BCL-2 protects against apoptosis-related microtubule alterations in neuronal cells: Implications for Alzheimer's disease

Nuydens, Rony; Dispersyn, Gwenda; Kieboom, Gerd Van Den; Jongh, Mirjam De; Connors, Richard W.; Ramaekers, Frans C.S.; Borgers, M.; Geerts, Hugo

doi:10.1016/s0197-4580(00)82880-8

Cited by 15 publications

(16 citation statements)

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“…Furthermore, the prevention of Bcl-2 decrease has been associated with the protective effects of olanzapine on methamphetamine-induced neurotoxicity (He et al, 2004). Thus our own previous data, together with the findings by other investigators that OA-induced apoptosis is associated with downregulation of Bcl-2 and can be prevented by upregulation of Bcl-2 (Benito et al, 1997;Nuydens et al, 2000;Cabado et al, 2004), suggest that Bcl-2 plays an important role in the neuroprotective effects of olanzapine on OA-induced neurodegeneration and apoptosis. Olanzapine may also attenuate OA-induced neurotoxicity by upregulating superoxide dismutase (Manna et al, 1998;Li et al, 1999;Matias et al, 1999), and perform protective effects on OA-induced apoptotic cell death by modulating the expression of pro-and antiapoptotic proteins such as Bax and Bcl-X L (Wei et al, 2003b;Cabado et al, 2004).…”

Section: Discussionsupporting

confidence: 72%

Olanzapine Attenuates the Okadaic Acid-Induced Spatial Memory Impairment and Hippocampal Cell Death in Rats

Yang

et al. 2005

Neuropsychopharmacol

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It is hypothesized that olanzapine, an atypical antipsychotic drug, has beneficial effects on cognitive impairment and neuropathological changes in treating neurodegenerative diseases. In the present study, we investigated the effects of chronic administration of olanzapine on the spatial memory impairment and hippocampal cell death induced by the direct injection of okadaic acid (OA), a potent neurotoxin, into the rat hippocampus. After being pretreated with olanzapine (0.5 or 2 mg/kg/day, i.p.) for 2 weeks, the rats were unilaterally microinjected with OA (100 ng) into the hippocampus, and then were continuously administrated with olanzapine for an additional week. The rats were trained on a spatial memory task in an eight-arm radial maze before OA administration, and tested on the same task 18 h after the last olanzapine injection. After the behavioral test, the rats were killed for Nissl staining and terminal deoxynucleutidyl transferase-mediated biotinylated UTP nick end labeling staining. OA significantly induced spatial memory impairment, and caused pyramidal cell loss in the CA1 and apoptotic cell death in the hippocampus. Olanzapine significantly attenuated OA-induced spatial memory impairment and the OA-induced neuropathological changes in the hippocampus. These findings suggest that olanzapine may have therapeutic effects in treatment of cognitive impairment and neuropathological changes of schizophrenia and other neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 72%

Olanzapine Attenuates the Okadaic Acid-Induced Spatial Memory Impairment and Hippocampal Cell Death in Rats

Yang

et al. 2005

Neuropsychopharmacol

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“…Furthermore, overexpression of bcl-2 inhibited TSA-induced apoptosis. This finding bears significance in the context of the investigation by Nuydens et al (33) of the effects of paclitaxel on neuronal morphology and microtubule stability. These investigators found that bcl-2 overexpression attenuated the increased ratio of acetylated tubulin to total tubulin induced by paclitaxel treatment.…”

Section: Discussionsupporting

confidence: 54%

Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells

Dowdy

Jiang

Zhou³

et al. 2006

Molecular Cancer Therapeutics

134

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The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies. In this investigation, we define the activity of this class of inhibitors in combination with traditional cytotoxic chemotherapy in endometrial cancer cells. Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This combination also resulted in significant changes in cell morphology. Using cell cycle analysis, nuclear staining, and Western blot analysis for poly(ADPribose) polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most dramatic activation of the apoptotic cascade. These effects were also observed when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for TSA. The anticancer properties of paclitaxel are known to result in part from inhibition of microtubule depolymerization, which results in apoptosis. We show that TSA administration also stabilizes microtubules via A-tubulin acetylation. Furthermore, using Western blot and immunohistochemical analysis, treatment with TSA/paclitaxel led to a significant increase in acetylated tubulin and microtubule stabilization. These effects were confirmed in a mouse xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor weight compared with either agent alone. This study provides in vivo evidence of nonhistone protein acetylation as one possible mechanism by which HDAC inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold promise for the treatment of serous endometrial carcinoma and other malignancies with limited sensitivity to paclitaxel.

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“…However, our results indicate that, in paclitaxel-resistant untransformed human mammary epithelial cells, association of microtubular network disruption with apoptosis defect could greatly contribute to trigger aneuploidy in response to paclitaxel. As various processes could associate microtubule defects and paclitaxel resistance, further studies should ascertain mechanisms that impede microtubule-related cell death initiation in PSP sublines (Davis and Johnson, 1999;Nuydens et al, 2000;Mollinedo and Gajate, 2003). Of note, an other interesting issue would consist in determining whether modified tubulin expressions have been initially selected in HME1 cells because of their paclitaxel-resistance properties or whether they result from paclitaxel-induced aberrant but viable phenotypes.…”

Section: Discussionmentioning

confidence: 99%

Paclitaxel resistance in untransformed human mammary epithelial cells is associated with an aneuploidy-prone phenotype

et al. 2007

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Despite its increasing clinical use, almost no data are currently available about paclitaxel effects on non-cancerous mammary epithelial cells. We have previously established paclitaxel-resistant sub-cell lines (paclitaxel-surviving populations, PSPs; n ¼ 20), and sensitive controls (control clones, CCs; n ¼ 10), from the untransformed human mammary epithelial cell line HME1. In this study, we aimed to establish whether paclitaxel resistance was associated with a modified sensitivity to paclitaxel-induced aneuploidy. For this purpose, we analysed basal and paclitaxel-induced chromosome missegregation, apoptosis and aberrant spindle multipolarisation as well as microtubular network composition for each subline. PSP sublines showed higher basal and paclitaxel-induced chromosome missegregation than the CC sublines. This phenomenon was associated with resistance to paclitaxel-induced apoptosis. No significant difference in paclitaxel-induced spindle pole abnormalities between CC and PSP sublines was found. Besides, we showed that a majority of PSPs display a constitutively disrupted microtubular network composition due to aberrant tubulin expression and posttranslational modifications. These results clearly indicate that paclitaxel resistance in untransformed human mammary epithelial cells is related to an increased susceptibility to acquire aneuploidy in response to this agent. The consequences of these paclitaxel-associated alterations could be deleterious as they can potentially trigger tumorigenesis. British Journal of Cancer (2007) (Colella et al, 1999;Branch et al, 2000). However, increased genetic damages could also have adverse consequences if the affected cells are not malignant. In fact, it has been previously shown that genetic instability, characterised by an abnormal number of chromosomes, is associated with secondary malignancies. Thus, consideration of the potential aneugenicity of chemotherapy to humans is a necessary adjunct to its clinical use.Paclitaxel is a chemotherapeutic agent that is frequently used in several human cancers, including lung, ovarian and breast cancer. Several previous works have addressed the aneugenic potential of this agent in various in vitro and in vivo models (Tinwell and Ashby, 1994;Jagetia and Adiga, 1995;Jagetia and Nayak, 1996;Digue et al, 1999;Galmarini et al, 2007). However, despite its increasing use, almost no data are currently available concerning its effects in normal human mammary epithelial cells. In a precedent work, we described that sub-cell lines of untransformed human mammary epithelial cells (HME1) were able to survive to a 1-week paclitaxel treatment (paclitaxel-surviving populations, PSPs) (Galmarini et al, 2006). In most of these sublines, the emergence of a transitory or stable drug resistance phenotype was related to the inactivation of p21/WAF1 protein.In this study, we sought to determine whether paclitaxel resistance could be related to a modified sensitivity to paclitaxel aneugenicity. For this purpose, we firstly assayed whether paclitaxel tre...

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BCL-2 protects against apoptosis-related microtubule alterations in neuronal cells: Implications for Alzheimer's disease

Cited by 15 publications

References 0 publications

Olanzapine Attenuates the Okadaic Acid-Induced Spatial Memory Impairment and Hippocampal Cell Death in Rats

Olanzapine Attenuates the Okadaic Acid-Induced Spatial Memory Impairment and Hippocampal Cell Death in Rats

Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells

Paclitaxel resistance in untransformed human mammary epithelial cells is associated with an aneuploidy-prone phenotype

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