Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

So, Ho; Kim, Hyung Jun; Jh, Lee; Sy, Park; Park, C; Yh, Kim; Jk, Kim; Km, Lee; Ks, Kim; Chung, Sy; Jang, W.; Sk, Moon; Chung, Habong; Park, R-K

doi:10.1038/sj.cdd.4401863

Cited by 82 publications

(74 citation statements)

References 50 publications

(52 reference statements)

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“…CoPPIX inhibits cisplatin-induced death in the HEI-OC1 auditory-derived cell line (Kim et al 2006a(Kim et al , 2009So et al 2006So et al , 2008Choi et al 2007Choi et al , 2008Choi et al , 2011Gao et al 2010). HO-1 expression has been reported in cochlear hair cells and stria vascularis following a variety of stressors, including noise stress, heat stress, and pharmacological induction (Fairfield et al 2004;Lopez et al 2008;Kim et al 2009;Matsunobu et al 2009;Fetoni et al 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Pharmacological induction of HO-1 is protective against multiple stresses in many tissue types, including ischemia-reperfusion injury in liver and retina (Tsuchihashi et al 2007;Sun et al 2010). Several studies have demonstrated that inducers of HO-1 protect against cisplatin-induced death in the HEI-OC1 auditory cell line (Kim et al 2006a(Kim et al , 2009So et al 2006So et al , 2008Choi et al 2007Choi et al , 2008Choi et al , 2011Gao et al 2010). We have shown that HO-1 induction inhibits hearing loss and hair cell death caused by aminoglycoside antibiotics (Francis et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 −/− mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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“…The NF-B reporter plasmid contains three copies of the B-binding sequence fused to the firefly luciferase gene (Clontech, Mountain View, CA). The ARE-luciferase reporter plasmid contains enhancer 2 (E2) and a minimal promoter sequence of the mouse HO-1 gene fused to the luciferase gene (So et al, 2006). BV2 cells (2 ϫ 10 5 cells per well in a 12-well plate) were transfected with 1 g of the reporter construct mixed with Geneporter.…”

Section: Methodsmentioning

confidence: 99%

Anti-Inflammatory Mechanism of Compound K in Activated Microglia and Its Neuroprotective Effect on Experimental Stroke in Mice

Park

Shin²,

Jung³

et al. 2011

J Pharmacol Exp Ther

122

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Microglial activation plays a pivotal role in the pathogenesis of various neurologic disorders, such as cerebral ischemia, Alzheimer's disease, and Parkinson's disease. Thus, controlling microglial activation is a promising therapeutic strategy for such brain diseases. In the present study, we found that a ginseng saponin metabolite, compound K [20-O-D-glucopyranosyl-20(S)-protopanaxadiol], inhibited the expressions of inducible nitric-oxide synthase, proinflammatory cytokines, monocyte chemotactic protein-1, matrix metalloproteinase-3, and matrix metalloproteinase-9 in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary cultured microglia. Subsequent mechanistic studies revealed that compound K suppressed microglial activation via inhibiting reactive oxygen species, mitogen-activated protein kinases, and nuclear factor-B/ activator protein-1 activities with enhancement of heme oxygenase-1/antioxidant response element signaling. To address the anti-inflammatory effects of compound K in vivo, we used two brain disease models of mice: sepsis (systemic inflammation) and cerebral ischemia. Compound K reduced the number of Iba1-positive activated microglia and inhibited the expressions of tumor necrosis factor-␣ and interleukin-1␤ in the LPS-induced sepsis brain. Furthermore, compound K reduced the infarct volume of ischemic brain induced by middle cerebral artery occlusion and suppressed microglial activation in the ischemic cortex. The results collectively suggest that compound K is a promising agent for prevention and/or treatment of cerebral ischemia and other neuroinflammatory disorders.

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“…For example, flunarizine inhibits membrane lysis and DNA fragmentation in explanted embryonic rat ventral mesencephalic cells [4] and impairs neuron death induced by a number of stimuli, including serum starvation and growth factor deprivation [5,6] and oxidative stress [7,8]. Flunarizine also protects auditory cells from the cytotoxic effects of cisplatin by inducing cytoprotective Akt activation and expression of heme oxygenase-1 [9]. Conversely, in some types of cancer cells flunarizine causes or potentiates cell death.…”

Section: Introductionmentioning

confidence: 99%

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

Conrad¹,

Furlong²,

Doucette³

et al. 2010

Apoptosis

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Flunarizine is a Ca(2+) channel blocker that can be either cytoprotective or cytotoxic, depending on the cell type that is being examined. We show here that flunarizine was cytotoxic for Jurkat T-leukemia cells, as well as for other hematological maligancies, but not for breast or colon carcinoma cells. Treatment of Jurkat cells with flunarizine resulted in caspase-3 activation, poly (ADP-ribose) polymerase cleavage, and laddering of DNA fragments, all of which are hallmarks of apoptosis. Flunarizine-induced DNA fragmentation was inhibited by the caspase-3 inhibitor z-DEVD-fmk, the caspase-8/caspase-10 inhibitor z-IETD-fmk, and the caspase-10 inhibitor z-AEVD-fmk, but was not reduced in caspase-8-deficient Jurkat cells, indicating the involvement of caspase-10 upstream of caspase-3 activation. Interestingly, FADD recruitment to a death receptor was not involved since flunarizine caused DNA fragmentation in FADD-deficient Jurkat cells. Flunarizine treatment of Jurkat cells also resulted in reactive oxygen species production, dissipation of mitochondrial transmembrane potential, release of cytochrome c from mitochondria, and caspase-9 activation, although none of these events were necessary for apoptosis induction. Collectively, these findings indicate that flunarizine triggers apoptosis in Jurkat cells via FADD-independent activation of caspase-10. Flunarizine warrants further investigation as a potential anti-cancer agent for the treatment of hematological malignancies.

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Flunarizine induces Nrf2-mediated transcriptional activation of heme oxygenase-1 in protection of auditory cells from cisplatin

Cited by 82 publications

References 50 publications

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Anti-Inflammatory Mechanism of Compound K in Activated Microglia and Its Neuroprotective Effect on Experimental Stroke in Mice

The Ca2+ channel blocker flunarizine induces caspase-10-dependent apoptosis in Jurkat T-leukemia cells

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