A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress

Takano, Katsura; Kitao, Yasuko; Tabata, Yoshiyuki; Miura, Hikari; Sato, Kosuke; Takuma, Kazuhiro; Yamada, Kiyofumi; Hibino, Satoshi; Choshi, Tominari; Iinuma, Munekazu; Suzuki, Hiroto; Murakami, Rika; Yamada, Masashi; Ogawa, Satoshi; Hori, Osamu

doi:10.1152/ajpcell.00305.2007

Cited by 44 publications

(32 citation statements)

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“…2BI) but not by carbazole (Fig. 2BII), suggesting that 16-14 improves an ER luminal environment that reduces the level of ER stress after treating the cells with ER stressors, as previously described (9). Cells showed similar responses when treated with BFA (data not shown).…”

Section: Regulation Of Er Stress By Carbazole Derivatives In Pc12 Cellssupporting

confidence: 79%

“…1A and B). Protection against ER stress / ER stressinduced cell death can be obtained in several ways: enhancement of the UPR activity or induction of the UPR-target genes (4); suppression of general protein synthesis (2); and improvement of the ER luminal environment, either through the maintenance of Ca 2+ homeostasis or through the reduction of oxidative stress in the ER (9,24). As the regulation of ER stress by16-14 was associated with the reduced levels of expressions of the UPR-target genes in both Tm-treated cells and GFP-KDEL transfected cells, (Fig.…”

Section: Discussionmentioning

confidence: 99%

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A Carbazole Derivative Protects Cells Against Endoplasmic Reticulum (ER) Stress and Glutathione Depletion

et al. 2008

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Abstract. Enhanced levels of intracellular stresses such as oxidative stress and endoplasmic reticulum (ER) stress are implicated in various neuropathological conditions including brain ischemia and neurodegeneration. During a search for compounds that regulate ER stress and ER stress-induced cell death, we identified a carbazole derivative 16-14 [9-(3-cyanobenzyl)-1,4-dimethylcarbazole] that protected against both ER stress and glutathione depletion. 16-14 suppressed tunicamycin (Tm)-induced cell death in both F9 Herp KO cells and PC12 cells, and its regulation of ER stress was associated with reduced levels of unfolded protein response (UPR) signaling. ER stress caused by overexpression of a fluorescent ER-resident protein, GFP-KDEL, was also attenuated by 16-14 without altering the expression levels of GFP-KDEL. 16-14 also prevented glutathione depletion-induced cell death caused by buthionine sulfoximine (BSO), but not likely via its anti-oxidative activity. Further analysis revealed that 16-14 suppressed increases in intracellular Ca 2+ in response to thapsigargin (Tg). These results suggest that 16-14 may protect cells against different stresses via the maintenance of intracellular Ca 2+ homeostasis. [ Supplementary Fig. 1: available only at http://dx.doi.org / 10.1254 / jphs.08136FP]

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Section: Regulation Of Er Stress By Carbazole Derivatives In Pc12 Cellssupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

A Carbazole Derivative Protects Cells Against Endoplasmic Reticulum (ER) Stress and Glutathione Depletion

et al. 2008

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“…The molecular mechanism of their interference with microtubules and their vascular disrupting effect is not fully understood, yet. Some studies even invoked a neuroprotective effect of chalcones [8][9].Previously we disclosed a comparison of the effects of chalcone 1 and its platinum complex 2 on twenty-one tumour cell lines [1]. Now, we present a study of their mechanisms of action and effects in living cells.…”

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confidence: 94%

Section: Introductionmentioning

confidence: 99%

Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: A comparative study of uptake, cell cycle and damage to cellular compartments

Zoldáková

Környei

Brown

et al. 2010

Biochemical Pharmacology

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Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: a comparative study of uptake, cell cycle and damage to cellular compartments. Biochemical Pharmacology, Elsevier, 2010, 80 (10) Please cite this article as: Zoldakova M, Kornyei Z, Brown A, Biersack B, Madarász E, Schobert R, Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: a comparative study of uptake, cell cycle and damage to cellular compartments, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 48A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Effects of a combretastatin A4 analogous chalcone and its Pt ((classification: antibiotics and chemotherapeutics))Page 2 of 48 A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ((Abstract))The combretastatin A4 analogous chalcone (2E)-3-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one 1 and its dichloridoplatinum(II) (6-aminomethylnicotinate) complex 2 were previously found to be highly active against a variety of cancer cell lines while differing in their apoptosis induction and long-term regrowth retardation (Schobert R et al. J Med Chem 2009;52:241-6) [1]. Further differences were identified now.The cellular uptake of complex 2, like that of oxaliplatin, occurred mainly via organic cation transporters (OCT-1/2; ~32%) and copper transporter related proteins (Ctr1; ~24%), whereas that of chalcone 1 was dependent on endocytosis (~80%). Complex 2 was more tumourspecific than 1 concerning neural cells. This was apparent from the ratios of IC 50 (48 h) values against primary astrocytes versus human astroglioma cells U87 ( > 7000 for complex 2; 55 for compound 1). In tubulin-rich neurons and 518A2 melanoma cells complex 2 disrupted microtubules and actin filaments. Cancer cells treated with 2 could repair the cytoskeletal damage but ceased to proliferate and perished. Complex 2 was particularly cytotoxic against P-gp-rich cells. It acted as a substrate for ABC-transporters of types BCRP, MRP3, and MRP1 and so was less active against the corresponding can...

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“…6 Different pharmacological compounds modulated the UPR and protected against ER stress-induced apoptosis. 7 These include antioxidants 8,9 indicating a close relation between ER stress and oxidative damage. 10 Additionally, pharmacological applications that interfere with alterations of the intracellular calcium homeostasis have a protective potential against ER stress-induced cell death.…”

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Activation of SK2 channels preserves ER Ca2+ homeostasis and protects against ER stress-induced cell death

et al. 2015

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Alteration of endoplasmic reticulum (ER) Ca2+ homeostasis leads to excessive cytosolic Ca 2+ accumulation and delayed neuronal cell death in acute and chronic neurodegenerative disorders. While our recent studies established a protective role for SK channels against excessive intracellular Ca 2+ accumulation, their functional role in the ER has not been elucidated yet. We show here that SK2 channels are present in ER membranes of neuronal HT-22 cells, and that positive pharmacological modulation of SK2 channels with CyPPA protects against cell death induced by the ER stressors brefeldin A and tunicamycin. Calcium imaging of HT-22 neurons revealed that elevated cytosolic Ca 2+ levels and decreased ER Ca 2+ load during sustained ER stress could be largely prevented by SK2 channel activation. Interestingly, SK2 channel activation reduced the amount of the unfolded protein response transcription factor ATF4, but further enhanced the induction of CHOP. Using siRNA approaches we confirmed a detrimental role for ATF4 in ER stress, whereas CHOP regulation was dispensable for both, brefeldin A toxicity and CyPPA-mediated protection. Cell death induced by blocking Ca 2+ influx into the ER with the SERCA inhibitor thapsigargin was not prevented by CyPPA. Blocking the K + efflux via K + /H + exchangers with quinine inhibited CyPPA-mediated neuroprotection, suggesting an essential role of proton uptake and K + release in the SK channel-mediated neuroprotection. Our data demonstrate that ER SK2 channel activation preserves ER Ca 2+ uptake and retention which determines cell survival in conditions where sustained ER stress contributes to progressive neuronal death.

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A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress

Abstract: O. A dibenzoylmethane derivative protects dopaminergic neurons against both oxidative stress and endoplasmic reticulum stress.

Cited by 44 publications

References 46 publications

A Carbazole Derivative Protects Cells Against Endoplasmic Reticulum (ER) Stress and Glutathione Depletion

A Carbazole Derivative Protects Cells Against Endoplasmic Reticulum (ER) Stress and Glutathione Depletion

Effects of a combretastatin A4 analogous chalcone and its Pt-complex on cancer cells: A comparative study of uptake, cell cycle and damage to cellular compartments

Activation of SK2 channels preserves ER Ca2+ homeostasis and protects against ER stress-induced cell death

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