Altered intracellular distribution of daunorubicin in immature acute myeloid leukemia cells

Lautier, Dominique; Bailly, Jean‐Denis; Demur, Cécile; Herbert, Jean‐Marc; Bousquet, Christine; Laurent, Guy

doi:10.1002/(sici)1097-0215(19970410)71:2<292::aid-ijc26>3.3.co;2-6

Cited by 8 publications

(14 citation statements)

References 13 publications

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“…When incubation takes place at 4jC, a fade diffuse fluorescent signal is observed at the membrane level ( Fig. 2A), in accord with previous results (Lautier et al, 1997). SIL encapsulation of Dox did not modify the intracellular distribution pattern being similar to that shown for free Dox at 4jC (Fig.…”

Section: Drug Uptake and Retentionsupporting

confidence: 91%

In vitro cytotoxic study of immunoliposomal doxorubicin targeted to human CD34+ leukemic cells

Carrión¹,

Madariaga²,

Domingo³

2004

Life Sciences

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Section: Drug Uptake and Retentionsupporting

confidence: 91%

In vitro cytotoxic study of immunoliposomal doxorubicin targeted to human CD34+ leukemic cells

Carrión¹,

Madariaga²,

Domingo³

2004

Life Sciences

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“…However, while many previous studies have associated MDR with vesicular accumulation of drugs (Gervasoni et al, 1991;Sognier et al, 1992;Sognier et al, 1994;Breuninger et al, 1995;Seidel et al, 1995;Cleary et al, 1997;Altan et al, 1998;Shapiro et al, 1998), we find that vesicular drug accumulation is more pronounced in the sensitive MES-SA cells than in the DOX-resistant Dx5 cells. Although other studies have shown vesicular drug accumulation in sensitive as well as resistant cells (Willingham et al, 1986;Lautier et al, 1997), this is the first study to our knowledge that describes a system in which MDR cells exhibit minimal vesicular drug accumulations.…”

Section: Discussionmentioning

confidence: 78%

“…Fluorescent drugs that are found in the nucleus and diffusely labeling the cytoplasm of sensitive cells are frequently found in peri-nuclear punctate vesicles in resistant cells (Beck, 1987;Klohs and Steinkampf, 1988;Gervasoni et al, 1991;de Lange et al, 1992;Rutherford and Willingham, 1993;Altan et al, 1998;Shapiro et al, 1998). Many studies have demonstrated an association between vesicular drug distributions and the expression of PGP (Gervasoni et al, 1991;Sognier et al, 1992;Sognier et al, 1994;Seidel et al, 1995;Cleary et al, 1997;Altan et al, 1998;Shapiro et al, 1998), or MRP (Breuninger et al, 1995 although drugs have also been observed in vesicles of sensitive cells (Willingham et al, 1986;Lelong et al, 1991;Lautier et al, 1997). Sequestration of drugs in endomembrane compartments may confer some degree of protection on cells from the effects of drugs whose cytotoxic targets are cytoplasmic or nuclear (Sognier et al, 1994;Breuninger et al, 1995).…”

mentioning

confidence: 99%

Lysosomal accumulation of drugs in drug-sensitive MES-SA but not multidrug-resistant MES-SA/Dx5 uterine sarcoma cells

2000

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Sequestration of drugs in intracellular vesicles has been associated with multidrug-resistance (MDR), but it is not clear why vesicular drug accumulation, which depends upon intracellular pH gradients, should be associated with MDR. Using a human uterine sarcoma cell line (MES-SA) and a doxorubicin (DOX)-resistant variant cell line (Dx-5), which expresses p-glycoprotein (PGP), we have addressed the relationship between multidrug resistance, vesicular acidification, and vesicular drug accumulation. Consistent with a pH-dependent mechanism of vesicular drug accumulation, studies of living cells vitally labeled with multiple probes indicate that DOX and daunorubicin (DNR) predominately accumulate in lysosomes, whose lumenal pH was measured at < 4.5, but are not detected in endosomes, whose pH was measured at 5.9. However, vesicular DOX accumulation is more pronounced in the drug-sensitive MES-SA cells and minimal in Dx5 cells even when cellular levels of DOX are increased by verapamil treatment. While lysosomal accumulation of DOX correlated well with pharmacologically induced differences in lysosome pH in MES-SA cells, lysosomal accumulation was minimal in Dx5 cells regardless of lysosomal pH. We found no differences in the pH of either endosomes or lysosomes between MES-SA and Dx5 cells, suggesting that, in contrast to other MDR cell systems, the drug-resistant Dx5 cells are refractory to pH-dependent vesicular drug accumulation. These studies demonstrate that altered endomembrane pH regulation is not a necessary consequence of cell transformation, and that vesicular sequestration of drugs is not a necessary characteristic of MDR.

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“…The confocal imaging system was a Zeiss (Oberkochen, Germany) scanning assembly incorporating argon and helium/neon lasers coupled to a Zeiss Axiovert 100 fluorescence microscope. Images were digitized and photographs were taken using Ilford FP4 films (44). Laser settings were kept identical for the examination of samples to be compared.…”

Section: Methodsmentioning

confidence: 99%

Implication of Protein Kinase C in the Regulation of DNA Mismatch Repair Protein Expression and Function

Humbert¹,

Hermine²,

Hernandez³

et al. 2002

Journal of Biological Chemistry

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The DNA mismatch repair (MMR) proteins are essential for the maintenance of genomic stability of human cells. Compared with hereditary or even sporadic carcinomas, MMR gene mutations are very uncommon in leukemia. However, genetic instability, attested by either loss of heterozygosity or microsatellite instability, has been extensively documented in chronic or acute malignant myeloid disorders. This observation suggests that in leukemia some internal or external signals may interfere with MMR protein expression and/or function. We investigated the effects of protein kinase C (PKC) stimulation by 12-O-tetradecanoylphorbol-13-acetate (TPA) on MMR protein expression and activity in human myeloid leukemia cell lines. First, we show here that unstimulated U937 cells displayed low level of PKC activity as well as MMR protein expression and activity compared with a panel of myeloid cell lines. Second, treatment of U937 cells with TPA significantly increased (3-5-fold) hMSH2 expression and, to a lesser extent, hMSH6 and hPMS2 expression, correlated to a restoration of MMR function. In addition, diacylglycerol, a physiological PKC agonist, induced a significant increase in hMSH2 expression, whereas chelerythrine or calphostin C, two PKC inhibitors, significantly decreased TPA-induced hMSH2 expression. Reciprocally, treatment of HEL and KG1a cells that exhibited a high level of PKC expression, with chelerythrine significantly decreased hMSH2 and hMSH6 expression. Moreover, the alteration of MMR protein expression paralleled the difference in microsatellite instability and cell sensitivity to 6-thioguanine. Our results suggest that PKC could play a role in regulating MMR protein expression and function in some myeloid leukemia cells.

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Altered intracellular distribution of daunorubicin in immature acute myeloid leukemia cells

Cited by 8 publications

References 13 publications

In vitro cytotoxic study of immunoliposomal doxorubicin targeted to human CD34+ leukemic cells

In vitro cytotoxic study of immunoliposomal doxorubicin targeted to human CD34+ leukemic cells

Lysosomal accumulation of drugs in drug-sensitive MES-SA but not multidrug-resistant MES-SA/Dx5 uterine sarcoma cells

Implication of Protein Kinase C in the Regulation of DNA Mismatch Repair Protein Expression and Function

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