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

Abstract

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.

Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma

“…Apart from these well described targets, it has been reported recently that flavopiridol inhibits glycogen phosphorylase, reducing the available glucose for glycolysis of cancer cells [ 35 ]. Succeeding this report, it has been demonstrated that flavopiridol reduces various components of the glycolytic pathway in glioblastoma cell lines, limiting glycolysis, which could be a new perspective to flavopiridol [ 36 ]. Despite these broad ranges of molecular effects by flavopiridol, the drug is well tolerated in patients while inducing tumor regression [ 37 ].…”

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“…Since each GB patient shows a peculiar molecular profile, the response at radio- and chemotherapies is different. On this basis, different GB cell lines may show a different response to Cdk inhibitors (Caracciolo et al, 2012; Cimini et al, 2017).…”

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“…Furthermore, flavopiridol is a synthetic flavonoid that inhibits cyclin-dependent kinases [ 156 ]. Although most chronic lymphocytic leukemia (CLL) patients receiving chemoimmunotherapy achieve complete remission, patients with significantly shortened progression-free intervals still represent an important obstacle.…”