Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C0023473 (
chronic myeloid leukemia
)
18,916
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Chronic myeloid leukemia
(
CML
) is characterized by the expression of the oncoprotein, BCR-ABL. BCR-ABL inhibitors revolutionized
CML
chemotherapy while blast crisis (BC)
CML
patients are less responsive. Since suppression of ribosomal protein S6 kinase1 (S6K1) phosphorylation reverses the resistance to BCR-ABL inhibitor in
CML
cells and S6K1 inhibitors augment cisplatin toxicity in lung cancer cells, we speculated that combination of S6K1 inhibitor and cisplatin may be beneficial for eliminating BC
CML
cells. To our surprise, S6K1 inhibition decreased cisplatin-induced DNA damage and cell death only in p53
-/-
BC
CML
cells but not in p53
+/+
BC
CML
cells. During the progression of
CML
, p53 expression either decreases or mutates. Moreover, the expression of p53 affects drug response of
CML
cells. Our results confirmed that S6K1 inhibition reversed cisplatin toxicity is dependent on p53 expression in
CML
cells. Moreover, p53 attenuated the phosphorylation and localization of S6K1 via attenuating
3-phosphoinositide dependent protein kinase-1
(PDK1) phosphorylation. Furthermore, S6K1 acts via DNA-PKcs to regulate H2AX phosphorylation and PARP cleavage, respectively. Taken together, our results suggest that p53/PDK1/S6K1 is a novel pathway regulating cisplatin toxicity in BC
CML
cells.
...
PMID:p53 modulates the effect of ribosomal protein S6 kinase1 (S6K1) on cisplatin toxicity in chronic myeloid leukemia cells. 2831 28
The efficacy and side-effects of drugs do not just reflect the biochemical and pharmacodynamic properties of the parent compound, but often comprise of cooperative effects between the properties of the parent and active metabolites. Metabolites of imatinib, nilotinib and midostaurin have been synthesised and evaluated in assays to compare their properties as protein kinase inhibitors with the parent drugs. The
N
-desmethyl-metabolite of imatinib is substantially less active than imatinib as a BCR-ABL1 kinase inhibitor, thus providing an explanation as to why patients producing high levels of this metabolite show a relatively low response rate in
chronic myeloid leukaemia
(
CML
) treatment. The hydroxymethylphenyl and
N
-oxide metabolites of imatinib and nilotinib are only weakly active as BCR-ABL1 inhibitors and are unlikely to play a role in the efficacy of either drug in
CML
. The 3-(
R
)-HO-metabolite of midostaurin shows appreciable accumulation following chronic drug administration and, in addition to mutant forms of FLT3, potently inhibits the
PDPK1
and VEGFR2 kinases (IC
50
values <100 nM), suggesting that it might contribute to drug efficacy in acute myeloid leukaemia patients. The case studies discussed here provide further examples of how the synthesis and characterisation of metabolites can make important contributions to understanding the clinical efficacy of drugs.
...
PMID:Investigations into the Potential Role of Metabolites on the Anti-Leukemic Activity of Imatinib, Nilotinib and Midostaurin. 3143 Dec 16
