Tropolone: A lipid solubilizing agent for cationic metals

Hendershott, Lynn R.; Gentilcore, Rita C.; Ordway, Frederick S.; Fletcher, James; Donati, Robert M.

doi:10.1007/bf00256471

Cited by 16 publications

(4 citation statements)

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“…These differences may be important with respect to potential in vivo antagonism. Plasma iron binding is a concern for potential in vivo applications, as some tropolones appear to bind iron more tightly than transferrin [38]. While the bulk of plasma iron exists in complex with transferrin and does not reach our experimental levels [39], it is possible that total plasma iron would be sufficient to block tropolone distribution in vivo .…”

Section: Discussionmentioning

confidence: 99%

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Jin

Falcone

Holstein

et al. 2016

Pharmacological Research

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Tropolones, such as β-thujaplicin, are small lead-like natural products that possess a variety of biological activities. While the β-substituted natural products and their synthetic analogs are potent inhibitors of human cancer cell growth, less is known about their α-substituted counterparts. Recently, we synthesized a series of α-substituted tropolones including 2-hydroxy-7-(naphthalen-2-yl)cyclohepta-2,4,6-trien-1-one (α-naphthyl tropolone). Here, we evaluate the antiproliferative mechanisms of α-naphthyl tropolone and the related α-benzodioxinyl analog. The α-substituted tropolones inhibit growth of lymphocytic leukemia cells, but not healthy blood cells, with nanomolar potency. Treatment of leukemia cell lines with the tropolone dose-dependently induces apoptosis as judged by staining with annexin V and propidium iodide and Western blot analysis of cleaved caspase 3 and 7. Moreover, pre-treatment of cells with the caspase inhibitor Z-VAD-FMK inhibited the apoptotic effects of the tropolone in two lymphocytic lines. Caspase inhibition also blocked elevated histone acetylation caused by the tropolone, indicating that its effects on histone acetylation are potentiated by caspases. In contrast, α-naphthyl tropolone upregulated p53 expression and phosphorylation of Akt and mTOR in a manner that was not rescued by caspase inhibition. The effects of tropolone were blocked by co-incubation with high levels of free extracellular iron but not by pre-loading with iron. Additionally, dose and time dependent reduction in ex vivo viability of cells from leukemia patients was observed. Taken together, we demonstrate that α-substituted tropolones upregulate DNA damage repair pathways leading to caspase-dependent apoptosis in malignant lymphocytes.

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Section: Discussionmentioning

confidence: 99%

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Jin

Falcone

Holstein

et al. 2016

Pharmacological Research

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“…In addition, this compound and its derivatives reportedly inhibit growth of human and murine cell lines (5) and of methicillinresistant Staphylococcus aureus (15). These reports indicate that the virulence of tropolone in rice seedlings can be attributed to its potent cationic metal-chelating effect (15,16).…”

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confidence: 99%

Carot-4-en-9,10-Diol, a Conidiation-Inducing Sesquiterpene Diol Produced by Trichoderma virens PS1-7 upon Exposure to Chemical Stress from Highly Active Iron Chelators

Wang

Hashimoto

Hashidoko

2013

Appl Environ Microbiol

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To screen biocontrol agents against Burkholderia plantarii, the causative agent of rice seedling blight, we employed catechol, an analog of the virulence factor tropolone, to obtain chemical stress-resistant microorganisms. The fungal isolate PS1-7, identified as a strain of Trichoderma virens, showed the highest resistance to catechol (20 mM) and exhibited efficacy as a biocontrol agent for rice seedling blight. During investigation of metabolic traits of T. virens PS1-7 exposed to catechol, we found a secondary metabolite that was released extracellularly and uniquely accumulated in the culture. The compound induced by chemical stress due to catechol was subsequently isolated and identified as a sesquiterpene diol, carot-4-en-9,10-diol, based on spectroscopic analyses. T. virens PS1-7 produced carot-4-en-9,10-diol as a metabolic response to tropolone at concentrations from 0.05 to 0.2 mM, and the response was enhanced in a dose-dependent manner, similar to its response to catechol at concentrations from 0.1 to 1 mM. Some iron chelators, such as pyrogallol, gallic acid, salicylic acid, and citric acid, at 0.5 mM also showed activation of T. virens PS1-7 production of carot-4-en-9,10-diol. This sesquiterpene diol, formed in response to chemical stress, promoted conidiation of T. virens PS1-7, suggesting that it is involved in an autoregulatory signaling system. In a bioassay of the metabolic and morphological responses of T. virens PS1-7, conidiation in hyphae grown on potato dextrose agar (PDA) plates was either promoted or induced by carot-4-en-9,10-diol. Carot-4-en-9,10-diol can thus be regarded as an autoregulatory signal in T. virens, and our findings demonstrate that intrinsic intracellular signaling regulates conidiation of T. virens.

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“…Other lipid-soluble complexes have nonetheless been investigated to label blood cells, such as tropolone derivatives, with good results [34,35]. Tropolone, or 2-Hydroxy-2,4,6-cycloheptatrien-1-one, readily forms lipid-soluble complexes with di-or trivalent metals [36]. Besides 111 In, tropolone has been used to complex 57 Co [37], 59 Fe [36], 64 Cu [38], 67/68 Ga [39,40], 89 Zr [41] and 99m Tc [42].…”

Section: Introductionmentioning

confidence: 99%

“…Tropolone, or 2-Hydroxy-2,4,6-cycloheptatrien-1-one, readily forms lipid-soluble complexes with di-or trivalent metals [36]. Besides 111 In, tropolone has been used to complex 57 Co [37], 59 Fe [36], 64 Cu [38], 67/68 Ga [39,40], 89 Zr [41] and 99m Tc [42]. Using an analogy between oxine and tropolone, we have decided to investigate the potential usefulness of tropolone to label Lipiodol.…”

Section: Introductionmentioning

confidence: 99%

Labeling of Hinokitiol with 90Y for Potential Radionuclide Therapy of Hepatocellular Carcinoma

et al. 2021

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Hepatocellular carcinoma (HCC), the most common form of primary liver tumors, is the fifth cancer in the world in terms of incidence, and third in terms of mortality. Despite significant advances in the treatment of HCC, its prognosis remains bleak. Transarterial radioembolization with radiolabeled microspheres and Lipiodol has demonstrated significant effectiveness. Here we present a new, simple radiolabeling of Lipiodol with Yttrium-90, for the potential treatment of HCC.

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Tropolone: A lipid solubilizing agent for cationic metals

Cited by 16 publications

References 1 publication

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Novel α-substituted tropolones promote potent and selective caspase-dependent leukemia cell apoptosis

Carot-4-en-9,10-Diol, a Conidiation-Inducing Sesquiterpene Diol Produced by Trichoderma virens PS1-7 upon Exposure to Chemical Stress from Highly Active Iron Chelators

Labeling of Hinokitiol with 90Y for Potential Radionuclide Therapy of Hepatocellular Carcinoma

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