Publisher Summary This chapter reviews the studies on the mechanism of tumor promotion in mouse skin by croton oil and phorbol diesters and on the effects of these compounds on cell cultures of various types. The chapter discusses the findings in the field of tumor promoters during mid- 1979 and provides sources in the literature that are useful as background. For an historical perspective of the concept of two-stage carcinogenesis and tumor promotion are described. The demonstration of two distinct stages in experimentally induced cancer in animals suggests that there are two stages in environmentally induced cancer in humans. Tumor induction can be divided into two distinct treatment stages, initiation and promotion, and that the promotion stage is reversible. Compounds with tumor-promoting activity are a class of cocarcinogens that are not themselves mutagenic or carcinogenic but that cause the formation of tumors when applied repeatedly after an irreversible event has been "initiated" by a carcinogen. Prevention of human cancer requires the identification and, wherever possible, the elimination of these agents. Because promotion is a reversible process that requires repeated exposure over a period of time, in contrast to the rapid, irreversible process of initiation by carcinogens, manipulation of promotion would seem to be the best method of cancer prevention. The identification of promoters in the environment, and the elucidation of their mechanisms of action, could lead to prophylactic measures such as the development of drugs specifically designed to interfere with the promotion mechanism and prevent tumor formation.

Tumor promoters and the mechanism of tumor promotion.

https://cancerres.aacrjournals.org/content/canres/28/11/2338.full.pdf

Cocarcinogenic principles from the seed oil of Croton tiglium and from other Euphorbiaceae.

NETosis, an antimicrobial form of neutrophil cell death, is considered a primary source of citrullinated autoantigens in rheumatoid arthritis (RA) and immunogenic DNA in systemic lupus erythematosus (SLE). Activation of the citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is believed to be essential for neutrophil extracellular trap (NET) formation and NETosis. PAD4 is therefore viewed as a promising therapeutic target to inhibit the formation of NETs in both diseases. In this review, we examine the evidence for PAD4 activation during NETosis and provide experimental data to suggest that protein citrullination is not a universal feature of NETs. We delineate two distinct biological processes, leukotoxic hypercitrullination (LTH) and defective mitophagy, which have been erroneously classified as "NETosis." While these NETosis mimics share morphological similarities with NETosis (i.e., extracellular DNA release), they are biologically distinct. As such, these processes can be readily classified by their stimuli, activation of distinct biochemical pathways, the presence of hypercitrullination, and antimicrobial effector function. NETosis is an antimicrobial form of cell death that is NADPH oxidase-dependent and not associated with hypercitrullination. In contrast, LTH is NADPH oxidase-independent and not bactericidal. Rather, LTH represents a bacterial strategy to achieve immune evasion. It is triggered by pore-forming pathways and equivalent signals that cumulate in calcium-dependent hyperactivation of PADs, protein hypercitrullination, and neutrophil death. The generation of citrullinated autoantigens in RA is likely driven by LTH, but not NETosis. Mitochondrial DNA (mtDNA) expulsion, the result of a constitutive defect in mitophagy, represents a second NETosis mimic. In the presence of interferon-α and immune complexes, this process can generate highly interferogenic oxidized mtDNA, which has previously been mistaken for NETosis in SLE. Distinguishing NETosis from LTH and defective mitophagy is paramount to understanding the role of neutrophil damage in immunity and the pathogenesis of human diseases. This provides a framework to design specific inhibitors of these distinct biological processes in human disease.

/pdf/a-critical-reappraisal-of-neutrophil-extracellular-traps-and-55vl6n06d0.pdf

A Critical Reappraisal of Neutrophil Extracellular Traps and NETosis Mimics Based on Differential Requirements for Protein Citrullination.

Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are "receptors" for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: PKC isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer's disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: "to go beyond is as wrong as to fall short."

/pdf/protein-kinase-c-perfectly-balanced-1criwj1bz0.pdf

Protein kinase C: perfectly balanced.

The first indication that experimental carcinogenesis could be augmented by the addition of noncarcinogenic stimuli resulted from scarification of mouse skin combined with, or following, tar painting (Deelman, 1924; Deelman and van Erp, 1926), and later, from combined applications of carcinogenic hydrocarbons with (noncarcinogenic) creosote oil (Sall et al., 1940). But the establishment of sequential stages in carcinogenesis arose by the convergence of two subsequent lines of inquiry.

Sequential Aspects of Chemical Carcinogenesis: Skin

Zur Isolierung der Wirkstoffgruppen A und B aus Crotonol wird ein verkurzter Trennungsgang beschrieben. Damit werden die Wirkstoffe A1 sowie B1 und B2, die den groseren Teil der cocarcinogenen Inhaltsstoffe des Ols ausmachen, fur biologische und biochemische Untersuchungen leicht zuganglich. Ferner werden aus der Wirkstoffgruppe A auser dem bekannten A1 drei weitere entzundliche und cocarcinogene Wirkstoffe A2, A3 und A4 isoliert und rein dargestellt. Es handelt sich um Diester des Phorbols C20H28O6 mit Essigsaure als kurzkettiger sowie Caprin-bzw. Laurin-bzw. Palmitinsaure als langkettiger Fettsaure. Die neuen Wirkstoffe A2 und A3 sind mit den bekannten Wirkstoffen B4 und B7 isomer.

Über die Wirkstoffe des Crotonöls

Structure and stereochemistry of the tetracyclic diterpene phorbol from croton tiglium L.

http://link.springer.com/content/pdf/10.1007/BF00524429.pdf

H. Bresch

Papers

Über die Wirkstoffe des Crotonöls

Structure and stereochemistry of the tetracyclic diterpene phorbol from croton tiglium L.

ber die Wirkstoffe des Crotonls: VI. Entzndungsteste am Museohr

[on the active agent of croton oil. 3. pure demonstration and characterization of a toxic, inflammatory and cocarcinogenic highly active substance].

On the active substances of croton oil. IX. Partial synthesis of active substances in croton oil