Flavopiridol induces phosphorylation of AKT in a human glioblastoma cell line, in contrast to siRNA-mediated silencing of Cdk9: Implications for drug design and development

Caracciolo, Valentina; Laurenti, Giulio; Romano, Gaetano; Carnevale, Vincenzo; Cimini, Annamaria; Crozier-Fitzgerald, Catena; Warschauer, Emilio Gentile; Russo, Giuseppe; Giordano, Antonio

doi:10.4161/cc.11.6.19663

Cited by 21 publications

(26 citation statements)

References 79 publications

(191 reference statements)

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“…Flavopiridol may alter transcription by other mechanisms in addition to CDK9 inhibition or may inhibit other CDKs, although with lower efficacy. Indeed, the phosphorylation of Serine 5 on the CTD of the RNAPII is reduced by flavopiridol via its inhibitory effect on CDK7 in human glioblastoma cells 5 . Furthermore, a recent screen seeking binding inhibitors to a panel of 119 kinases indicated that flavopiridol also binds the transcription regulator Calcium/Calmodulin kinase 1 with higher affinity than other CDKs and CDK-related kinases 31 .…”

Section: Discussionmentioning

confidence: 99%

“…So far, several CDKs inhibitor compounds have been developed with a range of selectivity for CDK9: Flavopiridol, 5 Roscovitine, 6 iCDK9, 7 DRB, 8 SNS-032, 9 RGB-286147 10 and AT7515 11 . Flavopiridol, Roscovitine and SNS-032 are the best known CDK9 inhibitors tested in clinical trials, particularly as anticancer agents 12-15 .…”

Section: Introductionmentioning

confidence: 99%

“…It has been tested in-vitro in several cell models of pathology, including human chronic lymphocytic leukemia cells, 18 glioblastoma cells, 5 leucocytes 19 and smooth muscle cells 20 . While in-vitro assays, using cell culture and bioinformatics tools, can provide a reasonably thorough assessment of toxicity many novel drug candidates can display off-target effects in-vivo at the level of whole organism which may not be apparent from these types of analyses.…”

Section: Introductionmentioning

confidence: 99%

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Effects of Cyclin Dependent Kinase 9 inhibition on zebrafish larvae

et al. 2016

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CDK9 is a known regulator of cellular transcription, growth and proliferation. Small molecule inhibitors are currently being developed and assessed in clinical trials as anti-cancer drugs. The zebrafish embryo provides an ideal model to explore the effects of CDK9 inhibition in-vivo. This has not been adequately explored previously at the level of a whole organism. We have compared and contrasted the effects of pharmacological and molecular inhibition of CDK9 on somatic growth, apoptosis and cellular proliferation in zebrafish larvae between 0 to 120 hours post fertilisation (hpf) using flavopiridol, a selective CDK9 antagonist, and CDK9-targeting morpholino. We demonstrate that the inhibition of CDK9 diminishes cellular proliferation and increases apoptosis. Subsequently, it affects somatic growth and development of a number of key embryonic structures including the brain, heart, eye and blood vessels. For the first time, we have localized CDK9 at a subcellular level in whole-mounted larvae.This works shows, at a high-throughput level, that CDK9 clearly plays a fundamental role in early cellular growth and proliferation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Cyclin Dependent Kinase 9 inhibition on zebrafish larvae

et al. 2016

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“…Once CDKN1A is outside the cell nucleus, it can no longer impose a cell cycle arrest and, therefore, malignant cells recommence to proliferate [141]. A hyperactive PI3K/Akt signaling system is one of the contributing factors that are also responsible for the development of cancer cells with increased resistance to a broad spectrum of chemotherapeutics [136–194] and radiotherapy [143–150, 155–157]. Some of the anticancer drugs that become clinically ineffective comprise paclitaxel [171, 173–180], doxorubicin [180–182], gefitinib [152, 183–187], imatinib [186, 188–192], and flavopiridol [193, 194].…”

Section: Abnormal Akt-related Pathways In Resistance To Cancer Thementioning

confidence: 99%

“…A hyperactive PI3K/Akt signaling system is one of the contributing factors that are also responsible for the development of cancer cells with increased resistance to a broad spectrum of chemotherapeutics [136–194] and radiotherapy [143–150, 155–157]. Some of the anticancer drugs that become clinically ineffective comprise paclitaxel [171, 173–180], doxorubicin [180–182], gefitinib [152, 183–187], imatinib [186, 188–192], and flavopiridol [193, 194]. The clinical and/or preclinical studies on the Akt pathway-mediated enhanced resistance to chemo- and/or radiotherapy were conducted on several types of human hematological tumors [195–198] and human epithelial malignancies [143, 147–160].…”

Section: Abnormal Akt-related Pathways In Resistance To Cancer Thementioning

confidence: 99%

The Role of the Dysfunctional Akt-Related Pathway in Cancer: Establishment and Maintenance of a Malignant Cell Phenotype, Resistance to Therapy, and Future Strategies for Drug Development

Romano

2013

Scientifica

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Akt serine/threonine kinases, or PKB, are key players in the regulation of a wide variety of cellular activities, such as growth, proliferation, protection from apoptotic injuries, control of DNA damage responses and genome stability, metabolism, migration, and angiogenesis. The Akt-related pathway responds to the stimulation mediated by growth factors, cytokines, hormones, and several nutrients. Akt is present in three isoforms: Akt1, Akt2, and Akt3, which may be alternatively named PKBα, PKBβ, and PKBγ, respectively. The Akt isoforms are encoded on three diverse chromosomes and their biological functions are predominantly distinct. Deregulations in the Akt-related pathway were observed in many human maladies, including cancer, cardiopathies, neurological diseases, and type-2 diabetes. This review discusses the significance of the abnormal activities of the Akt axis in promoting and sustaining malignancies, along with the development of tumor cell populations that exhibit enhanced resistance to chemo- and/or radiotherapy. This occurrence may be responsible for the relapse of the disease, which is unfortunately very often related to fatal consequences in patients.

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Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs

Cimini

Benedetti

D’Angelo

et al. 2016

Journal Cellular Physiology

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Glioblastoma, the most common brain tumor, is characterized by high proliferation rate, invasion, angiogenesis, and chemo- and radio-resistance. One of most remarkable feature of glioblastoma is the switch toward a glycolytic energetic metabolism that leads to high glucose uptake and consumption and a strong production of lactate. Activation of several oncogene pathways like Akt, c-myc, and ras induces glycolysis and angiogenesis and acts to assure glycolysis prosecution, tumor proliferation, and resistance to therapy. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes resulting in an overproduction of pyruvate and lactate. Metabolism of glioblastoma thus represents a key issue for cancer research. Flavopiridol is a synthetic flavonoid that inhibits a wide range of Cyclin-dependent kinase, that has been demonstrate to inactivate glycogen phosphorylase, decreasing glucose availability for glycolysis. In this work the study of glucose metabolism upon flavopiridol treatment in the two different glioblastoma cell lines. The results obtained point towards an effect of flavopiridol in glycolytic cells, thus suggesting a possible new use of this compound or flavopiridol-derived formulations in combination with anti-proliferative agents in glioblastoma patients. J. Cell. Physiol. 232: 312-322, 2017. © 2016 Wiley Periodicals, Inc.

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Flavopiridol induces phosphorylation of AKT in a human glioblastoma cell line, in contrast to siRNA-mediated silencing of Cdk9: Implications for drug design and development

Cited by 21 publications

References 79 publications

Effects of Cyclin Dependent Kinase 9 inhibition on zebrafish larvae

Effects of Cyclin Dependent Kinase 9 inhibition on zebrafish larvae

The Role of the Dysfunctional Akt-Related Pathway in Cancer: Establishment and Maintenance of a Malignant Cell Phenotype, Resistance to Therapy, and Future Strategies for Drug Development

Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs

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