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.

Targeting Protein Kinase C in Glioblastoma Treatment

“…Similar phorbol derived diterpenes with a tigliane or lathyrane skeleton have been described with similar PKC activating properties that also promote NSC proliferation [109,110]. Additionally, semi-synthetic prostratin-like epoxytiglianes have proven to be efficacious against established tumors in mice [111]. Thus, a great variety of compounds that are able to target specific PKC isozymes are now available.…”

“…Although preclinical studies indicate that the specific activation of PKC enzymes may result in adequate cancer treatments, the use of the PKCβ inhibitor enzastaurin in clinical trials did not show a better efficacy than current GBM treatment drugs. Except for the recent study by Cullen et al [111], in which a library of putative PKC activating compounds were tested for the treatment of melanoma, most of the classical PKC activators used so far in cancer studies promote the sustained irreversible enzyme activation and degradation and lack specificity for individual isozymes such as PMA. It has recently been proposed that, in order to target PKC for cancer treatment, therapies should better focus on the induction or re-establishment of specific PKC activities rather than on the inhibition of these enzymes.…”

“…We hypothesize that the combination of these PKC targeting drugs with current treatments may enhance prognosis and survival time. Diterpenes with the capacity to individually regulate classical and novel PKC have recently been described for use in neuronal regeneration [113,114] and as putative treatments for other cancer types [111]. Thus, these agents could prove useful in the development of drugs either in standalone or in combined strategies with other compounds (e.g., PI3K inhibitors).…”

Yuanhuacine Is a Potent and Selective Inhibitor of the Basal-Like 2 Subtype of Triple Negative Breast Cancer with Immunogenic Potential

“…The synthetic C-6,7-epoxytigliane tigilanol tiglate (EBC-46) was recently approved in the EU for the localized treatment of non-metastatic skin cancers in dogs. Interestingly, EBC-46 displays a distinct PKC isoform activation pattern from non-epoxidated tigliane diterpenes marked by a preference for PKC-βI/II isoforms and, to a lesser degree, PKCα/γ [ 43 , 44 ]. These are all PKC isoforms that are inhibited by Ro 31-8220, which attenuated the ability of yuanhuacine ( 1 ) to inhibit BL2 TNBC cells in our study.…”

Tigilanol Tiglate-Mediated Margins: A Comparison With Surgical Margins in Successful Treatment of Canine Mast Cell Tumours

“…(b) Differences in the local immune context of the tumour in individual patients affecting both inflammatory response and immune cell recruitment that are associated with the mode of action of TT ( 4 , 5 , 8 , 9 );…”