Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents

Tanasova, Marina; Sturla, Shana J.

doi:10.1021/cr2001367

Cited by 88 publications

(81 citation statements)

References 243 publications

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“…However, limited efforts have focused on pharmacological means for enhancing activating enzymes, such as bioactive food components (Tanasova and Sturla, 2012). A series of studies by Begleiter and coworkers (Doherty et al, 1998;Wang et al, 1999;Begleiter et al, 2004;Digby et al, 2005) supports the feasibility of the approach.…”

Section: Human Ptgr1 Activates Acylfulvenes and Improves Efficacy 431mentioning

confidence: 95%

“…Outcomes from clinical trials with HMAF were mixed, ranging from little effects in non-small-cell lung cancer and gastric cancer to modest effects in ovarian and pancreatic cancer. The array of side effects included thrombocytopenia, nausea and vomiting, visual symptoms, and renal dysfunction (Tanasova and Sturla, 2012). These observations suggest a pressing need to better understand factors controlling toxicity with the aim of devising improved analogs or therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

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Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Xiang

Erzinger

Pietsch

et al. 2012

J Pharmacol Exp Ther

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Prostaglandin reductase 1 (PTGR1) is a highly inducible enzyme with enone reductase activity. Previous studies demonstrated the role of rat PTGR1 in the activation of acylfulvene analogs, a class of antitumor natural product derivatives. Of these, hydroxymethylacylfulvene (HMAF) was in advanced clinical development for the treatment of advanced solid tumors, including prostate, ovarian, and pancreatic cancers. However, the efficiency of human PTGR1 in activating acylfulvenes and its potential to enhance therapeutic efficacy have remained uncharacterized. In this study, human PTGR1 was polymerase chain reaction-cloned and purified. Conversion of HMAF to its cellular metabolite by the purified enzyme proceeded at a 20-fold higher rate than with the rat variant of the enzyme. The K m was 4.9 M, which was 40-fold lower than for the rat variant and similar to the therapeutic dose. Human cell lines, including colon cancer lines, were transfected with a vector containing rat PTGR1 or human PTGR1, and cell viability was examined after dosing with HMAF. New data obtained in this study suggest that transfection with human PTGR1, or its induction in colon and liver cancer cell lines with 1,2-dithiol-3-thione, enhances susceptibility to the cytotoxic influences of HMAF by 2-to 10-fold. Furthermore, similar or enhanced enzyme induction and HMAF toxicity results from preconditioning cancer cells with the bioactive food components curcumin and resveratrol. The functional impact of PTGR1 induction in human cells and chemical-based strategies for its activation can provide important knowledge for the design of clinical strategies involving reductively activated cytotoxic chemotherapeutics.

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Section: Human Ptgr1 Activates Acylfulvenes and Improves Efficacy 431mentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Xiang

Erzinger

Pietsch

et al. 2012

J Pharmacol Exp Ther

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“…[59] To the best of our knowledge, noteworthy progress has not been reported on the subject 14 since then. We will therefore not discuss the synthetic aspects of these sesquiterpenes any further in this review.…”

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confidence: 96%

Fungal Anticancer Metabolites: Synthesis Towards Drug Discovery

Barbero

Artuso

Prandi

2018

CMC

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This review summarizes the anticancer potential of fungal metabolites, highlighting the role of total 6 synthesis in sustaining their pharmacological development as an alternative to isolation. This paper also outlines the 7 feasibility of innovative synthetic procedures that facilitate the development of fungal metabolites into drugs that may 8 become a real future perspective. This review demonstrates that total chemical synthesis is a fruitful means of yielding 9 fungal derivatives as aided by recent technological and innovative advancements.

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“…exemplified by the semisynthetic analog of pleuromutilin (retapamulin) as clinically used antibiotic (28), illudins as anticancer drugs (29), and peptidic omphalotins as nematicidal agents (30). Addition to low molecular weight (MW) secondary metabolites, mushrooms produce a variety of proteins, such as lectins, with antitumor, antiviral, antimicrobial, antioxidative, and/or immunomodulatory activities (31).…”

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confidence: 99%

Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

Zhang

Yang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Glycans possess significant chemical diversity; glycan binding proteins (GBPs) recognize specific glycans to translate their structures to functions in various physiological and pathological processes. Therefore, the discovery and characterization of novel GBPs and characterization of glycan-GBP interactions are significant to provide potential targets for therapeutic intervention of many diseases. Here, we report the biochemical, functional, and structural characterization of a 130-amino-acid protein, Y3, from the mushroom Coprinus comatus. Biochemical studies of recombinant Y3 from a yeast expression system demonstrated the protein is a unique GBP. Additionally, we show that Y3 exhibits selective and potent cytotoxicity toward human T-cell leukemia Jurkat cells compared with a panel of cancer cell lines via inducing caspase-dependent apoptosis. Screening of a glycan array demonstrated GalNAcβ1-4(Fucα1-3)GlcNAc (LDNF) as a specific Y3-binding ligand. To provide a structural basis for function, the crystal structure was solved to a resolution of 1.2 Å, revealing a single-domain αβα-sandwich motif. Two monomers were dimerized to form a large 10-stranded, antiparallel β-sheet flanked by α-helices on each side, representing a unique oligomerization mode among GBPs. A large glycan binding pocket extends into the dimeric interface, and docking of LDNF identified key residues for glycan interactions. Disruption of residues predicted to be involved in LDNF/Y3 interactions resulted in the significant loss of binding to Jurkat T-cells and severely impaired their cytotoxicity. Collectively, these results demonstrate Y3 to be a GBP with selective cytotoxicity toward human T-cell leukemia cells and indicate its potential use in cancer diagnosis and treatment.

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Chemistry and Biology of Acylfulvenes: Sesquiterpene-Derived Antitumor Agents

Cited by 88 publications

References 243 publications

Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Up-Regulation of Human Prostaglandin Reductase 1 Improves the Efficacy of Hydroxymethylacylfulvene, an Antitumor Chemotherapeutic Agent

Fungal Anticancer Metabolites: Synthesis Towards Drug Discovery

Cytotoxic protein from the mushroom Coprinus comatus possesses a unique mode for glycan binding and specificity

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