Use-Dependent Block of Voltage-Gated Ca<sub>v</sub>2.1 Ca<sup>2+</sup>Channels by Petasins and Eudesmol Isomers

Horak, Silja B; Koschak, Alexandra; Stuppner, Hermann; Striessnig, Jörg

doi:10.1124/jpet.109.151183

Cited by 20 publications

(15 citation statements)

References 37 publications

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“…The main components identified in G. friesiana essential oil were eudesmol isomers (a-, band c-eudesmol; fig. 1), which exhibit multiple biological activities, such as antihypertensive [6], anticonvulsant [7], anti-angiogenic [8], antitumour [9], antimicrobial [10], acaricidal [11], antimigraine [12], insecticidal [13], antitrypanosomal [14] and anti-inflammatory properties [15]. These three eudesmol isomers have been also reported previously as cytotoxic agents, displaying cytotoxicity to several human tumour cell lines [5,8,9,16,17].…”

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confidence: 89%

Eudesmol Isomers Induce Caspase‐Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

Bomfim

Ferraz

Carvalho

et al. 2013

Basic Clin Pharma Tox

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Eudesmols are naturally occurring sesquiterpenoid alcohols that present cytotoxic effect to cancer cells. Herein, all eudesmol isomers displayed cytotoxicity to different tumour cell lines. a-Eudesmol showed IC 50 values ranging from 5.38 AE 1.10 to 10.60 AE 1.33 lg/mL for B16-F10 and K562 cell lines, b-eudesmol showed IC 50 values ranging from 16.51 AE 1.21 to 24.57 AE 2.75 lg/mL for B16-F10 and HepG2 cell lines, and c-eudesmol showed IC 50 values ranging from 8.86 AE 1.27 to 15.15 AE 1.06 lg/mL for B16-F10 and K562 cell lines, respectively. In addition, in this work, we studied the mechanisms of cytotoxic action of eudesmol isomers (a-, b-and c-eudesmol) in human hepatocellular carcinoma HepG2 cells. After 24-hr incubation, HepG2 cells treated with eudesmol isomers presented typical hallmarks of apoptosis, as observed by morphological analysis in cells stained with haematoxylin-eosin and acridine orange/ethidium bromide. None of eudesmol isomers caused membrane disruption at any concentration tested. Moreover, eudesmol isomers induced loss of mitochondrial membrane potential and an increase in caspase-3 activation in HepG2 cells, suggesting the induction of caspase-mediated apoptotic cell death. In conclusion, the eudesmol isomers herein investigated are able to reduce cell proliferation and to induce tumour cell death by caspase-mediated apoptosis pathways.Several studies have demonstrated that natural products and/or natural product structures continued to play a highly significant role in drug discovery and development process. In the case of approved therapeutic agents (01/1981-12/2010), only 20.2% of the total number of small-molecule anticancer drugs is classifiable into the synthetic category [1].Some studies have reported cytotoxic activity for plants belonging to the genus Guatteria of the Annonaceae plant family [2][3][4][5]. Our research group demonstrated that the leaf essential oil of Guatteria friesiana possesses in vitro and in vivo antitumour actions, without substantial systemic toxicity [5]. The main components identified in G. friesiana essential oil were eudesmol isomers (a-, b-and c-eudesmol; fig. 1 [15]. These three eudesmol isomers have been also reported previously as cytotoxic agents, displaying cytotoxicity to several human tumour cell lines [5,8,9,16,17]. Moreover, other plant species that contain eudesmol isomers also present cytotoxic activity [18,19]. In addition, Li et al. [20] reported that b-eudesmol induces c-Jun N-terminal kinases (JNK)-dependent apoptosis through the mitochondrial pathway in HL60 cells; however, the mechanism of cytotoxicity of aor c-eudesmol has not been investigated. Therefore, in the present work, we investigated the cytotoxic mechanism of eudesmol isomers (a-, b-and c-eudesmol) in human hepatocellular carcinoma HepG2 cells. Materials and MethodsEudesmols isolation. Guatteria friesiana leaves were collected at the Federal University of Amazonas (UFAM), Manaus, AM, Brazil, in January 2008. A voucher specimen (no. 7341) was deposited in the Herbar...

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confidence: 89%

Eudesmol Isomers Induce Caspase‐Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

Bomfim

Ferraz

Carvalho

et al. 2013

Basic Clin Pharma Tox

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“…Nicardipine IC50 = 21.1-85 mM L-type (IC50 = 9.6-24 mM); N-type (IC50 = 59.9 mM-7.6 mM) Verapamil Full block at 50 mM; IC50 = 62 mM L-type channel (IC50 = 4 mM); N-type channel (full block at 40 mM) Diochot et al, 1995;Ishibashi et al, 1995;Dobrev et al, 1999 a-Eudesmol IC50 = 3.6 mM N-type current: IC50 = 6.6 mM; Asakura et al, 1999;Horak et al, 2009 References in column 4 report activities on the P/Q-type channel. Activites on other targets are reported in the same references, unless explicitly stated in column 3.…”

Section: Yamamoto and Takahara 2009mentioning

confidence: 99%

“…Some plant extracts that are used as prophylactics for migraine (Diener et al, 2004;Lipton et al, 2004) also inhibit P/Q-type channels. a-Eudesmol (Eucalyptus williamsiania) and petasins (Petasites hybridus) statedependently inhibit recombinant P/Q-type currents (Horak et al, 2009). In rat cerebellar Purkinje cells, eudesmol (Juniperus virginiana) inhibits P/Q-type currents with an IC50 of 3.6 mM (Asakura et al, 1999).…”

Section: Suggested Primary Target Mediating Clinical Efficacy Referencementioning

confidence: 99%

P/Q‐type calcium channel modulators

Nimmrich

Groß

2012

British J Pharmacology

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P/Q-type calcium channels are high-voltage-gated calcium channels contributing to vesicle release at synaptic terminals. A number of neurological diseases have been attributed to malfunctioning of P/Q channels, including ataxia, migraine and Alzheimer's disease. To date, only two specific P/Q-type blockers are known: both are peptides deriving from the spider venom of Agelenopsis aperta, w-agatoxins. Other peptidic calcium channel blockers with activity at P/Q channels are available, albeit with less selectivity. A number of low molecular weight compounds modulate P/Q-type currents with different characteristics, and some exhibit a peculiar bidirectional pattern of modulation. Interestingly, there are a number of therapeutics in clinical use, which also show P/Q channel activity. Because selectivity as well as the exact mode of action is different between all P/Q-type channel modulators, the interpretation of clinical and experimental data is complicated and needs a comprehensive understanding of their target profile. The situation is further complicated by the fact that information on potency varies vastly in the literature, which may be the result of different experimental systems, conditions or the splice variants of the P/Q channel. This review attempts to provide a comprehensive overview of the compounds available that affect the P/Q-type channel and should help with the interpretation of results of in vitro experiments and animal models. It also aims to explain some clinical observations by implementing current knowledge about P/Q channel modulation of therapeutically used non-selective drugs. Chances and challenges of the development of P/Q channel-selective molecules are discussed. AbbreviationsAb, amyloid-b; AD, Alzheimer's disease; CDK, cycline-dependent kinase; LMW, low molecular weight; VGCC, voltage-gated calcium channel IntroductionThe P/Q-type calcium channel (also referred to as Cav2.1) is a presynaptic high-voltage-gated calcium channel, which couples neuronal excitation to secretion of neurotransmitter (Ishikawa et al., 2005). The ion-conducting pore is formed by four domains of the a1A subunit, whereas accessory subunits (b, a2d) modulate channel kinetics and the level of expression. P-type currents were first identified in Purkinje neurons of the cerebellum (Llinás et al., 1989) and are distinguished from Q-type currents identified in cerebellar granule neurons (Randall and Tsien, 1995). Both are characterized by their sensitivity to the venom of Agelenopsis aperta, w-agatoxin IVA (Mintz et al., 1992a), and are generated by ion channels encoded by the CACNA1A gene. A number of splice variants may explain different phenotypic characteristics of P-and Q-type channels (Bourinet et al., 1999). For convenience and because distinction between these channel subtypes is not always clear, we refer throughout this review to P/Q-type channels. Expression of P/Q-type channels often overlaps with its close analogue, the N-type calcium channel. Yet, the P/Q-type channel is preferably expressed in neurons o...

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“…In vitro blockage of neuronal Ca 2+ channels by α-eudesmol (11) has been linked to potential psychoactive effects [76]. This may be significant with regard to anecdotal accounts of Cedarwood essential oil associated with enhanced memory and creativity [77].…”

Section: Pharmacological Character Of Internationally Recognized Essementioning

confidence: 99%

A Contemporary Introduction to Essential Oils: Chemistry, Bioactivity and Prospects for Australian Agriculture

Sadgrove

Jones

2015

Agriculture

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This review is a comprehensive introduction to pertinent aspects of the extraction methodology, chemistry, analysis and pharmacology of essential oils, whilst providing a background of general organic chemistry concepts to readers from non-chemistry oriented backgrounds. Furthermore, it describes the historical aspects of essential oil research whilst exploring contentious issues of terminology. This follows with an examination of essential oil producing plants in the Australian context with particular attention to Aboriginal custom use, historical successes and contemporary commercial prospects. Due to the harsh dry environment of the Australian landmass, particularly to the cyclical climatic variation attendant upon repeated glaciation/post-glaciation cycles, the arid regions have evolved a rich assortment of unique endemic essential oil yielding plants. Though some of these aromatic plants (particularly myrtaceous species) have given birth to commercially valuable industries, much remains to be discovered. Given the market potential, it is likely that recent discoveries in our laboratory and elsewhere will lead to new product development. This review concludes with an emphasis on the use of chemotaxonomy in selection of commercially viable cultivar chemotypes from the Australian continent. Finally, drawing largely from our own results we propose a list of Australian endemic species with novel commercial potential. OPEN ACCESSAgriculture 2015, 5 49

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Use-Dependent Block of Voltage-Gated Ca_v2.1 Ca²⁺Channels by Petasins and Eudesmol Isomers

Cited by 20 publications

References 37 publications

Eudesmol Isomers Induce Caspase‐Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

Eudesmol Isomers Induce Caspase‐Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

P/Q‐type calcium channel modulators

A Contemporary Introduction to Essential Oils: Chemistry, Bioactivity and Prospects for Australian Agriculture

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Use-Dependent Block of Voltage-Gated Cav2.1 Ca2+Channels by Petasins and Eudesmol Isomers

Cited by 20 publications

References 37 publications

Eudesmol Isomers Induce Caspase‐Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

Eudesmol Isomers Induce Caspase‐Mediated Apoptosis in Human Hepatocellular Carcinoma HepG2 Cells

P/Q‐type calcium channel modulators

A Contemporary Introduction to Essential Oils: Chemistry, Bioactivity and Prospects for Australian Agriculture

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Use-Dependent Block of Voltage-Gated Ca_v2.1 Ca²⁺Channels by Petasins and Eudesmol Isomers