Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: Neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3

Florea, Ana-Maria; Splettstoesser, Frank; Dopp, Elke; Rettenmeier, Albert W.; Büsselberg, Dietrich

doi:10.1016/j.tox.2005.05.029

Cited by 32 publications

(13 citation statements)

References 35 publications

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“…Cells were loaded with Fluo-4/AM, which increases fluorescence upon binding free calcium. 30 Cells were incubated in calcium-free media with EGTA to reduce potentially confounding effects of extracellular calcium, and incubated with or without 1.5 M flavopiridol for 1, 3, and 5 hours. Increases in intracellular free calcium were noted in each sample following treatment ( Figure 4A), although the time at which maximal fluorescence occurred varied and data are therefore shown by individual sample.…”

Section: Flavopiridol Induces Mobilization Of Intracellular Calciummentioning

confidence: 99%

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Hussain

Lucas

Johnson

et al. 2008

Blood

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Effective administration of flavopiridol in advanced-stage chronic lymphocytic leukemia (CLL) is often associated with early biochemical evidence of tumor cell lysis. Previous work using other cell types showed that flavopiridol impacts mitochondria, and in CLL cells flavopiridol down-regulates the mitochondrial protein Mcl-1. We therefore investigated mitochondrial structure and function in flavopiridol-treated CLL patient cells and in the lymphoblastic cell line 697 using concentrations and times at which tumor lysis is observed in treated patients. Mitochondrial membrane depolarization was detected in flavopiridol-treated CLL cells by 6 hours, well before the onset of cell death. Flavopiridol-induced mitochondrial depolarization was not blocked by caspase inhibitors or by the calcium chelator EGTA, but was reduced by Bcl-2 overexpression. Intracellular calcium mobilization was noted at early time points using fluorescence microscopy. Furthermore, electron paramagnetic resonance oximetry showed a gradual but significant reduction in cellular oxygen consumption rate by 6 hours, corresponding with ultrastructural mitochondrial damage detected by electron microscopy. IntroductionFlavopiridol is a semisynthetic flavone (N-methylpiperidinyl chlorophenyl flavone) that is considered to act broadly as a cyclindependent kinase (CDK) inhibitor. 1 However, the in vivo mechanism of action of flavopiridol is not well understood, and may involve actions other than or inclusive of CDK inhibition. Our group recently demonstrated significant clinical efficacy of flavopiridol in patients with refractory chronic lymphocytic leukemia (CLL) using a novel schedule of administration. 2 Approximately 50% of CLL patients who receive flavopiridol using this schedule exhibit biochemical signs of tumor lysis (elevated potassium and phosphate levels, reduced calcium levels) occurring as early as 4.5 hours after treatment initiation. In limited cases with highly elevated peripheral white blood cell counts, this tumor lysis can be severe enough to require dialysis. This observation suggests that flavopiridol, when effectively administered, induces very rapid cell death that is atypical of classical apoptosis. However, more work is needed to understand this process and to better predict which patients may experience severe tumor lysis.Multiple previous studies in different cell types have incriminated mitochondrial mechanisms in flavopiridol-induced apoptosis, although conditions and time points under which this is noted vary widely and are often reported in combination with other agents. [3][4][5][6][7][8][9][10][11] Several reports showed that flavopiridol induces mitochondrial membrane disruption and release of cytochrome c in the U937 human monoblastic leukemia cell line and that these effects were potentiated by phorbol myristate acetate (PMA). 4,9,10 This process in U937 cells was noted to be partially caspase independent, as a general caspase inhibitor blocked flavopiridol-induced loss of mitochondrial membrane potential (⌬⌿ m ) but ...

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Section: Flavopiridol Induces Mobilization Of Intracellular Calciummentioning

confidence: 99%

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Hussain

Lucas

Johnson

et al. 2008

Blood

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“…Neuronal damage shows a subacute pattern developing over three weeks [25] and is associated with astroglial and microglial activation [26]–[29], enhanced neurogenesis [30], seizures and cognitive impairment [17], [18]. While the mechanisms by which TMT induces neurodegeneration are still not conclusively clarified, many hypotheses suggest that neuronal damage could be largely dependent on calcium overload, possibly as a consequence of its release from intracellular stores [24], [31], [32].…”

Section: Introductionmentioning

confidence: 99%

The Neurogenic Effects of Exogenous Neuropeptide Y: Early Molecular Events and Long-Lasting Effects in the Hippocampus of Trimethyltin-Treated Rats

et al. 2014

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Modulation of endogenous neurogenesis is regarded as a promising challenge in neuroprotection. In the rat model of hippocampal neurodegeneration obtained by Trimethyltin (TMT) administration (8 mg/kg), characterised by selective pyramidal cell loss, enhanced neurogenesis, seizures and cognitive impairment, we previously demonstrated a proliferative role of exogenous neuropeptide Y (NPY), on dentate progenitors in the early phases of neurodegeneration. To investigate the functional integration of newly-born neurons, here we studied in adult rats the long-term effects of intracerebroventricular administration of NPY (2 µg/2 µl, 4 days after TMT-treatment), which plays an adjuvant role in neurodegeneration and epilepsy. Our results indicate that 30 days after NPY administration the number of new neurons was still higher in TMT+NPY-treated rats than in control+saline group. As a functional correlate of the integration of new neurons into the hippocampal network, long-term potentiation recorded in Dentate Gyrus (DG) in the absence of GABAA receptor blockade was higher in the TMT+NPY-treated group than in all other groups. Furthermore, qPCR analysis of Kruppel-like factor 9, a transcription factor essential for late-phase maturation of neurons in the DG, and of the cyclin-dependent kinase 5, critically involved in the maturation and dendrite extension of newly-born neurons, revealed a significant up-regulation of both genes in TMT+NPY-treated rats compared with all other groups. To explore the early molecular events activated by NPY administration, the Sonic Hedgehog (Shh) signalling pathway, which participates in the maintenance of the neurogenic hippocampal niche, was evaluated by qPCR 1, 3 and 5 days after NPY-treatment. An early significant up-regulation of Shh expression was detected in TMT+NPY-treated rats compared with all other groups, associated with a modulation of downstream genes. Our data indicate that the neurogenic effect of NPY administration during TMT-induced neurodegeneration involves early Shh pathway activation and results in a functional integration of newly-generated neurons into the local circuit.

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“…It has been previously found that TMT could elevate (Ca 2+ )i in different cells, such as HeLa S3 cells (Florea et al, 2005a), SY5Y cells (Florea et al, 2005b), spiral ganglion cells and outer hair cells (Liu and Fechter, 1996). To investigate a possible role for Ca 2+ in the response of TMT in rat colon, the effects of extracellular Ca 2+ and the intracellular Ca 2+ store were examined.…”

Section: Resultsmentioning

confidence: 99%

“…Although progress of research in the biological activities of TMT has been made, its specific mechanism still needs to be clearly investigated. The main mechanisms of the toxic effects of TMT were focused on oxidative stress (Skarning et al, 2002; Yoneyama et al, 2008), induction of apoptosis (Buck‐Koehntop et al, 2005) and (Ca 2+ )i (intracellular Ca 2+ ) (Yu et al, 2000; Florea et al, 2005a, 2005b).…”

Section: Introductionmentioning

confidence: 99%

Trimethyltin chloride induced chloride secretion across rat distal colon

Hou

Chen

Yang

et al. 2010

Cell Biology International

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TMT (trimethyltin chloride), an organotin, is ubiquitous in the environment. The consumption of contaminated food may cause exposure of the human diet to this toxic compound. The present study was to investigate the effects of TMT on the regulation of ion transport across the rat distal colon. The rat colonic mucosa was mounted in Ussing chambers. The effects of TMT were assessed using the Isc (short-circuit current). Both apical and basolateral TMT induced, dose-dependently, an increase in Isc, which was due to a stimulation of Cl- secretion as measured using ion substitution experiments and pharmacological manoeuvres. The secretion was also inhibited by several K+ channel blockers administrated at the basolateral side. When the apical side was permeabilized by nystatin, the TMT-induced K+ conductance was effectively blocked by tetrapentylammonium, a Ca2+-sensitive K+ channel blocker. The response of TMT was sensitive to the basolateral Ca2+ and the intracellular Ca2+ store, which could be disclosed by applying the inhibitors of ryanodine receptors and inositol 1,4,5-trisphosphate receptors. In conclusion, TMT led to Cl- secretion, which was essentially regulated by basolateral Ca2+-sensitive K+ channels. These results suggest the importance of K+ channels in the toxicity hazard of TMT.

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Modulation of intracellular calcium homeostasis by trimethyltin chloride in human tumour cells: Neuroblastoma SY5Y and cervix adenocarcinoma HeLa S3

Cited by 32 publications

References 35 publications

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

Flavopiridol causes early mitochondrial damage in chronic lymphocytic leukemia cells with impaired oxygen consumption and mobilization of intracellular calcium

The Neurogenic Effects of Exogenous Neuropeptide Y: Early Molecular Events and Long-Lasting Effects in the Hippocampus of Trimethyltin-Treated Rats

Trimethyltin chloride induced chloride secretion across rat distal colon

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