Mechanisms of cellular anthracycline resistance in childhood acute leukemia

Boer, Monique L. den; Pieters, Rob; Veerman, A. J. P.

doi:10.1038/sj.leu.2401175

Cited by 25 publications

(10 citation statements)

References 131 publications

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“…Because a single agent can induce cross‐resistance to dissimilar chemotherapeutic drugs (Den Boer et al , 1998), we tested parental and drug‐resistant cell lines for multidrug resistance (Fig 2A–F respectively). We found that DNR resistant Jurkat cells showed a 310‐fold ( c. 0·80–250 nmol/l) increase in resistance to VCR, and a 120‐fold ( c. 3·1–380 nmol/l) increase in resistance to PRED (Fig 2A).…”

Section: Resultsmentioning

confidence: 99%

“…Experimentally induced drug resistance in several leukaemic cell lines through the sequential escalation of drug dosage has provided insights into the underlying mechanisms of treatment failure (Beck, 1983; Den Boer et al , 1998; Sonneveld, 2000; Aslanian et al , 2001; Liu et al , 2002; Efferth et al , 2006; Munteanu et al , 2006). Nevertheless, only the CCRF‐CEM, MOLT‐4 and Jurkat T‐ALL cell lines have been developed to show drug resistance to anthracyclines, vinca alkaloids, glucocorticoids, or l ‐asparaginase ( l ‐asp).…”

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confidence: 99%

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Genetic alterations determine chemotherapy resistance in childhood T‐ALL: modelling in stage‐specific cell lines and correlation with diagnostic patient samples

Estes¹,

Lovato²,

Khawaja³

et al. 2007

Br J Haematol

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Summary Acquired drug resistance eventually leads to treatment failure in T‐cell acute lymphoblastic leukaemia (T‐ALL). Immunophenotypic and cytogenetic heterogeneities within T‐ALL influence susceptibility to cytotoxic therapy, and little is known about the mechanisms of drug resistance at specific stages of T‐cell ontogeny. We developed tolerance to therapeutic concentrations of daunorubicin (DNR) and l‐asparaginase (l‐asp) in Jurkat (CD1a−, sCD3+) and Sup T1 (CD1a+, sCD3−) cell lines, having respective ‘mature’ and ‘cortical’ stages of developmental arrest. DNR resistant cells acquired multidrug resistance: 310‐fold increased resistance to vincristine (VCR) and a 120‐fold increased resistance to prednisolone (PRED). Microarray analysis identified upregulation of asparagine synthetase (ASNS) and argininosuccinate synthase 1 (ASS1) to cell lines with acquired resistance to l‐asp, and in the case of DNR, upregulation of ATP‐binding cassette B1 (ABCB1). Suppression of ABCB1, ASNS and ASS1 by RNA interference revealed their functional relevance to acquired drug resistance. Expression profiling of these genes in 80 T‐ALL patients showed correlation with treatment response. This study expands the pool of available drug resistant cell lines having cortical and mature stages of developmental arrest, introduces three new drug resistant T‐ALL cell lines, and identifies gene interactions leading to l‐asp and DNR resistance.

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Genetic alterations determine chemotherapy resistance in childhood T‐ALL: modelling in stage‐specific cell lines and correlation with diagnostic patient samples

Estes¹,

Lovato²,

Khawaja³

et al. 2007

Br J Haematol

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“…Drug resistance in adult ALL may be associated with activation of antiapoptotic pathways as a consequence of aberrant growth signalling, resulting from the bypassing of normal growth factor signalling pathways in malignant cells ( Baserga, 1994). Glucocorticoids, cytosine arabinoside and anthracyclines are thought to act on the proapoptotic pathway ( Alnemri et al , 1992 ; Kaspers et al , 1994b ; Den Boer et al , 1998 ; < Savasan et al , 1998 ). Probably, the other drugs also have a proapoptotic mechanism of action, and apoptosis resistance may play a role in the resistance to therapy.…”

Section: Discussionmentioning

confidence: 99%

In vitro drug resistance profiles of adult versus childhood acute lymphoblastic leukaemia

et al. 2000

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The difference in the current cure rates between adult and childhood acute lymphoblastic leukaemia (ALL) may be caused by differences in drug resistance. Earlier studies showed that in vitro cellular drug resistance is a strong independent adverse risk factor in childhood ALL. Knowledge about cellular drug resistance in adult ALL is still limited. The present study compared the in vitro drug resistance profiles of 23 adult ALL patients with that of 395 childhood ALL patients. The lymphoblasts were tested by the MTT assay. The group of adult ALL samples was significantly more resistant to cytosine arabinoside, l‐asparaginase, daunorubicin, dexamethasone and prednisolone. The resistance ratio (RR) was highest for prednisolone (31·7‐fold) followed by dexamethasone (6·9‐fold), l‐asparaginase (6·1‐fold), cytosine arabinoside (2·9‐fold), daunorubicin (2·5‐fold) and vincristine (2·2‐fold). Lymphoblasts from adult patients were not more resistant to mercaptopurine, thioguanine, 4‐HOO‐ifosfamide, mitoxantrone and teniposide. There were no significant differences in drug resistance between adult T‐cell (T‐) ALL (n = 11) and adult common/pre‐B‐cell (B‐) ALL (n = 10). Additionally, adult T‐ALL did not differ from childhood T‐ALL (n = 69). There were significant differences between adult common/pre‐B‐ALL and childhood common/pre‐B‐ALL (n = 310) for prednisolone (RR = 302, P = 0·008), dexamethasone (RR = 20·9, P = 0·017) and daunorubicin (RR = 2·7, P = 0·009). Lymphoblasts from adults proved to be relatively resistant to drugs commonly used in therapy. This might contribute to the difference in outcome between children and adults with ALL.

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“…Anthracyclines efficiently arrest cell division and induce apoptotic cell death by intercalation with DNA, generation of free radicals, interaction with cellular membranes, and inhibition of topoisomerase II (Gewirtz, 1999; Hussein, 2007). However, drug resistance and side effects such as cardiotoxicity seriously limit their clinical success (Shan et al , 1996; Den Boer et al , 1998), and it is critical to understand their intracellular metabolism and pharmacokinetics.…”

Section: Introductionmentioning

confidence: 99%

“…Cancer cell resistance toward anthracyclines, intrinsic or acquired, is induced by multiple factors, such as multidrug resistant protein expression, apoptotic pathway alterations, and drug-detoxifying enzyme induction (Gianni, 1997; Den Boer et al , 1998; Gottesman, 2002; Hembruff et al , 2008). Intracellularly, anthracyclines are metabolized by either glycosidic cleavage of bio-functional glycosidic amino sugar or reduction of ketonic groups.…”

Section: Introductionmentioning

confidence: 99%

AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group

Zhong

Shen

Huang

et al. 2011

Toxicology and Applied Pharmacology

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Daunorubicin, idarubicin, doxorubicin and epirubicin are anthracyclines widely used for the treatment of lymphoma, leukemia, and breast, lung, and liver cancers, but tumor resistance limits their clinical success. Aldo-keto reductase family 1 B10 (AKR1B10) is an NADPH-dependent enzyme overexpressed in liver and lung carcinomas. This study was aimed to determine the role of AKR1B10 in tumor resistance to anthracyclines. AKR1B10 activity toward anthracyclines was measured using recombinant protein. Cell resistance to anthracycline was determined by ectopic expression of AKR1B10 or inhibition by epalrestat. Results showed that AKR1B10 reduces C13-ketonic group on side chain of daunorubicin and idarubicin to hydroxyl forms. In vitro, AKR1B10 converted daunorubicin to daunorubicinol at Vmax of 837.42±81.39 nmol/mg/min, Km of 9.317±2.25 mM and kcat/Km of 3.24. AKR1B10 showed better catalytic efficiency toward idarubicin with Vmax at 460.23±28.12 nmol/mg/min, Km at 0.461±0.09 mM and kcat/Km at 35.94. AKR1B10 was less active toward doxorubicin and epirubicin with a C14-hydroxyl group. In living cells, AKR1B10 efficiently catalyzed reduction of daunorubicin (50nM) and idarubicin (30nM) to corresponding alcohols. Within 24 hours, approximately 20±2.7% of daunorubicin (1μM) or 23±2.3% of idarubicin (1μM) was converted to daunorubicinol or idarubicinol in AKR1B10 expression cells compared to 7±0.9% and 5±1.5% in vector control. AKR1B10 expression led to cell resistance to daunorubicin and idarubicin, but inhibitor epalrestat showed a synergistic role with these agents. Together our data suggests that AKR1B10 participates in cellular metabolism of daunorubicin and idarubicin, resulting in drug resistance. These data are informative for the clinical use of idarubicin and daunorubicin.

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Mechanisms of cellular anthracycline resistance in childhood acute leukemia

Cited by 25 publications

References 131 publications

Genetic alterations determine chemotherapy resistance in childhood T‐ALL: modelling in stage‐specific cell lines and correlation with diagnostic patient samples

Genetic alterations determine chemotherapy resistance in childhood T‐ALL: modelling in stage‐specific cell lines and correlation with diagnostic patient samples

In vitro drug resistance profiles of adult versus childhood acute lymphoblastic leukaemia

AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group

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