis, with a growing body of evidence suggesting that certain PKC isoforms may act as tumor suppressors
The hallmark of most tigliane diterpenoids from F. picrosperma is the presence of multiple oxidation on the B-ring and a tigliate group on the ring C13-hydroxyl, with differences limited to the acyl decoration of the 12-hydroxyl and the glicidyl/triol nature of the trioxygenated ring B fragment

Summary

Introduction

The long-standing perception of Protein Kinase C (PKC) as a family of oncoproteins has increasingly been challenged by evidence that some PKC isoforms may act as tumor suppressors. To explore the hypothesis that activation, rather than inhibition, of these isoforms is critical for anticancer activity, we isolated and characterized a family of 16 novel phorboids closely-related to tigilanol tiglate (EBC-46), a PKC-activating epoxytigliane showing promising clinical safety and efficacy for intratumoral treatment of cancers. Epoxytiglianes without evidence of PKC activation showed limited antitumor efficacy. Taken together, these findings provide a strong rationale to reassess the role of PKC isoforms in cancer, and suggest in some situations their activation can be a promising strategy for anticancer drug discovery. It is extremely challenging to develop pharmacological agents capable of enhancing PKC signaling in a sustained way, while avoiding down-regulation or degradation[11,12]

Methods

Results

Conclusion