Sequential Dosing in Chemosensitization: Targeting the PI3K/Akt/mTOR Pathway in Neuroblastoma

被引:44
作者
Westhoff, Mike-Andrew [1 ]
Faham, Najmeh [1 ]
Marx, Daniela [1 ]
Nonnenmacher, Lisa [1 ]
Jennewein, Claudia [1 ]
Enzenmueller, Stefanie [1 ]
Gonzalez, Patrick [1 ]
Fulda, Simone [1 ]
Debatin, Klaus-Michael [1 ]
机构
[1] Univ Med Ctr Ulm, Dept Pediat & Adolescent Med, Ulm, Germany
关键词
HIGH-RISK NEUROBLASTOMA; CELL-DEATH; GLIOBLASTOMA CELLS; TOPOISOMERASE-II; AKT; ACTIVATION; INHIBITOR; APOPTOSIS; CHEMOTHERAPY; AUTOPHAGY;
D O I
10.1371/journal.pone.0083128
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Breaking resistance to chemotherapy is a major goal of combination therapy in many tumors, including advanced neuroblastoma. We recently demonstrated that increased activity of the PI3K/Akt network is associated with poor prognosis, thus providing an ideal target for chemosensitization. Here we show that targeted therapy using the PI3K/mTOR inhibitor NVP-BEZ235 significantly enhances doxorubicin-induced apoptosis in neuroblastoma cells. Importantly, this increase in apoptosis was dependent on scheduling: while pretreatment with the inhibitor reduced doxorubicin-induced apoptosis, the sensitizing effect in co-treatment could further be increased by delayed addition of the inhibitor post chemotherapy. Desensitization for doxorubicin-induced apoptosis seemed to be mediated by a combination of cell cycle-arrest and autophagy induction, whereas sensitization was found to occur at the level of mitochondria within one hour of NVP-BEZ235 posttreatment, leading to a rapid loss of mitochondrial membrane potential with subsequent cytochrome c release and caspase-3 activation. Within the relevant time span we observed marked alterations in a similar to 30 kDa protein associated with mitochondrial proteins and identified it as VDAC1/Porin protein, an integral part of the mitochondrial permeability transition pore complex. VDAC1 is negatively regulated by the PI3K/Akt pathway via GSK3 beta and inhibition of GSK3b, which is activated when Akt is blocked, ablated the sensitizing effect of NVP-BEZ235 posttreatment. Our findings show that cancer cells can be sensitized for chemotherapy induced cell death - at least in part - by NVP-BEZ235-mediated modulation of VDAC1. More generally, we show data that suggest that sequential dosing, in particular when multiple inhibitors of a single pathway are used in the optimal sequence, has important implications for the general design of combination therapies involving molecular targeted approaches towards the PI3K/Akt/mTOR signaling network.
引用
收藏
页数:14
相关论文
共 49 条
[1]   B-cell-derived lymphotoxin promotes castration-resistant prostate cancer [J].
Ammirante, Massimo ;
Luo, Jun-Li ;
Grivennikov, Sergei ;
Nedospasov, Sergei ;
Karin, Michael .
NATURE, 2010, 464 (7286) :302-U187
[2]   The novel orally bioavailable inhibitor of phosphoinositol-3-kinase and mammalian target of rapamycin, NVP-BEZ235, inhibits growth and proliferation in multiple myeloma [J].
Baumann, Philipp ;
Mandl-Weber, Sonia ;
Oduncu, Fuat ;
Schmidmaier, Ralf .
EXPERIMENTAL CELL RESEARCH, 2009, 315 (03) :485-497
[3]   PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis [J].
Bender, A. ;
Opel, D. ;
Naumann, I. ;
Kappler, R. ;
Friedman, L. ;
von Schweinitz, D. ;
Debatin, K-M ;
Fulda, S. .
ONCOGENE, 2011, 30 (04) :494-503
[4]   Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial [J].
Berthold, F ;
Boos, J ;
Burdach, S ;
Erttmann, R ;
Henze, G ;
Hermann, J ;
Klingebiel, T ;
Kremens, B ;
Schilling, FH ;
Schrappe, M ;
Simon, T ;
Hero, B .
LANCET ONCOLOGY, 2005, 6 (09) :649-658
[5]   Doxorubicin-induced cell death requires cathepsin B in HeLa cells [J].
Bien, S. ;
Rimmbach, C. ;
Neumann, H. ;
Niessen, J. ;
Reimer, E. ;
Ritter, C. A. ;
Rosskopf, D. ;
Cinatl, J. ;
Michaelis, M. ;
Schroeder, H. W. S. ;
Kroemer, H. K. .
BIOCHEMICAL PHARMACOLOGY, 2010, 80 (10) :1466-1477
[6]   Targeting the phosphoinositide 3-kinase isoform p110δ impairs growth and survival in neuroblastoma cells [J].
Boller, Danielle ;
Schramm, Alexander ;
Doepfner, Kathrin T. ;
Shalaby, Tarek ;
von Bueren, Andre O. ;
Eggert, Angelika ;
Grotzer, Michael A. ;
Arcaro, Alexandre .
CLINICAL CANCER RESEARCH, 2008, 14 (04) :1172-1181
[7]   Neuroblastoma: Biological insights into a clinical enigma [J].
Brodeur, GM .
NATURE REVIEWS CANCER, 2003, 3 (03) :203-216
[8]  
Büki A, 2000, J NEUROSCI, V20, P2825
[9]   Mechanism of action of eukaryotic topoisomerase II and drugs targeted to the enzyme [J].
Burden, DA ;
Osheroff, N .
BIOCHIMICA ET BIOPHYSICA ACTA-GENE STRUCTURE AND EXPRESSION, 1998, 1400 (1-3) :139-154
[10]   High-risk neuroblastoma tumors with 11q-deletion display a poor prognostic, chromosome instability phenotype with later onset [J].
Caren, Helena ;
Kryh, Hanna ;
Nethander, Maria ;
Sjoberg, Rose-Marie ;
Trager, Catarina ;
Nilsson, Staffan ;
Abrahamsson, Jonas ;
Kogner, Per ;
Martinsson, Tommy .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2010, 107 (09) :4323-4328