Biomedical subjects

Josephine S Modica-Napolitano

Publications and source records attributed to Josephine S Modica-Napolitano.

6 recordsLinked to original sources

PubMed2004

Mitochondrial dysfunction in cancer.

Nearly a century of scientific research has revealed a number of notable differences in the structure and function of mitochondria between normal and cancer cells, including differences in metabolic activity, molecular composition, and mtDNA sequence. This article reviews several of these differences and discusses their clinical implications, especially with regard to the use of mitochondria as biomarkers for early detection of cancer, or as unique cellular targets for novel and selective anti-cancer agents.

Journal Article↗

PubMed2004

Ethanolamine and phosphoethanolamine inhibit mitochondrial function in vitro: implications for mitochondrial dysfunction hypothesis in depression and bipolar disorder.

BACKGROUND: A growing body of experimental evidence suggests that mitochondrial dysfunction, including alterations in phospholipid metabolism, might be involved in the pathophysiology of affective illnesses, such as depression and bipolar disorder. The purpose of this study was to determine whether the phosphomonoester phosphoethanolamine (PE) and the lipid metabolite choline (Cho), which are known to be altered in depression and bipolar disorder, and/or their precursors/metabolites, might directly affect mitochondrial bioenergetic function in vitro. METHODS: To this end, rates of oxygen consumption in freshly isolated, intact mitochondria were determined polarographically in the presence and absence of PE, Cho, ethanolamine (Etn), glycerophosphoethanolamine (GPE), and glycerophosphocholine (GPC). RESULTS: The data demonstrate that PE and Etn inhibit mitochondrial respiratory activity in a dose-dependent manner, whereas Cho, GPC, and GPE have no measurable effect on bioenergetic function. CONCLUSIONS: This reflects a specific inhibition by Etn and PE on mitochondrial function rather than a more generalized phenomenon induced by similarities in structure between the lipid metabolites. These results also suggest a possible relationship between mitochondrial dysfunction and altered phospholipid metabolism in the brains of patients with depression and bipolar disorder.

Animals↗

PubMed2003

The selective in vitro cytotoxicity of carcinoma cells by AZT is enhanced by concurrent treatment with delocalized lipophilic cations.

This study assessed the selective growth inhibitory effect on cultured carcinoma cells by 3'-azido-3'-deoxythymidine (AZT), as a single agent, and in combination with delocalized lipophilic cations (DLCs) that are known to inhibit mitochondrial function. In cytotoxicity assays, treatment of cells with varying concentrations of AZT induced a dose-dependent inhibition of cell growth of the human carcinoma lines DU-145 (prostate; IC50 at 24 microM), MCF-7 (breast; IC50 at 22 microM), and CX-1 (colon; IC50 at 23 microM), yet caused no significant effect on the growth of the control epithelial cell line CV-1 (monkey kidney) at a concentration as high as 50 microM AZT. Combination treatment employing a constant concentration (1.25 microM) of the DLC dequalinium chloride (DECA) plus varying concentrations of AZT (0-50 microM) enhanced the AZT-induced cytotoxicity of carcinoma cells at least fourfold for MCF-7 and CX-1 cells (IC50 at 5 microM AZT), and twofold for DU-145 cells (IC50 at 11 microM AZT). Similar results were obtained in DU-145 cells using a constant concentration of the DLC MKT-077 (1.0 microM) and varying concentrations of AZT (IC50 at 12.5 microM). As expected, the drug combination of constant DLC and varying AZT had no significant effect on the growth of CV-1 cells. Clonogenic assays demonstrated up to 20-fold enhancement of selective carcinoma cell killing by combination vs. single agent treatment, depending on the specific drug combination and concentrations used. It is hypothesized that the efficacy of the AZT/DLC drug combination in carcinoma cell killing may be based on a dual selectivity involving inhibition of mitochondrial energy metabolism and inhibition of DNA synthesis due to limited deoxythymidine monophosphate availability.

Adenosine Triphosphate↗

PubMed2003

Differential effects of typical and atypical neuroleptics on mitochondrial function in vitro.

A series of typical (chlorpromazine, haloperidol and thioridazine) and atypical (risperidone, quetiapine, clozapine and olanzapine) antipsychotics were tested for effects on integrated bioenergetic functions of isolated rat liver mitochondria. Polarographic measurement of oxygen consumption in freshly isolated mitochondria showed that electron transfer activity at respiratory complex I is inhibited by chlorpromazine, haloperidol, risperidone, and quetiapine, but not by clozapine, olanzapine, or thioridazine. Chlorpromazine and thioridazine act as modest uncouplers of oxidative phosphorylation. The typical neuroleptics inhibited NADH-coenzyme Q reductase in freeze-thawed mitochondria, which is a direct measure of complex I enzyme activity. The inhibition of NADH-coenzyme Q reductase activity by the atypicals risperidone and quetiapine was 2-4 fold less than that for the typical neuroleptics. Clozapine and olanzapine had only slight effects on NADH-coenzyme Q reductase activity, even at 200 microM. The relative potencies of these neuroleptic drugs as inhibitors of mitochondrial bioenergetic function is similar to their relative potencies as risk factors in the reported incidence of extrapyramidal symptoms, including tardive dyskinesia (TD). This suggests that compromised bioenergetic function may be involved in the cellular pathology underlying TD.

Animals↗

PubMed2003

Permeability transition in rat liver mitochondria is modulated by the ATP-Mg/Pi carrier.

Mitochondrial permeability transition, due to opening of the permeability transition pore (PTP), is triggered by Ca2+ in conjunction with an inducing agent such as phosphate. However, incubation of rat liver mitochondria in the presence of low micromolar concentrations of Ca2+ and millimolar concentrations of phosphate is known to also cause net efflux of matrix adenine nucleotides via the ATP-Mg/Pi carrier. This raises the possibility that adenine nucleotide depletion through this mechanism contributes to mitochondrial permeability transition. Results of this study show that phosphate-induced opening of the mitochondrial PTP is, at least in part, secondary to depletion of the intramitochondrial adenine nucleotide content via the ATP-Mg/Pi carrier. Delaying net adenine nucleotide efflux from mitochondria also delays the onset of phosphate-induced PTP opening. Moreover, mitochondria that are depleted of matrix adenine nucleotides via the ATP-Mg/Pi carrier show highly increased susceptibility to swelling induced by high Ca2+ concentration, atractyloside, and the prooxidant tert-butylhydroperoxide. Thus the ATPMg/Pi carrier, by regulating the matrix adenine nucleotide content, can modulate the sensitivity of rat liver mitochondria to undergo permeability transition. This has important implications for hepatocytes under cellular conditions in which the intramitochondrial adenine nucleotide pool size is depleted, such as in hypoxia or ischemia, or during reperfusion when the mitochondria are exposed to increased oxidative stress.

Adenosine Diphosphate↗

PubMed2002

Mitochondria as targets for detection and treatment of cancer.

Mitochondria are dynamic intracellular organelles that play a central role in oxidative metabolism and apoptosis. The recent resurgence of interest in the study of mitochondria has been fuelled in large part by the recognition that genetic and/or metabolic alterations in this organelle are causative or contributing factors in a variety of human diseases including cancer. Several distinct differences between the mitochondria of normal cells and cancer cells have already been observed at the genetic, molecular and biochemical levels. As reviewed in this article, certain of these alterations in mitochondrial structure and function might prove clinically useful either as markers for the early detection of cancer or as unique molecular sites against which novel and selective chemotherapeutic agents might be targeted.

Animals↗