Doxorubicin-resistant LoVo adenocarcinoma cells display resistance to apoptosis induction by some but not all inhibitors of ser/thr phosphatases 1 and 2A

Sieder, S.; Richter, Elke; Becker, Klaus; Heins, R.; Steinfelder, Hans Jürgen

doi:10.1016/s0300-483x(99)00017-7

Cited by 15 publications

(18 citation statements)

References 18 publications

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“…Cantharidic acid has been shown to be a selective inhibitor of ser/thr phosphatases 1 and 2A [59], an effect which correlated well with the induction of cell death in tumour cells [60]. The observation of a loss in LoVo cell viability by cantharidic acid comparable to TBNS confirmed data of [61]. Cantharidic acid treatment at 25 µM for 24 h (72 h) resulted in 35% (85%) dead cells even in a doxorubicin-resistant LoVo cell line displaying the MDR-phenotype [61].…”

Section: Discussionsupporting

confidence: 58%

Comparison of the rapid pro-apoptotic effect of trans-ß-nitrostyrenes with delayed apoptosis induced by the standard agent 5-fluorouracil in colon cancer cells

2006

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Trans-beta-nitrostyrene (TBNS) has been reported to be a potent inhibitor of protein phosphatases PTB1 and PP2A and to display a pro-apoptotic effect even in multidrug resistant tumour cells. Here we compared the anti-tumour potential of TBNS with 5-fluorouracil (5-FU) as the standard chemotherapeutic agent for colorectal cancer in LoVo cells. Resistance to 5-FU based therapy might be a consequence of 5-FU's delayed effect requiring long-term effective concentrations in the tumour tissue. Thus, alternatives like platin containing drugs with a more rapid effect have been introduced recently. Compared to 5-FU TBNS displayed a faster cytotoxic and pro-apoptotic effect. A 50% decrease in viability was observed already after 8 h with TBNS while 5-FU displayed no significant effect before 48 h. DNA fragmentation and caspase-3 assays confirmed the more rapid apoptotic effect of TBNS. Since apoptosis affects individual cells these results about a rapidly induced apoptosis were further studied on a single cell level in microscopic assays of caspase-3 and caspase-8 activation. Adducts of trans-beta-nitrostyrene displayed an anti-tumour effect comparable to TBNS which suggests the possibility of creating adducts with optimised tissue targeting. Finally, the calculation of a drug combination index displayed a synergistic effect for the combination of TBNS and 5-FU in Lovo as well as in HT-29 and HCT116 colon cancer cells.

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Section: Discussionsupporting

confidence: 58%

Comparison of the rapid pro-apoptotic effect of trans-ß-nitrostyrenes with delayed apoptosis induced by the standard agent 5-fluorouracil in colon cancer cells

2006

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“…commun.) displayed a comparable crossresistance to OA (Sieder et al 1999). These results support our hypothesis that OA might be a substrate of mdr1-type P-glycoproteins.…”

Section: Discussionsupporting

confidence: 86%

“…6), suggesting that the resistance was genetically determined. This assumption was further evaluated by analysis of chromosomal metaphase spreads of the resistant GH 3 cells in comparison to LoVo human adenocarcinoma cells (LoVoDx) which express an unstable doxorubicin resistance and a comparable OA cross-resistance (Sieder et al 1999). These metaphase spreads revealed extrachromosomal DNA in resistant LoVoDx cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Contribution of mdr1b-type P-glycoprotein to okadaic acid resistance in rat pituitary GH 3 cells

Ritz

Marwitz

Sieder

et al. 1999

Naunyn-Schmiedeberg's Archives of Pharmacology

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Okadaic acid as well as other, structurally different, inhibitors of serine/threonine phosphatases 1 and 2A induce apoptosis in pituitary GH3 cells. Incubation with stepwise raised concentrations of okadaic acid resulted in the isolation of cells that were increasingly less sensitive to the cytotoxic effect of this agent. After about 18 months cells were selected that survived at 300 nM okadaic acid, which is about 30 times the initially lethal concentration. This study revealed that a major pharmacokinetic mechanism underlying cell survival was the development of a P-glycoprotein-mediated multidrug resistance (MDR) phenotype. The increase in mRNA levels of the mdr1b P-glycoprotein isoform correlated with the extent of drug resistance. Functional assays revealed that increasing drug resistance was paralleled by a decreased accumulation of rhodamine 123, a fluorescent dye which is a substrate of mdr1-mediated efflux activity. Resistance could be abolished by structurally different chemosensitizers of P-glycoprotein function like verapamil and reserpine but not by the leukotriene receptor antagonist MK571 which is a modulator of the multidrug resistance-associated protein (MRP). Okadaic acid resistance included cross-resistance to other cytotoxic agents that are substrates of mdr1-type P-glycoproteins, like doxorubicin and actinomycin D, but not to non-substrates of mdr1, e.g. cytosine arabinoside. Thus, functional as well as biochemical features support the conclusion that okadaic acid is a substrate of the mdr1-mediated efflux activity in rat pituitary GH3 cells. Maintenance of resistance after withdrawal of okadaic acid as well as metaphase spreads of 100 nM okadaic acid-resistant cells suggested a stable MDR genotype without indications for the occurrence of extrachromosomal amplifications, e.g. double minute chromosomes.

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“…Upregulation of the multidrug resistance related P-gp channel has been shown in most cell clones that developed spontaneous OA resistance during prolonged exposure to low concentrations of OA. 35 ± 37 Such cells were still sensitive to cantharidin, 28 suggesting that mdr-1 upregulation had not taken place in OAR1 or OAR2. In In order to verify the effect and speci®city of oar1 and oar2, the cDNAs were reintroduced into virus vector (pBMN) carrying the gene for neomycin resistance.…”

Section: Optimisation Of the Selection Systemmentioning

confidence: 99%

Establishment of okadaic acid resistant cell clones using a cDNA expression library

2001

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The mechanism whereby the universal apoptogen and serine/ threonine phosphatase inhibitor okadaic acid (OA) kills cells, is still unclear. To create a novel tool for probing of OA action, fibroblasts were selectedfor OA-resistance after infection with a retroviral Jurkat T-cell cDNA expression library. Twenty-one cloneswereselected. Twoof these(OAR1,OAR2)werestudied in detail. OAR1 and 2 had each a retrovirally introduced short cDNA, corresponding to a human gene (oar1 and oar2, respectively) with unknown function. Reintroduction of oar1 or oar2 cDNA into wild-type cells reproduced the OA-resistant phenotype. OAR1 and 2 were cross-resistant to other phosphatase inhibitors (calyculin A, cantharidin), but not to staurosporineor microinjectedCytochromec,thus,indicating a disturbance in a limited number of death pathways, upstream or independent of apaf-1/caspases-3/9. The action of OA involved caspase-dependent and caspase-independent components. Both components were less efficient in OAR1 and 2, than in wild-type cells. Subtle differences existed between OAinduced phosphoprotein patterns in wild-type cells, OAR1, and OAR2, indicating that a narrow selection of protein phosphorylation events had been targeted. We propose that the clones have defects in a hitherto non-elucidated signal pathway linking OA-induced protein phosphorylation to initiation of a death execution pathway provided with a caspase-dependent amplification loop. The novel OAresistant cell clones will be used to elucidate the significance for apoptosis of oar1 and 2, their link to altered protein phosphorylation, and the potential link of the latter to initiation of apoptosis. Cell Death and Differentiation (2001) 8, 754 ± 766.

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Doxorubicin-resistant LoVo adenocarcinoma cells display resistance to apoptosis induction by some but not all inhibitors of ser/thr phosphatases 1 and 2A

Cited by 15 publications

References 18 publications

Comparison of the rapid pro-apoptotic effect of trans-ß-nitrostyrenes with delayed apoptosis induced by the standard agent 5-fluorouracil in colon cancer cells

Comparison of the rapid pro-apoptotic effect of trans-ß-nitrostyrenes with delayed apoptosis induced by the standard agent 5-fluorouracil in colon cancer cells

Contribution of mdr1b-type P-glycoprotein to okadaic acid resistance in rat pituitary GH 3 cells

Establishment of okadaic acid resistant cell clones using a cDNA expression library

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