Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

Hiwase, Devendra; Saunders, Verity A.; Nievergall, Eva; Ross, Douglas D.; White, Deborah L.; Hughes, Timothy P.

doi:10.3324/haematol.2012.070268

Cited by 10 publications

(7 citation statements)

References 20 publications

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“…This study found that TNFSF10 mRNA expression levels were elevated in CD34-positive cells from CML patients treated with IFN[g302] than CD34-positive cells from CML patients at diagnosis or cells from normal individuals. Although Pgp expression was not assessed in their work, CD34-positive cells do express Pgp, which may contribute to low levels of TNFSF10 expression in untreated cells [31]. We emphasize in our study that high TRAIL expression levels were independent of cytokine stimuli.…”

Section: Discussionmentioning

confidence: 67%

Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL

Souza

Madigan

Gillet

et al. 2015

Experimental Cell Research

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Multidrug resistance (MDR) has been associated with expression of ABC transporter genes including P-glycoprotein (Pgp, MDR1, ABCB1). However, deregulation of apoptotic pathways also renders cells resistant to chemotherapy. To discover apoptosis-related genes affected by Pgp expression, we used the HeLa MDR-off system. We found that using doxycycline to control Pgp expression has a significant advantage over tetracycline, in that doxycycline caused less endogenous gene expression modification/perturbation, and was more potent than tetracycline in suppressing Pgp expression. Cells overexpressing Pgp have lower TNFSF10 (TRAIL) expression than their parental cells. Controlled downregulation of Pgp increased endogenous TRAIL protein expression. Also, ectopic overexpression of TRAIL in Pgp-positive cells was associated with a reduction in Pgp levels. However, cells expressing a functionally defective mutant Pgp showed an increase in TRAIL expression, suggesting that Pgp function is required for TRAIL suppression. Cells in which Pgp is knocked down by upregulation of TRAIL expression are less susceptible to TRAIL ligand (sTRAIL)-induced apoptosis. Our findings reveal an inverse correlation between functional Pgp and endogenous TRAIL expression. Pgp function plays an important role in the TRAIL-mediated apoptosis pathway by regulating endogenous TRAIL expression and the TRAIL-mediated apoptosis pathway in MDR cancer cells.

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Section: Discussionmentioning

confidence: 67%

Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL

Souza

Madigan

Gillet

et al. 2015

Experimental Cell Research

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“…Also dasatinib is a substrate of ABCB1 [ 35 , 41 , 47 ], as showed by the recovery of its efficacy when resistant cells were exposed to PSC833, a specific ABCB1 inhibitor [ 48 ]. Analogously, a murine model, knock-out for ABCB1 and/or ABCG2, confirmed that dasatinib is an ABCB1 substrate [ 49 ].…”

Section: Many Pieces For the Pharmacogenetic Puzzlementioning

confidence: 99%

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia

Polillo

Galimberti

Baratè

et al. 2015

IJMS

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Chronic myeloid leukemia was the first haematological neoplasia that benefited from a targeted therapy with imatinib nearly 15 years ago. Since then, several studies have investigated the role of genes, their variants (i.e., polymorphisms) and their encoded proteins in the pharmacokinetics and pharmacodynamics of BCR-ABL1 tyrosine kinase activity inhibitors (TKIs). Transmembrane transporters seem to influence in a significant manner the disposition of TKIs, especially that of imatinib at both cellular and systemic levels. In particular, members of the ATP-binding cassette (ABC) family (namely ABCB1 and ABCG2) together with solute carrier (SLC) transporters (i.e., SLC22A1) are responsible for the differences in drug pharmacokinetics. In the case of the newer TKIs, such as nilotinib and dasatinib, the substrate affinity of these drugs for transporters is variable but lower than that measured for imatinib. In this scenario, the investigation of genetic variants as possible predictive markers has led to some discordant results. With the partial exception of imatinib, these discrepancies seem to limit the application of discovered biomarkers in the clinical settings. In order to overcome these issues, larger prospective confirmative trials are needed.

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“…Dasatinib may also have a more profound effect on the leukemic stem and progenitor cells than imatinib, and influences the tumor microenvironment, 4 , 25 , 26 but it still needs further confirmation. Some studies have also showed that dasatinib induces defects in spindle generation, cell cycle arrest, and centrosome alterations in leukemic cells, tumor cell lines, as well as in normal cells.…”

Section: Structure Mechanisms Pharmacokinetics and Pharmacogeneticmentioning

confidence: 99%

The role of dasatinib in the management of chronic myeloid leukemia

Chen¹,

Chen²

2015

DDDT

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Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) for chronic, blastic, or accelerated phase chronic myeloid leukemia (CML) patients who are resistant or intolerant to previous treatment. It potently inhibits BCR/ABL and SRC-family kinases (SRC, LCK, HCK, YES, FYN, FGR, BLK, LYN, FRK), as well as c-KIT, PDGFR-a and -b, and ephrin receptor kinase. Various clinical trials have provided evidence that it has more durable complete hematologic and cytogenetic responses, as well as more potency in imatinib-resistant or -intolerant CML, and it has also shown its advantages in newly diagnosed CML compared to imatinib. In this review, we mainly focus on the structure, mechanisms, pharmacokinetics, and pharmacogenetics of dasatinib. We also summarize clinical trials with dasatinib on CML and provide our recommendations for dasatinib in the treatment of CML.

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Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

Cited by 10 publications

References 20 publications

Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL

Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia

The role of dasatinib in the management of chronic myeloid leukemia

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Dasatinib targets chronic myeloid leukemia-CD34+ progenitors as effectively as it targets mature cells

Cited by 10 publications

References 20 publications

Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL

Expression of the multidrug transporter P-glycoprotein is inversely related to that of apoptosis-associated endogenous TRAIL

Pharmacogenetics of BCR/ABL Inhibitors in Chronic Myeloid Leukemia

The role of dasatinib in the management of&nbsp;chronic myeloid leukemia

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The role of dasatinib in the management of chronic myeloid leukemia