4-Hydroxyderricin from Angelica keiskei Roots Induces Caspase-dependent Apoptotic Cell Death in HL60 Human Leukemia Cells

Akihisa, Toshihiro; Kikuchi, Takashi; Nagai, Hisashi; Ishii, Koichi; Tabata, Keiichi; Suzuki, Takashi

doi:10.5650/jos.60.71

Cited by 39 publications

(48 citation statements)

References 23 publications

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“…YM-01 and JG-98), as well as other scaffolds, are extremely effective against cancer cell lines (3,43-48). The MKT-077-based compounds have been shown to trap all Hsp70 isoforms into an ADP bound conformer, which can disrupt a number of downstream cancer signaling pathways that regulate transactivation, cell invasion and adhesion (48)(49)(50). Because the induction of the Hsp72 isoform in oncogenic cell lines is known to be cyto-protective, most of the mechanistic studies regarding Hsp70 inhibitors in cancer have been focused on how these compounds influence this inducible Hsp70 isoform.…”

Section: Discussionmentioning

confidence: 99%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

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Section: Discussionmentioning

confidence: 99%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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“…Five new compounds (1−5) were isolated from the EtOAc extract of the aerial parts of A. keiskei, together with eight known compounds (6−13). The known compounds were identified as (±)-4,2′,4′-trihydroxy-3′-[(6E)-2-hydroxy-7-methyl-3-methylene-6-octenyl]chalcone (6), 31 xanthoangelol (7), 9 xanthoangelol F (8), 8 xanthoangelol G (9), 8 4-hydroxyderricin (10), 32 xanthoangelol D (11), 33 xanthoangelol E (12), 33 and xanthoangelol H (13). 8 Herein, we report the isolation and structure elucidation of 1−5 along with the evaluation of the effects of chalcones 1−13 on HSP expression.…”

mentioning

confidence: 99%

Chalcones from Angelica keiskei: Evaluation of Their Heat Shock Protein Inducing Activities

et al. 2015

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Five new chalcones, 4,2',4'-trihydroxy-3'-[(2E,5E)-7-methoxy-3,7-dimethyl-2,5-octadienyl]chalcone (1), (±)-4,2',4'-trihydroxy-3'-[(2E)-6-hydroxy-7-methoxy-3,7-dimethyl-2-octenyl]chalcone (2), 4,2',4'-trihydroxy-3'-[(2E)-3-methyl-5-(1,3-dioxolan-2-yl)-2-pentenyl]chalcone (3), 2',3'-furano-4-hydroxy-4'-methoxychalcone (4), and (±)-4-hydroxy-2',3'-(2,3-dihydro-2-methoxyfurano)-4'-methoxychalcone (5), were isolated from the aerial parts of Angelica keiskei Koidzumi together with eight known chalcones, 6-13, which were identified as (±)-4,2',4'-trihydroxy-3'-[(6E)-2-hydroxy-7-methyl-3-methylene-6-octenyl]chalcone (6), xanthoangelol (7), xanthoangelol F (8), xanthoangelol G (9), 4-hydroxyderricin (10), xanthoangelol D (11), xanthoangelol E (12), and xanthoangelol H (13), respectively. Chalcones 1-13 were evaluated for their promoter activity on heat shock protein 25 (hsp25, murine form of human hsp27). Compounds 1 and 6 activated the hsp25 promoter by 21.9- and 29.2-fold of untreated control at 10 μM, respectively. Further protein expression patterns of heat shock factor 1 (HSF1), HSP70, and HSP27 by 1 and 6 were examined. Compound 6 increased the expression of HSF1, HSP70, and HSP27 by 4.3-, 1.5-, and 4.6-fold of untreated control, respectively, without any significant cellular cytotoxicities, whereas 1 did not induce any expression of these proteins. As a result, 6 seems to be a prospective HSP inducer.

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“…2 , whereas kolavenic acid 1 was inactive at all concentrations. In contrast, the anti-cancer drug, 5-fluorouracil had an IC 50 of 9.5 μM toward HL-60 cells 18 . Compounds 1 and 2 have the same basic skeleton and carboxyl position C-15 , but a methyl group in 1 C-16 is replaced by an aldehyde group in 2, proposing that an aldehyde group in Fig.…”

Section: Resultsmentioning

confidence: 99%

Clerodane Diterpenes Isolated from Polyalthia longifolia Induce Apoptosis in Human Leukemia HL-60 Cells

et al. 2013

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4-Hydroxyderricin from Angelica keiskei Roots Induces Caspase-dependent Apoptotic Cell Death in HL60 Human Leukemia Cells

Cited by 39 publications

References 23 publications

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Chalcones from Angelica keiskei: Evaluation of Their Heat Shock Protein Inducing Activities

Clerodane Diterpenes Isolated from Polyalthia longifolia Induce Apoptosis in Human Leukemia HL-60 Cells

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