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Journal Article•DOI•

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

Naoto Morishita1, Hirokazu Tsukahara1, Kosuke Chayama, Toshiaki Ishida2, Kana Washio1, Takako Miyamura1, Nobuko Yamashita1, Megumi Oda1, Tsuneo Morishima1 •
Okayama University1, Boston Children's Hospital2
15 Jul 2012-Pediatric Blood & Cancer (Pediatr Blood Cancer)-Vol. 59, Iss: 1, pp 83-89
TL;DR: This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P‐Akt) in pediatric B‐pre ALL.
Abstract: Background Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. Procedure We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. Results P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. Conclusion These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. Pediatr Blood Cancer 2012; 59: 83–89. © 2011 Wiley Periodicals, Inc.

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氏 名
授 与 し た 学 位
専 攻 分 野 の名 称
学 位 授 与 番 号
学 位 授 与 の 日付
学 位 授 与 の 要 件
学 位 論 文 題 目
森 下 直 人
博 士
医 学
博 甲第 4468 号
平成 24年 3月 2 3 日
医歯薬学総合研究科病態制御科学専攻
(学位 規則 第 4条 第 1項該 当)
ActivationofAktisAssociatedWithPoorPrognosis
and Chemotherapeutic Resistance in Pediatric
B‑PrecursorAcuteLymphoblasticLeukemia
(Akt
の活性化は､小児のB前駆細胞性急性 リンパ性 白血病に
おける予後不良と化学療法抵抗性に関連 している)
論 文 審 査 委 員
教授 谷 本 光音 教授 岩 月 啓 氏 教 授 杉 山 育
学 位 論 文 内 容 の 要 旨
pt3Kl
触 経路壮生存促進性の経路であり､リン酸化によるjkt浄財 ヒは腰痛細胞の成長におい
て重要な役割を果たしている｡しかし､小児
B前納 包性急性リンパ性白血病 (以下､RpreJqL)
の樹散生理におけるjgdの役割はいまだ不明の部分が多Llo今回､我々R 小児BpreAu.にお
けるj
kt活性化が臨床検査学的に分袖 壁学的にどのような意義を有するのか調べた｡
21名の小児 BpreAL患者を対象に行った飽和 勺検討では 骨髄倹体でjgd:が括性化している
患者では菅性化していない患者i3ヒべて化学馳 こ対する反応性が有意に乏しく､生命予後も有
意に悪いことが示 された
CIn trarBfectionによりAktを持続 的に活性化させたBpreA⊥細胞
株 恥 Im6細骨砂 を用いた基砲的検討では､抗脚 Jにより誘導されるアポ トーシスが有意に抑
制されることが示 された｡以上の結果より､
Bpre凡Lにおいて､jgdl措性化樹 臓 超抗性を
もたらす機構
の 1つであり､Jqdが†㈱ こ抵抗性を示 机 ＼児Bpre,qLL患都 こおいて治療標的
になりえることが示唆された｡
論 文 審 査 結 果 の 要 旨
本研究では､′J､児 B･preALLにおいて､骨髄検体で Aktが活性化 している患者 と活性
化が明らかでない患者 との予後を比較 した結果､
Aktの活性化が生存 とかかわっているこ
とを見出 した｡予後に影響を与える機構を解明するため
､B･preALL細胞株であるNalm‑6
株に活性化 した Akt遺伝子をせん孔法で導入 した細胞株に於いては､化学療法剤である
ステロイ ド､オンコビン､ア ドリアマイシン添加によるアポ トーシスが明 らかに抑制 され
ていることを見出 した｡この結果は､A
kt遺伝子の活性化経路がアポ トーシス抑制を介 し
て化学療法治療に対する抵抗性を獲得 していることを示 した新たな知見である｡
よって､本研究者は博士 (医学)の学位を得る資格があると認める｡
Citations
More filters
Journal Article•DOI•
Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia

[...]

Erich Piovan1, Erich Piovan2, Jiyang Yu2, Valeria Tosello2, Daniel Herranz2, Alberto Ambesi-Impiombato2, Ana Carolina Da Silva2, Marta Sanchez-Martin2, Arianne Perez-Garcia2, Isaura Rigo2, Mireia Castillo3, Stefano Indraccolo, Justin R. Cross4, Elisa de Stanchina4, Elisabeth Paietta5, Elisabeth Paietta6, Janis Racevskis5, Janis Racevskis6, Jacob M. Rowe, Martin S. Tallman4, Giuseppe Basso1, Jules P.P. Meijerink7, Carlos Cordon-Cardo3, Andrea Califano, Adolfo A. Ferrando •
University of Padua1, Columbia University2, Icahn School of Medicine at Mount Sinai3, Memorial Sloan Kettering Cancer Center4, Montefiore Medical Center5, Albert Einstein College of Medicine6, Boston Children's Hospital7
09 Dec 2013-Cancer Cell
TL;DR: It is demonstrated that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucoc Corticoid therapy, and pharmacologic inhibition of AKT with MK2206 effectively reverses glucocORTicoid resistance.

223 citations

Cites background from "Activation of Akt is associated wit..."

  • ...…of mutational loss of PTEN and increased AKT1 phosphorylation with primary glucocorticoid resistance in the clinic (Bandapalli et al., 2013; Morishita et al., 2012) and the availability of PI3K-AKT specific inhibitors in clinical trials for the treatment of human cancer, prompted us to…...

    [...]

  • ...These results, together with the association of mutational loss of PTEN and increased AKT1 phosphorylation with primary glucocorticoid resistance in the clinic (Bandapalli et al., 2013; Morishita et al., 2012) and the availability of PI3K-AKT specific inhibitors in clinical trials for the treatment of human cancer, prompted us to analyze the mechanistic role of AKT1 in the control of glucocorticoid resistance in T-ALL....

    [...]

Journal Article•DOI•
Phytochemicals As Chemosensitizers: From Molecular Mechanism to Clinical Significance

[...]

Balachandran S Vinod1, Tessy Thomas Maliekal, Ruby John Anto•
Rajiv Gandhi Centre for Biotechnology1
25 Feb 2013-Antioxidants & Redox Signaling
TL;DR: An overview of the clinical relevance of chemosensitization is provided, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity.
Abstract: This review provides an overview of the clinical relevance of chemosensitization, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity. We also give a brief summary of all the clinical trials related to the important phytochemicals that emerge as chemosensitizers. The mode of action of these phytochemicals in regulating the key players of the death receptor pathway and multidrug resistance proteins is also abridged. Rigorous efforts in identifying novel chemosensitizers and unraveling their molecular mechanism have resulted in some of the promising candidates such as curcumin, genistein, and polyphenon E, which have gone into clinical trials. Even though considerable research has been conducted in identifying the salient molecular players either contributing to drug efflux or inhibiting DNA repair and apoptosis, both of which ultimately lead to the development of chemoresistance, the interdependence of the molecular pathways leading to chemoresistance is still the impeding factor in the success of chemotherapy. Even though clinical trials are going on to evaluate the chemosensitizing efficacy of phytochemicals such as curcumin, genistein, and polyphenon E, recent results indicate that more intense study is required to confirm their clinical efficacy. Current reports also warrant intense investigation about the use of more phytochemicals such as quercetin, emodin, and resveratrol as chemosensitizers, as all of them have been shown to modulate one or more of the key regulators of chemoresistance.

127 citations

Cites background from "Activation of Akt is associated wit..."

  • ...Vincristine Peripheral neurotoxicity Ak t (205, 326), p38 MAPK (96), P-gp, survivin (283)...

    [...]

Journal Article•DOI•
Outlook on PI3K/AKT/mTOR inhibition in acute leukemia

[...]

Lars Fransecky1, Liliana H. Mochmann1, Claudia D. Baldus1•
Charité1
20 Mar 2015
TL;DR: In this paper, the authors summarized key findings leading to aberrant activation of PI3K/AKT/mTOR pathways in acute leukemia and reflected on both promises and challenges of targeting PI3k/AKt/mtor in the acute leukemia setting.
Abstract: Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy.

112 citations

Cites background from "Activation of Akt is associated wit..."

  • ...Moreover, in a retrospective study, pAKT was associated to poor overall survival [42]....

    [...]

Journal Article•DOI•
Targeting the PI3K/Akt/mTOR signaling pathway in B-precursor acute lymphoblastic leukemia and its therapeutic potential.

[...]

Luca M. Neri1, Alice Cani1, Am Martelli2, Carolina Simioni1, Christian Junghanss3, Giovanna Tabellini4, Francesca Ricci, P. L. Tazzari, Pasqualepaolo Pagliaro, James A. McCubrey5, Silvano Capitani1 •
University of Ferrara1, University of Bologna2, University of Rostock3, University of Brescia4, East Carolina University5
01 Apr 2014-Leukemia
TL;DR: It is pointed out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.
Abstract: B-precursor acute lymphoblastic leukemia (B-pre ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. The prognosis of B-pre ALL has improved in pediatric patients, but the outcome is much less successful in adults. Constitutive activation of the phosphatidylinositol 3-kinase (PI3K), Akt and the mammalian target of rapamycin (mTOR) (PI3K/Akt/mTOR) network is a feature of B-pre ALL, where it strongly influences cell growth and survival. RAD001, a selective mTORC1 inhibitor, has been shown to be cytotoxic against many types of cancer including hematological malignancies. To investigate whether mTORC1 could represent a target in the therapy of B-pre ALL, we treated cell lines and adult patient primary cells with RAD001. We documented that RAD001 decreased cell viability, induced cell cycle arrest in G0/G1 phase and caused apoptosis in B-pre ALL cell lines. Autophagy was also induced, which was important for the RAD001 cytotoxic effect, as downregulation of Beclin-1 reduced drug cytotoxicity. RAD001 strongly synergized with the novel allosteric Akt inhibitor MK-2206 in both cell lines and patient samples. Similar results were obtained with the combination CCI-779 plus GSK 690693. These findings point out that mTORC1 inhibitors, either as a single agent or in combination with Akt inhibitors, could represent a potential therapeutic innovative strategy in B-pre ALL.

104 citations

Journal Article•DOI•
FUT family mediates the multidrug resistance of human hepatocellular carcinoma via the PI3K/Akt signaling pathway

[...]

Lei Cheng1, S Luo2, C Jin1, Hongye Ma1, Humin Zhou1, Li Jia1 •
Dalian Medical University1, Ruijin Hospital2
14 Nov 2013-Cell Death and Disease
TL;DR: The results suggest that FUT4-, FUT6- or FUT8-mediated MDR in human HCC is associated with the activation of the PI3K/Akt pathway and the expression of MRP1, but not of P-gp, indicating a possible novel mechanism by which the FUT family regulates M DR in humanHCC.
Abstract: The fucosyltransferase (FUT) family is the key enzymes in cell-surface antigen synthesis during various biological processes such as tumor multidrug resistance (MDR) The aim of this work was to analyze the alteration of FUTs involved in MDR in human hepatocellular carcinoma (HCC) cell lines Using mass spectrometry (MS) analysis, the composition profiling of fucosylated N-glycans differed between drug-resistant BEL7402/5-FU (BEL/FU) cells and the sensitive line BEL7402 Further analysis of the expressional profiles of the FUT family in three pairs of parental and chemoresistant human HCC cell lines showed that FUT4, FUT6 and FUT8 were predominant expressed in MDR cell lines The altered levels of FUT4, FUT6 and FUT8 were responsible for changed drug-resistant phenotypes of BEL7402 and BEL/FU cells both in vitro and in vivo In addition, regulating FUT4, FUT6 or FUT8 expression markedly modulated the activity of the phosphoinositide 3 kinase (PI3K)/Akt signaling pathway and MDR-related protein 1 (MRP1) expression Inhibition of the PI3K/Akt pathway by its specific inhibitor wortmannin, or by Akt small interfering RNA (siRNA), resulted in decreased MDR of BEL/FU cells, partly through the downregulation of MRP1 Taken together, our results suggest that FUT4-, FUT6- or FUT8-mediated MDR in human HCC is associated with the activation of the PI3K/Akt pathway and the expression of MRP1, but not of P-gp, indicating a possible novel mechanism by which the FUT family regulates MDR in human HCC

92 citations

Cites background from "Activation of Akt is associated wit..."

  • ...Activation of Akt was associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.(26) The PI3k/Akt pathway was involved in P-gp-associated survivin transcription activity in the multidrug-resistant MCF-7 breast cancer cells....

    [...]

References
More filters
Journal Article•DOI•
Activation of the PI3K/Akt pathway and chemotherapeutic resistance.

[...]

Kip A. West, S. Sianna Castillo, Phillip A. Dennis
01 Dec 2002-Drug Resistance Updates
TL;DR: In this review, small molecules designed to specifically target Akt and other components of the PI3K/Akt pathway are now being developed for clinical use as single agents and in combination with chemotherapy to overcome therapeutic resistance.

582 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...We assume that other pathways aside from P-glycoprotein play an important role in MDR in Nalm-6/Akt, such as expression of another ATP-binding cassette transporter, inhibition of BAD, inhibition of Caspase-9, activation of NF-kB, inhibition of p53, and so forth [6,24]....

    [...]

Journal Article•DOI•
Molecular targeting therapy of cancer: drug resistance, apoptosis and survival signal.

[...]

Takashi Tsuruo1, Mikihiko Naito1, Akihiro Tomida1, Naoya Fujita1, Tetsuo Mashima2, Hiroshi Sakamoto1, Hiroshi Sakamoto2, Naomi Haga1 •
University of Tokyo1, Japanese Foundation for Cancer Research2
01 Jan 2003-Cancer Science
TL;DR: In this article, a review on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches, is presented, focusing on the areas of drug resistance, apoptosis and apoptosis resistance, and survival-signaling.
Abstract: Recent progress in the development of molecular cancer therapeutics has revealed new types of antitumor drugs, such as Herceptin, Gleevec, and Iressa, as potent therapeutics for specific tumors. Our work has focused on molecular cancer therapeutics, mainly in the areas of drug resistance, apoptosis and apoptosis resistance, and survival-signaling, which is related to drug resistance. In this review, we describe our research on molecular cancer therapeutics, including molecular mechanisms and therapeutic approaches. Resistance to chemotherapeutic drugs is a principal problem in the treatment of cancer. P-Glycoprotein (P-gp), encoded by the MDR1 gene, is a multidrug transporter and has a major role in multidrug resistance (MDR). Targeting of P-gp by small-molecular compounds and/or antibodies is an effective strategy to overcome MDR in cancer, especially hematologic malignancies. Several P-gp inhibitors have been developed and are currently under clinical phased studies. In addition to the multidrug transporter proteins, cancer cells have several drug resistance mechanisms. Solid tumors are often placed under stress conditions, such as glucose starvation and hypoxia. These conditions result in topo II poison resistance that is due to proteasome-mediated degradation of DNA topoisomerases. Proteasome inhibitors effectively prevent this stress-induced drug resistance. Glyoxalase I, which is often elevated in drug- and apoptosis-resistant cancers, offers another possibility for overcoming drug resistance. It plays a role in detoxification of methylglioxal, a side product of glycolysis, which is highly reactive with DNA and proteins. Inhibitors of glyoxalase I selectively kill drug-resistant tumors that express glyoxalase I. Finally, the susceptibility of tumor cells to apoptosis induced by antitumor drugs appears to depend on the balance between pro-apoptotic and survival (anti-apoptotic) signals. PI3K-Akt is an important survival signal pathway, that has been shown to be the target of various antitumor drugs, including UCN-01 and geldanamycin, new anticancer drugs under clinical evaluation. Our present studies provide novel targets for future effective molecular cancer therapeutics.

487 citations

Journal Article•DOI•
Improved outcome for children with acute lymphoblastic leukemia: Results of Total Therapy Study XIIIB at St Jude Children's Research Hospital

[...]

Ching-Hon Pui, John T. Sandlund, Deqing Pei, Dario Campana, Gaston K. Rivera, Raul C. Ribeiro, Jeffrey E. Rubnitz, Bassem I. Razzouk, Scott C. Howard, Melissa M. Hudson, Cheng Cheng, Larry E. Kun, Susana C. Raimondi, Frederick G. Behm, James R. Downing, Mary V. Relling, William E. Evans 
01 Nov 2004-Blood
TL;DR: The results suggest the efficacy of early intensification of intrathecal chemotherapy and provide the basis for studies omitting cranial irradiation altogether and the addition of dexamethasone to postremission therapy.

462 citations

"Activation of Akt is associated wit..." refers background or methods in this paper

  • ...Diagnosis of B-pre ALL was based on standard morphologic and immunophenotypic evaluations [1]....

    [...]

  • ...Most children with B-pre ALL are expected to have long-term survival, with a survival rate higher than 70% at 5 years after diagnosis [1,2]....

    [...]

Journal Article•DOI•
Results of the Dana-Farber Cancer Institute ALL Consortium Protocol 95-01 for children with acute lymphoblastic leukemia.

[...]

Albert Moghrabi1, Donna E. Levy2, Barbara L. Asselin3, Ronald D. Barr4, Luis A. Clavell5, Craig A. Hurwitz, Yvan Samson6, Marshall A. Schorin7, Virginia Dalton2, Steven E. Lipshultz8, Donna Neuberg2, Richard D. Gelber2, Harvey J. Cohen9, Stephen E. Sallan5, Stephen E. Sallan2, Lewis B. Silverman5, Lewis B. Silverman2 •
Université de Montréal1, Harvard University2, University of Rochester3, McMaster University4, Boston Children's Hospital5, Laval University6, Tulane University7, University of Miami8, Stanford University9
01 Feb 2007-Blood
TL;DR: It is concluded that dexrazoxane does not interfere with the antileukemic effect of doxorubicin, intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in standard-risk patients, and once-weekly Erwinia is less toxic than E coli asparaginase, but also less efficacious.

388 citations

"Activation of Akt is associated wit..." refers background in this paper

  • ...Most children with B-pre ALL are expected to have long-term survival, with a survival rate higher than 70% at 5 years after diagnosis [1,2]....

    [...]

Journal Article•DOI•
Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia.

[...]

Am Martelli1, Maria Nyakern1, Giovanna Tabellini2, Roberta Bortul3, P. L. Tazzari, Camilla Evangelisti1, Lucio Cocco1 •
University of Bologna1, University of Brescia2, University of Trieste3
01 Jun 2006-Leukemia
TL;DR: The existing knowledge about PI3K/Akt signaling in AML cells is summarized, the rationale for targeting this fundamental signal transduction network by means of selective pharmacological inhibitors is examined and this pathway is an attractive target for the development of novel anticancer strategies.
Abstract: The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway is crucial to many aspects of cell growth, survival and apoptosis, and its constitutive activation has been implicated in the both the pathogenesis and the progression of a wide variety of neoplasias. Hence, this pathway is an attractive target for the development of novel anticancer strategies. Recent studies showed that PI3K/Akt signaling is frequently activated in acute myeloid leukemia (AML) patient blasts and strongly contributes to proliferation, survival and drug resistance of these cells. Upregulation of the PI3K/Akt network in AML may be due to several reasons, including FLT3, Ras or c-Kit mutations. Small molecules designed to selectively target key components of this signal transduction cascade induce apoptosis and/or markedly increase conventional drug sensitivity of AML blasts in vitro. Thus, inhibitory molecules are currently being developed for clinical use either as single agents or in combination with conventional therapies. However, the PI3K/Akt pathway is important for many physiological cellular functions and, in particular, for insulin signaling, so that its blockade in vivo might cause severe systemic side effects. In this review, we summarize the existing knowledge about PI3K/Akt signaling in AML cells and we examine the rationale for targeting this fundamental signal transduction network by means of selective pharmacological inhibitors.

325 citations

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