Doxorubicin-induced calcium release from cardiac sarcoplasmic reticulum vesicles

Kim, Do Han; Landry, Arthur B.; Lee, Young-Sup; Katz, Arnold M.

doi:10.1016/0022-2828(89)90782-7

Cited by 68 publications

(25 citation statements)

References 19 publications

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“…Our data corroborate that anthracyclins can reduce the ER Ca 2 þ concentration. [17][18][19] Although statistically significant and consistent (in more than 15 independent experiments), this effect is far from spectacular, at least in SH-SY5Y neuroblastoma cells. Upon RTN-1C overexpression (which reduces ER Ca 2 þ influx and hence further lowers the [Ca 2 þ ] ER ) or after treatment with the Ca 2 þ chelator BAPTA-AM (which also reduces ER Ca 2 þ influx), however, SH-SY5Y cells acquired the capacity to expose CRT in response to anthracyclins.…”

Section: Discussionmentioning

confidence: 64%

“…Thus, the anthracyclin-stimulated CRT exposure is not mediated by a classical DNA damage response (which would involve the nucleus). Anthracyclins have been reported to exert a direct toxic effect on the PM, 13 to stimulate ceramide synthesis, 14 to induce the generation of reactive oxygen species, 15,16 and to affect intracellular Ca 2 þ homeostasis, mainly by reducing ER Ca 2 þ concentrations, 17,18 perhaps through a direct effect on ER proteins such as calsequestrin. 19 Based on the aforementioned information, we decided to investigate the impact of ER Ca 2 þ homeostasis on the regulation of CRT exposure on the surface of anthracyclintreated tumor cells.…”

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confidence: 99%

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Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

et al. 2007

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Some chemotherapeutic agents can elicit apoptotic cancer cell death, thereby activating an anticancer immune response that influences therapeutic outcome. We previously reported that anthracyclins are particularly efficient in inducing immunogenic cell death, correlating with the pre-apoptotic exposure of calreticulin (CRT) on the plasma membrane surface of anthracyclintreated tumor cells. Here, we investigated the role of cellular Ca 2 þ homeostasis on CRT exposure. A neuroblastoma cell line (SH-SY5Y) failed to expose CRT in response to anthracyclin treatment. This defect in CRT exposure could be overcome by the overexpression of Reticulon-1C, a manipulation that led to a decrease in the Ca 2 þ concentration within the endoplasmic reticulum lumen. The combination of Reticulon-1C expression and anthracyclin treatment yielded more pronounced endoplasmic reticulum Ca 2 þ depletion than either of the two manipulations alone. Chelation of intracellular (and endoplasmic reticulum) Ca 2 þ , targeted expression of the ligand-binding domain of the IP 3 receptor and inhibition of the sarco-endoplasmic reticulum Ca 2 þ -ATPase pump reduced endoplasmic reticulum Ca 2 þ load and promoted pre-apoptotic CRT exposure on the cell surface, in SH-SY5Y and HeLa cells. These results provide evidence that endoplasmic reticulum Ca 2 þ levels control the exposure of CRT. In contrast to prior belief, apoptotic cell death can be immunogenic and hence elicits an active immune response against dying tumor cells. 1 This is therapeutically relevant because immune defects that compromise the response against apoptotic cells reduce the efficacy of anticancer chemotherapy, both in suitable animal models and in patients. 2 We found that anthracyclins and g-irradiation are particularly efficient in inducing immunogenic cell death, at least in mouse models. [3][4][5] The immunogenicity of cellular demise correlates with the exposure of calreticulin (CRT) on the plasma membrane (PM) surface of stressed tumor cells, a phenomenon that manifests before the cells acquire signs of apoptosis such as phosphatidylserine exposure. Inhibition of CRT exposure curtails the capacity of anthracyclin-treated or irradiated tumor cells to vaccinate against cancer and reduces the therapeutic efficacy of anthracyclins on tumors established in immunocompetent hosts. 3-5 Provision of recombinant CRT or drug-mediated enforcement of CRT exposure rendered per se nonimmunogenic chemotherapies (for instance with etoposide and mitomycin C) immunogenic and boosted their therapeutic efficacy. 5 These results suggest that CRT exposure is both necessary and sufficient to render conventional chemotherapies immunogenic.CRT is an abundant Ca 2 þ -binding chaperone that is mostly present in the endoplasmic reticulum (ER) lumen, although it can also be found in other subcellular localizations. 6,7 When present on the surface of damaged cells, it can serve as an 'eat-me' signal and hence facilitate the recognition and later engulfment of the dying cells by macrophages 8 or by dendrit...

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Section: Discussionmentioning

confidence: 64%

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confidence: 99%

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

et al. 2007

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“…Atrial cells were cultured in 96-well plates at a density of 3ϫ10 4 cells per well for 48 hours before changing to DMEM/SS. Cells were then treated with different concentrations of doxorubicin for 24 hours or 0.3 mol/L doxorubicin (Sigma Chemical Co) for variable periods of time.…”

Section: Cell Viability Bioassaymentioning

confidence: 99%

“…2 The mechanisms that underlie the cardiotoxicity are only partially understood. Possible mechanisms include direct or indirect release of endogenous toxins (eg, histamine), 3 alterations in intracellular calcium homeostasis, 4 generation of free radicals that damage cellular membranes, 5,6 and intercalation of drug in the nuclear and mitochondrial genome, resulting in diminished RNA and protein synthesis. 7 Of these mechanisms, the free radical hypothesis has received the most support.…”

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Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

1999

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Abstract-Doxorubicin is an antineoplastic agent with significant cardiotoxicity. We examined the effects of this agent on the expression of the natriuretic peptide (NP) genes in cultured neonatal rat atrial myocytes. Doxorubicin suppressed NP secretion, steady-state NP mRNA levels, and NP gene promoter activity. In each instance, brain NP (BNP) proved to be more sensitive than atrial NP (ANP) to the inhibitory effects of the drug. ICRF-187 and probucol reversed the inhibition by doxorubicin of ANP mRNA accumulation and ANP gene promoter activity while exerting no effect on BNP mRNA levels or promoter activity. This represents the first identification of the NP genes as targets of doxorubicin toxicity in the myocardial cell. This inhibition operates predominantly at a transcriptional locus and has more potent effects on BNP versus ANP secretion/gene expression.

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“…The discrepancy of these findings may be caused by different animal and cell culture models, the dosage of doxorubicin, the duration of the treatment and especially the developmental stage of the disease. In the early stage of the disease, doxorubicin tends to induce Ca 2+ release from SR and increase cardiomyocyte contractility (Brown et al, 1989b;Kim et al, 1989;Ondrias et al, 1990;Kapelko et al, 1996). In the late stage of the disease, doxorubicin inhibits Ca 2+ regulatory proteins and reduces cardiomyocyte contractility (Ondrias et al, 1990;Dodd et al, 1993;Maeda et al, 1998;Boucek et al, 1999;Chugun et al, 2000;Gambliel et al, 2002;Timolati et al, 2006).…”

Section: Doxorubicin Disturbs Calcium Homeostasis In Cardiomyocytesmentioning

confidence: 99%

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

Goukassian¹,

Morgan²,

Yan³

2012

Cardiotoxicity of Oncologic Treatments

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Doxorubicin-induced calcium release from cardiac sarcoplasmic reticulum vesicles

Cited by 68 publications

References 19 publications

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

Reduction of endoplasmic reticulum Ca2+ levels favors plasma membrane surface exposure of calreticulin

Doxorubicin Selectively Inhibits Brain Versus Atrial Natriuretic Peptide Gene Expression in Cultured Neonatal Rat Myocytes

Neuregulin1-ErbB Signaling in Doxorubicin-Induced Cardiotoxicity

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