Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia

Zhihong Zeng, Ismael J. Samudio, Weiguo Zhang, Zeev Estrov, Hélène Pelicano, David Harris, Olga Frolova, Numsen Hail, Wenjing Chen, Steven M. Kornblau, Peng Huang, Yiling Lu, Gordon Mills, Michael Andreeff, Marina Konopleva

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Abstract

Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser473 and Thr308; abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34+ cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC 50 < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.

Original languageEnglish (US)
Pages (from-to)3737-3746
Number of pages10
JournalCancer Research
Volume66
Issue number7
DOIs
StatePublished - Apr 1 2006
Externally publishedYes

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fms-Like Tyrosine Kinase 3
Acute Myeloid Leukemia
Apoptosis
Phosphotransferases
Cell Line
Phosphorylation
Proto-Oncogene Proteins c-akt
Phosphatidylserines
Caspases
Hematopoietic Stem Cells
KP372-1
Oxygen Consumption
Reactive Oxygen Species
Cell Survival
Leukemia
Stem Cells
Western Blotting
Drug Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. / Zeng, Zhihong; Samudio, Ismael J.; Zhang, Weiguo; Estrov, Zeev; Pelicano, Hélène; Harris, David; Frolova, Olga; Hail, Numsen; Chen, Wenjing; Kornblau, Steven M.; Huang, Peng; Lu, Yiling; Mills, Gordon; Andreeff, Michael; Konopleva, Marina.

In: Cancer Research, Vol. 66, No. 7, 01.04.2006, p. 3737-3746.

Research output: Contribution to journalArticle

Zeng, Z, Samudio, IJ, Zhang, W, Estrov, Z, Pelicano, H, Harris, D, Frolova, O, Hail, N, Chen, W, Kornblau, SM, Huang, P, Lu, Y, Mills, G, Andreeff, M & Konopleva, M 2006, 'Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia', Cancer Research, vol. 66, no. 7, pp. 3737-3746. https://doi.org/10.1158/0008-5472.CAN-05-1278
Zeng, Zhihong ; Samudio, Ismael J. ; Zhang, Weiguo ; Estrov, Zeev ; Pelicano, Hélène ; Harris, David ; Frolova, Olga ; Hail, Numsen ; Chen, Wenjing ; Kornblau, Steven M. ; Huang, Peng ; Lu, Yiling ; Mills, Gordon ; Andreeff, Michael ; Konopleva, Marina. / Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia. In: Cancer Research. 2006 ; Vol. 66, No. 7. pp. 3737-3746.
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abstract = "Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser473 and Thr308; abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34+ cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC 50 < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.",
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T1 - Simultaneous inhibition of PDK1/AKT and Fms-like tyrosine kinase 3 signaling by a small-molecule KP372-1 induces mitochondrial dysfunction and apoptosis in acute myelogenous leukemia

AU - Zeng, Zhihong

AU - Samudio, Ismael J.

AU - Zhang, Weiguo

AU - Estrov, Zeev

AU - Pelicano, Hélène

AU - Harris, David

AU - Frolova, Olga

AU - Hail, Numsen

AU - Chen, Wenjing

AU - Kornblau, Steven M.

AU - Huang, Peng

AU - Lu, Yiling

AU - Mills, Gordon

AU - Andreeff, Michael

AU - Konopleva, Marina

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N2 - Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser473 and Thr308; abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34+ cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC 50 < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.

AB - Phosphoinositol-3-kinase (PI3K)/protein kinase B (AKT) and Fms-like tyrosine kinase 3 (FLT3) signaling are aberrantly activated in acute myelogenous leukemia (AML) cells. Constitutively activated AKT and FLT3 regulate leukemia cell survival and resistance to chemotherapy. In this study, we investigated the effects of the novel multiple kinase inhibitor KP372-1 on the survival of AML cell lines and primary AML samples. KP372-1 directly inhibited the kinase activity of AKT, PDK1, and FLT3 in a concentration-dependent manner. Western blot analysis indicated that KP372-1 decreased the phosphorylation of AKT on both Ser473 and Thr308; abrogated the phosphorylation of p70S6 kinase, BAD, and Foxo3a via PI3K/AKT signaling; and down-regulated expression of PIM-1 through direct inhibition of FLT3. Treatment of AML cell lines with KP372-1 resulted in rapid generation of reactive oxygen species and stimulation of oxygen consumption, followed by mitochondrial depolarization, caspase activation, and phosphatidylserine externalization. KP372-1 induced pronounced apoptosis in AML cell lines and primary samples irrespective of their FLT3 status, but not in normal CD34+ cells. Moreover, KP372-1 markedly decreased the colony-forming ability of primary AML samples (IC 50 < 200 nmol/L) with minimal cytotoxic effects on normal progenitor cells. Taken together, our results show that the simultaneous inhibition of critical prosurvival kinases by KP372-1 leads to mitochondrial dysfunction and apoptosis of AML but not normal hematopoietic progenitor cells.

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