Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines

Furukawa, Yusuke; Vũ, Hoàng Anh; Akutsu, Miyuki; Odgerel, T; Izumi, Tohru; Tsunoda, Saburo; Matsuo, Yuji; Kirito, Keita; Sato, Yuko; Mano, Hiroyuki; Kano, Yasuhiko

doi:10.1038/sj.leu.2404593

Cited by 54 publications

(44 citation statements)

References 38 publications

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“…Interestingly, combinations with standard cytotoxic drugs used in RMS treatment showed only minimal synergistic effects. This is in contrast to acute myeloid leukaemia (AML) for which PKC412 is currently evaluated in phase II clinical trials, as combinations with conventional antileukemic agents demonstrate superior anti-cancer activity for FLT3 mutation-positive AML compared to single treatment alone (Furukawa et al, 2007). Only one study in AML suggested that HDAC inhibitors could be used effectively in combination with PKC412 (Bali et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

et al. 2010

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A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases where tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS) which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease.Recently, we were able to demonstrate that the small molecule inhibitor PKC412 (midostaurin) exhibits strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR.Here, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase (HDAC) inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo.We provide evidence that the antitumor effect upon combination treatment is achieved by VPAinduced reactivation of p21 which is downregulated in aRMS cells via destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

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Section: Discussionmentioning

confidence: 99%

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

et al. 2010

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“…Recently, we have reported that PKC412 has synergistic effects with most antileukemic agents for FLT3-mutated leukemia cell lines (Furukawa et al, 2007). In contrast, PKC412 is antagonistic to most drugs, except for those inducing mitotic arrest or active in the G 2 /M phase in leukemia cell lines without FLT3 mutations.…”

Section: Introductionmentioning

confidence: 98%

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

et al. 2007

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PKC412 is a staurosporine derivative that inhibits several protein kinases including FLT3, and is highly anticipated as a novel therapeutic agent for acute myeloblastic leukemia (AML) carrying FLT3 mutations. In this study, we show that PKC412 exerts differential cell cycle effects on AML cells depending on the presence of FLT3 mutations. PKC412 elicits massive apoptosis without markedly affecting cell cycle patterns in AML cell lines with FLT3 mutations (MV4-11 and MOLM13), whereas it induces G 2 arrest but not apoptosis in AML cell lines without FLT3 mutations (THP-1 and U937). In MV4-11 and MOLM13 cells, PKC412 inactivates Myt-1 and activates CDC25c, leading to the activation of CDC2. Activated CDC2 phosphorylates Bad at serine-128 and facilitates its translocation to the mitochondria, where Bad triggers apoptosis. In contrast, PKC412 inactivates CDC2 by inducing serine-216 phosphorylation and subsequent cytoplasmic sequestration of CDC25c in THP-1 and U937 cells. As a result, cells are arrested in the G 2 phase of the cell cycle, but do not undergo apoptosis because Bad is not activated. The FLT3 mutationdependent differential cell cycle effect of PKC412 is considered an important factor when PKC412 is combined with cell cycle-specific anticancer drugs in the treatment of cancer and leukemia.

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“…Inhibitors of histone deacetylase, proteasome and Bcl-2 antisense oligonucleotides have also been used as targeted drugs in the clinical treatment of AML (12). Furthermore, inhibitors of Fms-like tyrosine kinase 2 (FLT-2), such as lestaurtinib (CEP701), tandutinib (MLN518) and PKC412 have shown benefit in treating FLT3-associated AML (13).…”

Section: Introductionmentioning

confidence: 99%

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

Huang

Chen

et al. 2013

Oncology Reports

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Abstract. The present study was designed to evaluate the expression and subcellular distribution of the familial acute myelogenous leukemia-related factor (FAMLF). A 14-amino acid epitope of the predicted open reading frame of the FAMLF gene was identified using bioinformatics. This polypeptide was synthesized, conjugated to keyhole limpet hemocyanin and was subsequently used to produce antibodies. The antibody titer and specificity were characterized using ELISA and western blot assays, respectively. The antibody detected FAMLF protein expression in several human leukemia cell lines, bone marrow cells derived from one acute myeloid leukemia patient and one chronic myeloid leukemia patient, but not in bone marrow cells of healthy subjects. The FAMLF/ GFP fusion protein was expressed in both the nucleus and the cytoplasm of transfected NIH3T3 cells. Our results demonstrate that the FAMLF gene is expressed in an AML patient but not in healthy controls, suggesting its association with AML. IntroductionAcute myeloid leukemia (AML) is the most common hematological malignancy in adults, with a worldwide incidence of ~3.6 cases in 100,000 individuals (National Cancer Institute. SEER Stat Fact Sheets: Acute Myeloid Leukemia; http://seer. cancer.gov/statfacts/html/amyl.html). A number of AMLrelated chromosomal abnormalities and gene mutations have been identified, and their involvement in the regulation of DNA methylation, signal transduction, energy synthesis, and cellular structure has been reported (1).The identification of new AML-related genes may provide insight into disease prognosis, treatment response, and new therapeutic regimens for patients with AML. Mutations in CCAAT enhancer binding factor α (CEBPA) have been associated with prolonged recurrence-free survival in AML patients (2). Mutations in nucleophosmin-1 (NPM1) and the internal tandem duplications in FLT3 predict positive AML prognosis (3), and mutations in several genes such as MLL-PTD, FLT3/ITD, WT1, and C-KIT predict negative AML prognosis (4-7). Thus, screening for mutations in CEBPA, NPM1, FLT3, and KIT is part of the routine workup for AML (8,9).A number of drugs targeting AML-related genes have been tested for their efficacy in treating AML, including TNF-related apoptosis inducing ligand (TRAIL) and tipifarnib, an inhibitor of farnesyltransferase (FTase), alone or in combination with other anti-leukemia drugs (10,11). Inhibitors of histone deacetylase, proteasome and Bcl-2 antisense oligonucleotides have also been used as targeted drugs in the clinical treatment of AML (12). Furthermore, inhibitors of Fms-like tyrosine kinase 2 (FLT-2), such as lestaurtinib (CEP701), tandutinib (MLN518) and PKC412 have shown benefit in treating FLT3-associated AML (13).Previously, we identified a large family with a high incidence of AML in Fujian China (14). A total of 11 family members in 4 generations were diagnosed with AML; two patients developed acute erythroleukemia (M6), one suffered from minimally differentiated acute myeloblastic leukemia (M1), one ha...

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Divergent cytotoxic effects of PKC412 in combination with conventional antileukemic agents in FLT3 mutation-positive versus -negative leukemia cell lines

Cited by 54 publications

References 38 publications

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

The FLT3 inhibitor PKC412 exerts differential cell cycle effects on leukemic cells depending on the presence of FLT3 mutations

Protein expression and subcellular localization of familial acute myelogenous leukemia-related factor

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