Adriamycin and daunomycin induce programmed cell death (apoptosis) in tumour cells

Składanowski, Andrzej; Konopa, Jerzy

doi:10.1016/0006-2952(93)90512-u

Cited by 173 publications

(99 citation statements)

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“…39 The fact that anthracyclines had a pro-apoptotic effect 20 opened up new research fields to investigate the molecular mechanisms triggering tumor cell death. Better understanding of the anthracycline apoptotic effect may lead to new therapeutic agents and to better biological support for drug evaluation.…”

Section: Discussionmentioning

confidence: 99%

“…[19][20][21]23,49 Caspase 3 is currently described as a common effector of apoptosis required in many models of cell death. 7 Caspase 3 is characterized by the DEVDase activity it shared with other members of the caspase family.…”

Section: Figurementioning

confidence: 99%

“…14,18 For many years, the anthracyclines have been used in leukemia treatment and it is known that anthracyclines induce an apoptotic cell death in a wide range of cultured cells. [19][20][21] Therapeutic daunorubicin (DNR) concentrations are about 1-2 M. 22 At these doses, DNR induces apoptosis in U937 and HL60 leukemic cell lines. 23,24 The Fas apoptotic pathway could at least partially play a role, [12][13][14][15][16] involving both death receptor/ligand accumulation on the cell surface 17,[25][26][27] and activation of the death effectors such as caspases in the cytoplasm.…”

Section: Introductionmentioning

confidence: 99%

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Study of apoptosis-related responses of leukemic blast cells to in vitro anthracycline treatment

Durrieu

Labroille³

et al. 2000

Leukemia

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Anthracyclines trigger an apoptotic cell death but their molecular targets are not totally explored. We investigated the apoptotic response of blast cells and lymphocytes from medullary samples of 31 de novo acute leukemia. Mononuclear cells were treated in vitro by therapeutic concentrations of either daunorubicin (DNR) or idarubicin (IDA) for 1 h, washed and cultured for 18 h. A multivariate analysis using flow cytometry and a CD45 gating on lymphocytes and blast cells was performed. DNR and IDA induced a Fas enhancement on both leukemic and normal cells. In blast cells the DEVDases were activated and the caspase 3 was cleaved in relation to phosphatidyl serine exposure, showing a caspase-dependent pathway in anthracycline-induced apoptosis. Apoptotic percentages were always higher for blast cells than for lymphocytes, confirming that anthracycline toxicity mainly affected tumor cells. Moreover, drug-induced apoptosis was not related to spontaneous apoptosis, suggesting that variations in response intensities were due to individual variations of sensitivity rather than to programmed life span time. The apoptotic response of Pglycoprotein-expressing blast cells was not significant, giving biological argument for the poor prognosis of multidrug resistance leukemia. Finally, Fas induction and anthracyclineinduced apoptosis on blast cells were significantly higher when a complete remission was achieved, thus shedding light on potential new prognostic factors in acute leukemia. Leukemia (2000) 14, 1266-1275.

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Section: Discussionmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Study of apoptosis-related responses of leukemic blast cells to in vitro anthracycline treatment

Durrieu

Labroille³

et al. 2000

Leukemia

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“…Daunorubicin exposure was initially shown to induce apoptosis (Skladanowski and Konopa, 1993). More recent results show that clinical doses of daunorubicin induce apoptosis in only some acute myeloid leukaemia cells.…”

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Dual mechanism of daunorubicin-induced cell death in both sensitive and MDR-resistant HL-60 cells

et al. 1999

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Summary Exposure of some acute myeloid leukaemia (AML) cells to daunorubicin leads to rapid cell death, whereas other AML cells show natural drug resistance. This has been attributed to expression of functional P-glycoprotein resulting in reduced drug accumulation. However, it has also been proposed that P-glycoprotein-expressing multidrug-resistant (MDR) cells are inherently defective for apoptosis. To distinguish between these different possibilities, we have compared the cell death process in a human AML cell line (HL-60) with a MDR subline (HL-60/Vinc) at doses that yield either similar intracellular daunorubicin concentrations or comparable cytotoxicity. Adjustment of the dose to obtain the same intracellular drug accumulation in the two cell lines did not result in equal cytotoxicity, suggesting the presence of additional resistance mechanisms in the P-glycoprotein-expressing HL-60/Vinc cells. However, at equitoxic doses, similar cell death pathways were observed. In HL-60 cells, daunorubicin induced rapid apoptosis at 0.5-1 µM and delayed mitotic cell death at 0.1 µM. These concentrations are within the clinical dose range. Similarly, HL-60/Vinc cells underwent apoptosis at 50-100 µM daunorubicin and mitotic cell death at 10 µM. These results show, for the first time, that anthracyclines can induce cell death by a dual mechanism in both sensitive and MDR cells. Our results also show that not only the cytotoxicity, but also the kinetics and mechanism of cell death, are dose dependent. Interestingly, regrowth was observed only in association with delayed cell death and the formation of enlarged, often polyploid, cells with micronucleation, suggesting that morphological criteria may be useful to evaluate treatment efficacy in patients with myeloid leukaemias.Keywords: drug resistance; P-glycoprotein; cell death; daunorubicin; myeloid leukaemia; response prediction 1090British Journal of Cancer (1999) 79(7/8), 1090-1097 © 1999 Cancer Research Campaign Article no. bjoc.1998 Received 25 February 1998 Revised 11 May 1998 Accepted 12 June 1998 Correspondence to: AK Larsen apoptotic morphological features and only very low levels of internucleosomal DNA fragmentation in the KG1 and KG1a cell lines (Quillet-Mary et al, 1996). Both KG1 and KG1a cells overexpress the MDR-1 gene as well as functional P-glycoprotein and are naturally resistant to daunorubicin compared with HL-60 or U937 cells. It has also been reported that another anthracycline, doxorubicin, induces internucleosomal fragmentation in parental P388 leukaemia cells but not in resistant P388/ADR cells that express the P-glycoprotein (Ling et al, 1993). These results can be interpreted in different ways. It is possible that P-glycoprotein expression and an altered cell death process represent two independent resistance mechanisms, which can occur together. Alternatively, the lack of apoptosis in MDR cells might be causally linked to the transport abnormalities as a minimum intracellular concentration of anthracycline may be required to trigger apoptosis...

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“…DNA internucleosomal fragmentation was also charac-MTT cytotoxicity assay terized by conventional agarose gel electrophoresis as previously described. 18 Briefly, cells (2 × 10 6 ) were lysed in Exponentially grown AML cells (5 × 10 5 cells/ml) were incubated with or without mitoxantrone for 6 h at 37°C. Cells were 10 mM Tris-HCl, 10 mM EDTA, 10 mM NaCl, 0.5% SDS, pH 7.4 and 0.5 mg/ml proteinase K and incubated 1 h at then washed and resuspended at 2 × 10 5 cells/ml, and 0.1 ml aliquots were removed and seeded in 96-well plates for an 50°C.…”

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confidence: 99%

Natural resistance of acute myeloid leukemia cell lines to mitoxantrone is associated with lack of apoptosis

et al. 1997

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The purpose of this study was to characterize mitoxantronetreated with chemotherapy alone remains low. In first-line induced cytotoxicity in KG1a and TF-1, two P-glycoprotein therapy, the 'gold standard' induction regimen consists of the expressing AML cell lines which display early differentiation administration of the anthracycline daunorubicin (DNR) in phenotypes, compared to more mature HL-60 and U937 cells.association with cytosine-arabinoside (Ara-C). While the KG1a and TF-1 cells were found to be 30-40-fold more resistant DNR/Ara-C combination induces a relatively high rate of to mitoxantrone than HL-60 and U937 cells. Uptake and efflux of mitoxantrone were similar for all cell lines. Moreover, a complete remission, the high incidence of early relapse indi- less recognized by the P-gp 9 and therefore may be more active Keywords: mitoxantrone; chemoresistance; apoptosis; leukemia than DNR towards immature AML cells.Mitoxantrone, an anthracenedione derivative, is a potent antitumor agent with proven activity against a number of Introduction human neoplasias, including AML. [10][11][12] The cytotoxic action Acute myeloid leukemia (AML) is a neoplastic disorder of mitoxantrone is believed to be associated with its ability to characterized by the clonal expansion of leukemic myeloid stabilize a covalent DNA-topoisomerase II reaction product, cells. In spite of apparent uniformity, AML cells consist of a the so-called cleavable complex (for review see Ref. 10). More heterogeneous cellular population. A small fraction of leurecently, it has been demonstrated that mitoxantrone induces kemic progenitor cells (CFU-L) proliferate and differentiate programmed cell death (apoptosis) in certain leukemia cells 13 into terminal division blast cells which comprise the vast although it remains unclear whether mitoxantrone-induced majority of leukemic cells observed in the blood and marrow apoptosis is a direct consequence of the mitoxantrone-topoof AML patients. 1 Similar to normal hemopoiesis, the leuisomerase II interaction. kemic myeloid progenitor compartment appears to be heteroTo the best of our knowledge, no study has been performed geneous with the less mature progenitors providing the selfevaluating the cytotoxic effects of mitoxantrone on AML cells renewal activity of the AML clone. 2 The phenotypic identifiderived from distinct stages of differentiation. Therefore, we cation of the most primitive AML cells has been lacking until have evaluated drug transport, drug-topoisomerase II interacrecent studies showed that leukemia initiating cells (SL-IC) tions, and cytotoxicity of mitoxantrone in two AML cell lines which can engraft SCID mice, and which can therefore be which express the early differentiation phenotype (KG1a and considered as leukemic stem cells, display the early CD34 + TF-1) compared to two AML cell lines which display a more CD33 − CD38 − phenotype. 3 Thus, the elimination of this early mature phenotype (HL-60 and U937). Our results show that AML cell subpopulation by chemotherapy is probably the ...

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Adriamycin and daunomycin induce programmed cell death (apoptosis) in tumour cells

Cited by 173 publications

References 13 publications

Study of apoptosis-related responses of leukemic blast cells to in vitro anthracycline treatment

Study of apoptosis-related responses of leukemic blast cells to in vitro anthracycline treatment

Dual mechanism of daunorubicin-induced cell death in both sensitive and MDR-resistant HL-60 cells

Natural resistance of acute myeloid leukemia cell lines to mitoxantrone is associated with lack of apoptosis

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