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

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

doi:10.1038/s41598-020-80397-9

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

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

^*Corresponding author for this work

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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.

Original language	English
Article number	207
Number of pages	14
Journal	Scientific Reports
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-80397-9
Publication status	Published - 8 Jan 2021
Externally published	Yes

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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.

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Cullen, J. K., Boyle, G. M., Yap, P. Y., Elmlinger, S., Simmons, J. L., Broit, N., Johns, J., Ferguson, B., Maslovskaya, L. A., Savchenko, A. I., Mirzayans, P. M., Porzelle, A., Bernhardt, P. V., Gordon, V. A., Reddell, P. W., Pagani, A., Appendino, G., Parsons, P. G., & Williams, C. M. (2021). Activation of PKC supports the anticancer activity of tigilanol tiglate and related epoxytiglianes. Scientific Reports, 11(1), Article 207. https://doi.org/10.1038/s41598-020-80397-9

@article{a66ebc8a22ad4dc4a336035601784cb2,

title = "Activation of PKC supports the anticancer activity of tigilanol tiglate and related epoxytiglianes",

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.",

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

note = "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. ",

year = "2021",

month = jan,

day = "8",

doi = "10.1038/s41598-020-80397-9",

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Cullen, JK, Boyle, GM, Yap, PY, Elmlinger, S, Simmons, JL, Broit, N, Johns, J, Ferguson, B, Maslovskaya, LA, Savchenko, AI, Mirzayans, PM, Porzelle, A, Bernhardt, PV, Gordon, VA, Reddell, PW, Pagani, A, Appendino, G, Parsons, PG & Williams, CM 2021, 'Activation of PKC supports the anticancer activity of tigilanol tiglate and related epoxytiglianes', Scientific Reports, vol. 11, no. 1, 207. https://doi.org/10.1038/s41598-020-80397-9

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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.

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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

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VL - 11

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 207

ER -

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

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