Quantitative confocal spectral imaging analysis of mitoxantrone within living K562 cells: intracellular accumulation and distribution of monomers, aggregates, naphtoquinoxaline metabolite, and drug-target complexes

Feofanov, Alexei V.; Sharonov, S.; Fleury, Fabrice; Kudelina, Irina A.; Nabiev, Igor

doi:10.1016/s0006-3495(97)78357-7

Cited by 50 publications

(42 citation statements)

References 23 publications

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“…The localization of mitoxantrone in both cellular nuclei and cytoplasm has been also reported by other investigators (Fox and Smith, 1995;Feofanov et al, 1997). We reported previously that the intracellular distribution pattern of doxorubicin in MDA-MB-435wt cells was mainly in the cellular nuclei.…”

Section: Discussionsupporting

confidence: 86%

Dynamic Assessment of Mitoxantrone Resistance and Modulation of Multidrug Resistance by Valspodar (PSC833) in Multidrug Resistance Human Cancer Cells

Shen

Bailey

Chu

et al. 2009

J Pharmacol Exp Ther

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P-glycoprotein (Pgp), a member of the ATP-binding cassette transporter family, is one of the major causes for multidrug resistance (MDR). We report using confocal microscopy to study the roles of Pgp in mediating the efflux of the anticancer agent mitoxantrone and the reversal of MDR by the specific Pgp inhibitor valspodar (PSC833). The net uptake and efflux of mitoxantrone and the effect of PSC833 were quantified and compared in Pgp-expressing human cancer MDA-MB-435 (MDR) cells and in parental wild-type cells. The MDR cells, transduced with the human Pgp-encoding gene MDR1 construct, were approximately 8-fold more resistant to mitoxantrone than the wild-type cells. Mitoxantrone accumulation in the MDR cells was 3-fold lower than that in the wild-type cells.The net uptake of mitoxantrone in the nuclei and cytoplasm of MDR cells was only 58 and 67% of that in the same intracellular compartment of the wild-type cells. Pretreatment with PSC833 increased the accumulation of mitoxantrone in the MDR cells to 85% of that in the wild-type cells. In living animals, the accumulation of mitoxantrone in MDA-MB-435mdr xenograft tumors was 61% of that in the wild-type tumors. Administration of PSC833 to animals before mitoxantrone treatment increased the accumulation of mitoxantrone in the MDR tumors to 94% of that in the wild-type tumors. These studies have added direct in vitro and in vivo visual information on how Pgp processes anticancer compounds and how Pgp inhibitors modulate MDR in resistant cancer cells.

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Section: Discussionsupporting

confidence: 86%

Dynamic Assessment of Mitoxantrone Resistance and Modulation of Multidrug Resistance by Valspodar (PSC833) in Multidrug Resistance Human Cancer Cells

Shen

Bailey

Chu

et al. 2009

J Pharmacol Exp Ther

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“…The interest in the study of the metabolism of MTX has emerged due to the discover that the naphtoquinoxaline metabolite, which herein we called metabolite 5 (Table 1), is involved in the anti-tumoral effect of MTX (Feofanov et al 1997;Mewes et al 1993;Panousis et al 1997). The metabolite 5 was already described as the product of MTX metabolism through heme containing enzymes systems, CYP450, and peroxidases (Brück and Brück 2011;Blanz et al 1991).…”

Section: Discussionmentioning

confidence: 99%

The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity

et al. 2013

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Mitoxantrone (MTX) is an antitumor agent that causes cardiotoxicity in 18 % patients. The metabolic profile of MTX was assessed after incubation of 100 lM MTX with hepatic S9 fraction isolated from rats. The presence of MTX and its metabolites was also assessed in vivo through the analysis of liver and heart extracts of MTX-treated rats. The cytotoxic effects of MTX and MTX metabolites were evaluated in the H9c2 cells after 24-h incubation with MTX alone and MTX ? metabolites. The influence of CYP450-and CYP2E1-mediated metabolism for the cytotoxicity of MTX was assessed after 96-h incubation with MTX (100 nM and 1 lM) in the presence/ absence of CYP450 or CYP2E1 inhibitors. After 4-h incubation in supplemented S9 fraction, the MTX content was 35 % lower and 5 metabolites were identified: an acetoxy ester derivative (never described before), two glutathione conjugates, a monocarboxylic acid derivative, and the naphtoquinoxaline, the later commonly related to MTX pharmacological effects. The presence of MTX and naphtoquinoxaline metabolite was evidenced in vivo in liver and heart of MTX-treated rats. The cytotoxicity caused by MTX ? metabolites was higher than that observed in the H9c2 cells incubated with non-metabolized MTX group. The co-incubation of MTX with CYP450 and CYP2E1 inhibitors partially prevented the cytotoxicity observed in the MTX groups incubated with H9c2 cells, highlighting that the metabolism of MTX is relevant for its undesirable effects. The naphtoquinoxaline metabolite is described in heart and liver in vivo, highlighting that this metabolite accumulates in these tissues. It was demonstrated that MTX P450-mediated metabolism contributed to MTX toxicity.

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“…Decreases in the ATP hepatic levels are observed in the human non-alcoholic steatohepatitis [31], and are associated with covalent binding of drugs with intracellular proteins [32]. As already stated, MTX and its toxic known metabolite accumulates in the liver tissue [5,28] and its long-lasting effects can be attributed to MTX persistence in the cells and its strong affinity for cellular macromolecules and membranes [33]. Additionally, the ATP decreases can be related to mitochondrial disruption.…”

Section: Discussionmentioning

confidence: 99%

Cumulative Mitoxantrone‐Induced Haematological and Hepatic Adverse Effects in a Subchronic In vivo Study

Rossato

Costa

Dallegrave

et al. 2013

Basic Clin Pharma Tox

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Mitoxantrone (MTX) is an antineoplastic agent that can induce hepato-and haematotoxicity. This work aimed to investigate the occurrence of cumulative early and late MTX-induced hepatic and haematological disturbances in an vivo model. A control group and two groups treated with three cycles of 2.5 mg/kg MTX at days 0, 10 and 20 were formed. One of the treated groups suffered euthanasia on day 22 (MTX22) to evaluate early MTX toxic effects, while the other suffered euthanasia on day 48 (MTX48), to allow the evaluation of MTX late effects. An early immunosuppression with a drop in the IgG levels was observed, causing a slight decrease in the plasma total protein content. The early bone marrow depression was followed by signs of recovery in MTX48. The genotoxic potential of MTX was demonstrated by the presence of several micronuclei in MTX22 leucocytes. Increases in plasma iron and cholesterol levels in the MTX22 rats were observed, while in both groups increases in the unconjugated bilirubin, C4 complement, and decreases in the triglycerides, alanine aminotransferase, alkaline phosphatase and transferrin were found in plasma samples. On MTX 48, the liver histology showed more hepatotoxic signs, the hepatic levels of reduced and oxidized glutathione were increased, and ATP hepatic levels were decreased. However, the hepatic total protein levels were decreased only in the livers of MTX22 group. Results demonstrated the MTX genotoxic effects, haemato-and direct hepatotoxicity. While the haematological toxicity is ameliorated with time, the same was not observed in the hepatic injury.Mitoxantrone (MTX) is an anticancer and immunosuppressive drug that has been used in the treatment of tumours such as acute leukaemia, lymphoma, prostatic and breast cancer [1] and in the active forms of relapsing-remitting or secondary progressive multiple sclerosis [2]. MTX acts as an intercalating agent that causes double breaks in DNA by stabilization of a complex formed between DNA and topoisomerase II [1,3]. The regimen of MTX administration varies depending on disease progression and the clinical condition of the patient. Additionally, MTX is a substrate of membrane efflux pumps, namely the transporter breast cancer resistance protein (BCRP), which could interfere in MTX biodisposition [4]. However, the doses commonly employed range between 12-14 mg/m 2 and the maximum recommended cumulative dose is 140 mg/m 2 [1].One of the most serious adverse events related to MTX therapy is the late and irreversible cardiotoxicity [1], whose underlying mechanisms have been studied by us [5][6][7]. It is known that cardiotoxic drugs such as MTX can cause acute liver failure as a result of a primary congestive heart failure with low cardiac output and consequent reduced hepatic blood flow [8]. However, the precise origin of liver failure, due to a direct effect or secondary to the cardiomyopathy, is not easy to define, because clinical signs of cardiac decompensating can be undetected in a first moment delaying the diagnosis [8]. Additi...

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Quantitative confocal spectral imaging analysis of mitoxantrone within living K562 cells: intracellular accumulation and distribution of monomers, aggregates, naphtoquinoxaline metabolite, and drug-target complexes

Cited by 50 publications

References 23 publications

Dynamic Assessment of Mitoxantrone Resistance and Modulation of Multidrug Resistance by Valspodar (PSC833) in Multidrug Resistance Human Cancer Cells

Dynamic Assessment of Mitoxantrone Resistance and Modulation of Multidrug Resistance by Valspodar (PSC833) in Multidrug Resistance Human Cancer Cells

The metabolic profile of mitoxantrone and its relation with mitoxantrone-induced cardiotoxicity

Cumulative Mitoxantrone‐Induced Haematological and Hepatic Adverse Effects in a Subchronic In vivo Study

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