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Antitumoral effects of cyclin-dependent kinases inhibitors CR8 and MR4 on chronic myeloid leukemia cell lines.

Troadec S, Blairvacq M, Oumata N, Galons H, Meijer L, Berthou C - J. Biomed. Sci. (2015)

Bottom Line: Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia.CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Thérapie Cellulaire et Immunobiologie du Cancer, Université de Bretagne Occidentale, CHRU Morvan, 5 avenue Foch, 29609, Brest Cedex, France. samuel.troadec@univ-brest.fr.

ABSTRACT

Background: Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia. Alternative or additional targeting of signalling pathways deregulated in Bcr-Abl-driven chronic myeloid leukemia may provide a feasible option for improving clinical response and overcoming resistance.

Results: In this study, we investigate ability of CR8 isomers (R-CR8 and S-CR8) and MR4, three derivatives of the cyclin-dependent kinases (CDKs) inhibitor Roscovitine, to exert anti-leukemic activities against chronic myeloid leukemia in vitro and then, we decipher their mechanisms of action. We show that these CDKs inhibitors are potent inducers of growth arrest and apoptosis of both Imatinib-sensitive and -resistant chronic myeloid leukemia cell lines. CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.

Conclusions: These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.

No MeSH data available.


Related in: MedlinePlus

Assessment of apoptosis as cell death mechanism induced by CDKs inhibitors. a Analysis of Annexin V-positive cells on Imatinib-sensitive K562 (a), KCL22 (c), and BaF3 Bcr-Abl WT (e) and Imatinib-resistant K562-R (b), KCL22-R (d), and BaF3 Bcr-Abl T315I (f) CML cell lines treating with increasing concentrations of drugs for 48 h. Negative and positive controls of cell viability were obtained with etoposide-treated or untreated cells, respectively. b Analysis of K562 and KCL22 Annexin V-positive cells treated for 24, 48 or 72 h with 10 μM drugs. c DNA fragmentation analysis of KCL22 cells treated by CDK inhibitors. NT not treated, I Imatinib, R Roscovitine, R8 R-CR8, S8 S-CR8, MR4 MR4, D DMSO, MW molecular weight
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Fig4: Assessment of apoptosis as cell death mechanism induced by CDKs inhibitors. a Analysis of Annexin V-positive cells on Imatinib-sensitive K562 (a), KCL22 (c), and BaF3 Bcr-Abl WT (e) and Imatinib-resistant K562-R (b), KCL22-R (d), and BaF3 Bcr-Abl T315I (f) CML cell lines treating with increasing concentrations of drugs for 48 h. Negative and positive controls of cell viability were obtained with etoposide-treated or untreated cells, respectively. b Analysis of K562 and KCL22 Annexin V-positive cells treated for 24, 48 or 72 h with 10 μM drugs. c DNA fragmentation analysis of KCL22 cells treated by CDK inhibitors. NT not treated, I Imatinib, R Roscovitine, R8 R-CR8, S8 S-CR8, MR4 MR4, D DMSO, MW molecular weight

Mentions: Annexin-V/PI staining assays confirmed the dose-dependent cell death-inducing effects of these CDKs inhibitors with similar IC50 values (Fig. 4a). Moreover, additional time-course experiments (Fig. 4b) demonstrated that cytotoxic effects of drugs were time-dependent with maximal response obtained from 48 h exposure time on K562 and KCL22 cells.Fig. 4


Antitumoral effects of cyclin-dependent kinases inhibitors CR8 and MR4 on chronic myeloid leukemia cell lines.

Troadec S, Blairvacq M, Oumata N, Galons H, Meijer L, Berthou C - J. Biomed. Sci. (2015)

Assessment of apoptosis as cell death mechanism induced by CDKs inhibitors. a Analysis of Annexin V-positive cells on Imatinib-sensitive K562 (a), KCL22 (c), and BaF3 Bcr-Abl WT (e) and Imatinib-resistant K562-R (b), KCL22-R (d), and BaF3 Bcr-Abl T315I (f) CML cell lines treating with increasing concentrations of drugs for 48 h. Negative and positive controls of cell viability were obtained with etoposide-treated or untreated cells, respectively. b Analysis of K562 and KCL22 Annexin V-positive cells treated for 24, 48 or 72 h with 10 μM drugs. c DNA fragmentation analysis of KCL22 cells treated by CDK inhibitors. NT not treated, I Imatinib, R Roscovitine, R8 R-CR8, S8 S-CR8, MR4 MR4, D DMSO, MW molecular weight
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4504225&req=5

Fig4: Assessment of apoptosis as cell death mechanism induced by CDKs inhibitors. a Analysis of Annexin V-positive cells on Imatinib-sensitive K562 (a), KCL22 (c), and BaF3 Bcr-Abl WT (e) and Imatinib-resistant K562-R (b), KCL22-R (d), and BaF3 Bcr-Abl T315I (f) CML cell lines treating with increasing concentrations of drugs for 48 h. Negative and positive controls of cell viability were obtained with etoposide-treated or untreated cells, respectively. b Analysis of K562 and KCL22 Annexin V-positive cells treated for 24, 48 or 72 h with 10 μM drugs. c DNA fragmentation analysis of KCL22 cells treated by CDK inhibitors. NT not treated, I Imatinib, R Roscovitine, R8 R-CR8, S8 S-CR8, MR4 MR4, D DMSO, MW molecular weight
Mentions: Annexin-V/PI staining assays confirmed the dose-dependent cell death-inducing effects of these CDKs inhibitors with similar IC50 values (Fig. 4a). Moreover, additional time-course experiments (Fig. 4b) demonstrated that cytotoxic effects of drugs were time-dependent with maximal response obtained from 48 h exposure time on K562 and KCL22 cells.Fig. 4

Bottom Line: Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia.CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.

View Article: PubMed Central - PubMed

Affiliation: Laboratoire de Thérapie Cellulaire et Immunobiologie du Cancer, Université de Bretagne Occidentale, CHRU Morvan, 5 avenue Foch, 29609, Brest Cedex, France. samuel.troadec@univ-brest.fr.

ABSTRACT

Background: Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia. Alternative or additional targeting of signalling pathways deregulated in Bcr-Abl-driven chronic myeloid leukemia may provide a feasible option for improving clinical response and overcoming resistance.

Results: In this study, we investigate ability of CR8 isomers (R-CR8 and S-CR8) and MR4, three derivatives of the cyclin-dependent kinases (CDKs) inhibitor Roscovitine, to exert anti-leukemic activities against chronic myeloid leukemia in vitro and then, we decipher their mechanisms of action. We show that these CDKs inhibitors are potent inducers of growth arrest and apoptosis of both Imatinib-sensitive and -resistant chronic myeloid leukemia cell lines. CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.

Conclusions: These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.

No MeSH data available.


Related in: MedlinePlus