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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.

SUBMITTER: Cullen JK

PROVIDER: S-EPMC7794351 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Cullen Jason K JK Boyle Glen M GM Yap Pei-Yi PY Elmlinger Stefan S Simmons Jacinta L JL Broit Natasa N Johns Jenny J Ferguson Blake B Maslovskaya Lidia A LA Savchenko Andrei I AI Mirzayans Paul Malek PM Porzelle Achim A Bernhardt Paul V PV Gordon Victoria A VA Reddell Paul W PW Pagani Alberto A Appendino Giovanni G Parsons Peter G PG Williams Craig M CM

Scientific reports 20210108 1

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 intratu ...[more]

PMID: 33420238

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Project description:Tigilanol tiglate (TT) is a novel small molecule registered as a veterinary pharmaceutical for intratumoural treatment of canine mast cell tumours (MCTs). The drug has a multifactorial mode of action resulting in rapid destruction of the treated tumour by haemorrhagic necrosis and subsequent slough of the necrotic tumour to reveal a tissue deficit that is left to heal by second intention with minimal to no veterinary intervention. Here we introduce the concept of TT-mediated margins, the calculated margin of tissue loss analogous to surgically applied margins to help clinicians conceptualise tissue deficits formed following tumour destruction by TT relative to surgical excision. We used data from 51 dogs that were recurrence-free 12 months after a single administered TT dose into a single target MCT <10 cm3 in volume in a randomised, controlled clinical trial in the USA. We calculated TT-mediated margins based on length of the longest axis of (i) the tumour prior to treatment and (ii) the maximum tissue deficit formed 7-14 days after TT treatment. We compared these TT-mediated margins for each tumour to two surgical approaches to MCT excision in general practise: modified proportional margins (with 2 cm upper limit) and 3 cm fixed margins. For most dogs, TT-mediated margins were less than half the length of the margins calculated for the two surgical approaches in removing the same tumour. There was a trend for TT-mediated margins to increase with increasing tumour volume. Nonetheless, even for the larger tumours in this study (>2 cm3 volume), 50% of TT-mediated margins were less than half the length of the two surgical margins. Eighteen cases were lower limb MCTs, sites often surgically challenging in veterinary practise. On these lower limbs, TT-mediated margins were less than half the length of the corresponding proportional margins in 56% of cases and larger than proportional margins in only two cases. This study suggests that, in many cases, smaller and more targeted margins could be expected when treating MCTs <10 cm3 volume with TT compared with surgical excision. TT-mediated margins are a novel approach to conceptualise tissue deficits after intratumoural TT treatment.

Dataset Information

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

Publications

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

Similar Datasets

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