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Targeting cell cycle regulators in hematologic malignancies.

Aleem E, Arceci RJ - Front Cell Dev Biol (2015)

Bottom Line: An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented.These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775.The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Child Health, The Ronald A. Matricaria Institute of Molecular Medicine at Phoenix Children's Hospital, University of Arizona College of Medicine-Phoenix Phoenix, AZ, USA ; Department of Zoology, Faculty of Science, Alexandria University Alexandria, Egypt.

ABSTRACT
Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.

No MeSH data available.


Related in: MedlinePlus

DNA damage pathways and how CHK1-, WEE1-, or CDK1 inhibitors can synergize with cytarabine to increase its DNA damaging efficacy in AML. Ataxia-telangectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR), radiomimetic agents, and agents which cause double-strand DNA breaks (DSBs). Ataxia-telangiectasia-related (ATR) protein kinase is activated by a broader range of genotoxic stimuli that result in single-strand DNA breaks (SSB). In addition, ATM can also activate ATR. Initial sensing of DNA damage can also be mediated by the NBS1-MRE11-RAD50 complex and by RAD17-RAD1-HUS1-RAD9 at the site of DNA breaks. This is followed by phosphorylating CHK2, p53, MDM2 and CHK1, which mediate cell cycle checkpoint responses to arrest the cells until DNA damage is repaired. Activated p53 will induce p21 and the CDC25A protein, which inhibit CDK2 and prevents G1/S transition. Altered phosphorylation (by CHK1) or cytoplasmic sequestration of CDC25C (by 14-3-3σ) will inactivate CDK1/cyclin B preventing cells from entering mitosis. CHK1 also phosphorylates/activates WEE-1, which phosphorylates and inactivates CDK1/cyclin B complex on Tyr15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair. In AML, treatment with cytarabine (Ara-C) activates the DNA damage pathway through CHK1, which stabilizes stalled replication fork and induces S phase arrest. This will allow DNA damage induced by Ara-C to be repaired. To increase the DNA damaging efficacy of Ara-C the checkpoint pathway can be blocked by a selective CHK1 inhibitor such as MK-8776 that overrides the S-phase checkpoint activation. To overcome the G2/M checkpoint blocking WEE-1 kinase using the selective inhibitor MK-1775 will result in CDK1 activation and cells die due to accumulation of genetic lesions. CHEM, genotoxic chemicals; Rep stress, replication stress; UV, ultra violet radiation.
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Figure 2: DNA damage pathways and how CHK1-, WEE1-, or CDK1 inhibitors can synergize with cytarabine to increase its DNA damaging efficacy in AML. Ataxia-telangectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR), radiomimetic agents, and agents which cause double-strand DNA breaks (DSBs). Ataxia-telangiectasia-related (ATR) protein kinase is activated by a broader range of genotoxic stimuli that result in single-strand DNA breaks (SSB). In addition, ATM can also activate ATR. Initial sensing of DNA damage can also be mediated by the NBS1-MRE11-RAD50 complex and by RAD17-RAD1-HUS1-RAD9 at the site of DNA breaks. This is followed by phosphorylating CHK2, p53, MDM2 and CHK1, which mediate cell cycle checkpoint responses to arrest the cells until DNA damage is repaired. Activated p53 will induce p21 and the CDC25A protein, which inhibit CDK2 and prevents G1/S transition. Altered phosphorylation (by CHK1) or cytoplasmic sequestration of CDC25C (by 14-3-3σ) will inactivate CDK1/cyclin B preventing cells from entering mitosis. CHK1 also phosphorylates/activates WEE-1, which phosphorylates and inactivates CDK1/cyclin B complex on Tyr15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair. In AML, treatment with cytarabine (Ara-C) activates the DNA damage pathway through CHK1, which stabilizes stalled replication fork and induces S phase arrest. This will allow DNA damage induced by Ara-C to be repaired. To increase the DNA damaging efficacy of Ara-C the checkpoint pathway can be blocked by a selective CHK1 inhibitor such as MK-8776 that overrides the S-phase checkpoint activation. To overcome the G2/M checkpoint blocking WEE-1 kinase using the selective inhibitor MK-1775 will result in CDK1 activation and cells die due to accumulation of genetic lesions. CHEM, genotoxic chemicals; Rep stress, replication stress; UV, ultra violet radiation.

Mentions: In the mammalian cell cycle there are three checkpoints that function in G1, S and G2, respectively. Depending on the type of genotoxic stress, either ataxia-telangiectasia mutated (ATM) protein kinase (Supplementary Table 2, Figure 2) or ataxia-telangiectasia-related (ATR) protein kinase is preferentially activated (Do et al., 2013). ATM is activated in response to ionizing radiation, radiomimetic agents, and agents, which cause double-strand DNA breaks (DSBs). It phosphorylates and activates CHK2, which, in turn, phosphorylates CDC25C at Ser216, creating a binding site for the 14-3-3σ protein (Matsuoka et al., 2000). This leads to nuclear export and cytoplasmic sequestration of CDC25C. Suppression of CDC25C phosphatase activity results in inhibitory phosphorylation of the CDK1/cyclin B complex, maintaining CDK1 in an inactive form and preventing entry into mitosis (Figure 2). If the checkpoints are defective (or pharmacologically inhibited) DNA damage will not be repaired and cells die due to accumulation of genetic lesions. ATR is activated by a broader range of genotoxic stimuli that result in single-strand DNA breaks (Jazayeri et al., 2006; Johnson et al., 2009). ATR phosphorylates and activates CHK1 that can also be activated by ATM. CHK1 then phosphorylates WEE-1 and CDC25C, thereby activating WEE-1 kinase activity and inactivating CDC25C phosphatase activity. WEE-1, then, phosphorylates and inactivates CDK1/cyclin B complex on Tyr15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair (Do et al., 2013).


Targeting cell cycle regulators in hematologic malignancies.

Aleem E, Arceci RJ - Front Cell Dev Biol (2015)

DNA damage pathways and how CHK1-, WEE1-, or CDK1 inhibitors can synergize with cytarabine to increase its DNA damaging efficacy in AML. Ataxia-telangectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR), radiomimetic agents, and agents which cause double-strand DNA breaks (DSBs). Ataxia-telangiectasia-related (ATR) protein kinase is activated by a broader range of genotoxic stimuli that result in single-strand DNA breaks (SSB). In addition, ATM can also activate ATR. Initial sensing of DNA damage can also be mediated by the NBS1-MRE11-RAD50 complex and by RAD17-RAD1-HUS1-RAD9 at the site of DNA breaks. This is followed by phosphorylating CHK2, p53, MDM2 and CHK1, which mediate cell cycle checkpoint responses to arrest the cells until DNA damage is repaired. Activated p53 will induce p21 and the CDC25A protein, which inhibit CDK2 and prevents G1/S transition. Altered phosphorylation (by CHK1) or cytoplasmic sequestration of CDC25C (by 14-3-3σ) will inactivate CDK1/cyclin B preventing cells from entering mitosis. CHK1 also phosphorylates/activates WEE-1, which phosphorylates and inactivates CDK1/cyclin B complex on Tyr15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair. In AML, treatment with cytarabine (Ara-C) activates the DNA damage pathway through CHK1, which stabilizes stalled replication fork and induces S phase arrest. This will allow DNA damage induced by Ara-C to be repaired. To increase the DNA damaging efficacy of Ara-C the checkpoint pathway can be blocked by a selective CHK1 inhibitor such as MK-8776 that overrides the S-phase checkpoint activation. To overcome the G2/M checkpoint blocking WEE-1 kinase using the selective inhibitor MK-1775 will result in CDK1 activation and cells die due to accumulation of genetic lesions. CHEM, genotoxic chemicals; Rep stress, replication stress; UV, ultra violet radiation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
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Figure 2: DNA damage pathways and how CHK1-, WEE1-, or CDK1 inhibitors can synergize with cytarabine to increase its DNA damaging efficacy in AML. Ataxia-telangectasia mutated (ATM) protein kinase is activated in response to ionizing radiation (IR), radiomimetic agents, and agents which cause double-strand DNA breaks (DSBs). Ataxia-telangiectasia-related (ATR) protein kinase is activated by a broader range of genotoxic stimuli that result in single-strand DNA breaks (SSB). In addition, ATM can also activate ATR. Initial sensing of DNA damage can also be mediated by the NBS1-MRE11-RAD50 complex and by RAD17-RAD1-HUS1-RAD9 at the site of DNA breaks. This is followed by phosphorylating CHK2, p53, MDM2 and CHK1, which mediate cell cycle checkpoint responses to arrest the cells until DNA damage is repaired. Activated p53 will induce p21 and the CDC25A protein, which inhibit CDK2 and prevents G1/S transition. Altered phosphorylation (by CHK1) or cytoplasmic sequestration of CDC25C (by 14-3-3σ) will inactivate CDK1/cyclin B preventing cells from entering mitosis. CHK1 also phosphorylates/activates WEE-1, which phosphorylates and inactivates CDK1/cyclin B complex on Tyr15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair. In AML, treatment with cytarabine (Ara-C) activates the DNA damage pathway through CHK1, which stabilizes stalled replication fork and induces S phase arrest. This will allow DNA damage induced by Ara-C to be repaired. To increase the DNA damaging efficacy of Ara-C the checkpoint pathway can be blocked by a selective CHK1 inhibitor such as MK-8776 that overrides the S-phase checkpoint activation. To overcome the G2/M checkpoint blocking WEE-1 kinase using the selective inhibitor MK-1775 will result in CDK1 activation and cells die due to accumulation of genetic lesions. CHEM, genotoxic chemicals; Rep stress, replication stress; UV, ultra violet radiation.
Mentions: In the mammalian cell cycle there are three checkpoints that function in G1, S and G2, respectively. Depending on the type of genotoxic stress, either ataxia-telangiectasia mutated (ATM) protein kinase (Supplementary Table 2, Figure 2) or ataxia-telangiectasia-related (ATR) protein kinase is preferentially activated (Do et al., 2013). ATM is activated in response to ionizing radiation, radiomimetic agents, and agents, which cause double-strand DNA breaks (DSBs). It phosphorylates and activates CHK2, which, in turn, phosphorylates CDC25C at Ser216, creating a binding site for the 14-3-3σ protein (Matsuoka et al., 2000). This leads to nuclear export and cytoplasmic sequestration of CDC25C. Suppression of CDC25C phosphatase activity results in inhibitory phosphorylation of the CDK1/cyclin B complex, maintaining CDK1 in an inactive form and preventing entry into mitosis (Figure 2). If the checkpoints are defective (or pharmacologically inhibited) DNA damage will not be repaired and cells die due to accumulation of genetic lesions. ATR is activated by a broader range of genotoxic stimuli that result in single-strand DNA breaks (Jazayeri et al., 2006; Johnson et al., 2009). ATR phosphorylates and activates CHK1 that can also be activated by ATM. CHK1 then phosphorylates WEE-1 and CDC25C, thereby activating WEE-1 kinase activity and inactivating CDC25C phosphatase activity. WEE-1, then, phosphorylates and inactivates CDK1/cyclin B complex on Tyr15 residue, resulting in cell cycle arrest at G2, allowing time for DNA repair (Do et al., 2013).

Bottom Line: An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented.These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775.The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Child Health, The Ronald A. Matricaria Institute of Molecular Medicine at Phoenix Children's Hospital, University of Arizona College of Medicine-Phoenix Phoenix, AZ, USA ; Department of Zoology, Faculty of Science, Alexandria University Alexandria, Egypt.

ABSTRACT
Hematologic malignancies represent the fourth most frequently diagnosed cancer in economically developed countries. In hematologic malignancies normal hematopoiesis is interrupted by uncontrolled growth of a genetically altered stem or progenitor cell (HSPC) that maintains its ability of self-renewal. Cyclin-dependent kinases (CDKs) not only regulate the mammalian cell cycle, but also influence other vital cellular processes, such as stem cell renewal, differentiation, transcription, epigenetic regulation, apoptosis, and DNA repair. Chromosomal translocations, amplification, overexpression and altered CDK activities have been described in different types of human cancer, which have made them attractive targets for pharmacological inhibition. Mouse models deficient for one or more CDKs have significantly contributed to our current understanding of the physiological functions of CDKs, as well as their roles in human cancer. The present review focuses on selected cell cycle kinases with recent emerging key functions in hematopoiesis and in hematopoietic malignancies, such as CDK6 and its role in MLL-rearranged leukemia and acute lymphocytic leukemia, CDK1 and its regulator WEE-1 in acute myeloid leukemia (AML), and cyclin C/CDK8/CDK19 complexes in T-cell acute lymphocytic leukemia. The knowledge gained from gene knockout experiments in mice of these kinases is also summarized. An overview of compounds targeting these kinases, which are currently in clinical development in various solid tumors and hematopoietic malignances, is presented. These include the CDK4/CDK6 inhibitors (palbociclib, LEE011, LY2835219), pan-CDK inhibitors that target CDK1 (dinaciclib, flavopiridol, AT7519, TG02, P276-00, terampeprocol and RGB 286638) as well as the WEE-1 kinase inhibitor, MK-1775. The advantage of combination therapy of cell cycle inhibitors with conventional chemotherapeutic agents used in the treatment of AML, such as cytarabine, is discussed.

No MeSH data available.


Related in: MedlinePlus