TY - JOUR
T1 - Activation of PKC supports the anticancer activity of tigilanol tiglate and related epoxytiglianes
AU - Cullen, Jason K.
AU - Boyle, Glen M.
AU - Yap, Pei Yi
AU - Elmlinger, Stefan
AU - Simmons, Jacinta L.
AU - Broit, Natasa
AU - Johns, Jenny
AU - Ferguson, Blake
AU - Maslovskaya, Lidia A.
AU - Savchenko, Andrei I.
AU - Mirzayans, Paul Malek
AU - Porzelle, Achim
AU - Bernhardt, Paul V.
AU - Gordon, Victoria A.
AU - Reddell, Paul W.
AU - Pagani, Alberto
AU - Appendino, Giovanni
AU - Parsons, Peter G.
AU - Williams, Craig M.
N1 - Copyright the Author(s) 2021. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2021/1/8
Y1 - 2021/1/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85098970518&partnerID=8YFLogxK
UR - http://purl.org/au-research/grants/arc/FT110100851
UR - http://purl.org/au-research/grants/arc/DP120102359
UR - http://purl.org/au-research/grants/nhmrc/1017676
UR - http://purl.org/au-research/grants/nhmrc/1093569
U2 - 10.1038/s41598-020-80397-9
DO - 10.1038/s41598-020-80397-9
M3 - Article
C2 - 33420238
AN - SCOPUS:85098970518
VL - 11
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 207
ER -