Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody

The hyperpermeability of tumor vessels to macromolecules, compared with normal vessels, is presumably due to vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) released by neoplastic and/or host cells. In addition, VEGF/VPF is a potent angiogenic factor. Removal of this growth factor may reduce the permeability and inhibit tumor angiogenesis. To test these hypotheses, we transplanted a human glioblastoma (U87), a human colon adenocarcinoma (LS174T), and a human melanoma (P-MEL) into two locations in immunodeficient mice: the cranial window and the dorsal skinfold chamber. The mice bearing vascularized tumors were treated with a bolus (0.2 ml) of either a neutralizing antibody (A4.6.1) (492 μg/ml) against VEGF/VPF or PBS (control). We found that tumor vascular permeability to albumin in antibody-treated groups was lower than in the matched controls and that the effect of the antibody was time-dependent and influenced by the mode of injection. Tumor vascular permeability did not respond to i.p. injection of the antibody until 4 days posttreatment. However, the permeability was reduced within 6 h after i.v. injection of the same amount of antibody. In addition to the reduction in vascular permeability, the tumor vessels became smaller in diameter and less tortuous after antibody injections and eventually disappeared from the surface after four consecutive treatments in U87 tumors. These results demonstrate that tumor vascular permeability can be reduced by neutralization of endogenous VEGF/VPF and suggest that angiogenesis and the maintenance of integrity of tumor vessels require the presence of VEGF/VPF in the tissue microenvironment. The latter finding reveals a new mechanism of tumor vessel regression—i.e., blocking the interactions between VEGF/VPF and endothelial cells or inhibiting VEGF/VPF synthesis in solid tumors causes dramatic reduction in vessel diameter, which may block the passage of blood elements and thus lead to vascular regression.

Recombinant immunotoxins specific for a mutant epidermal growth factor receptor: Targeting with a single chain antibody variable domain isolated by phage display

EGFRvIII is a mutant epidermal growth factor receptor found in glioblastoma, and in carcinoma of the breast, ovary, and lung. The mutant receptor has a deletion in its extracellular domain that results in the formation of a new, tumor-specific extracellular sequence. Mice were immunized with a synthetic peptide corresponding to this sequence and purified EGFRvIII. A single chain antibody variable domain (scFv) phage display library of 8 × 106 members was made from the spleen of one immunized mouse. A scFv specific for EGFRvIII was isolated from this library by panning with successively decreasing amounts of synthetic peptide. This was used to make an immunotoxin by fusing the scFv DNA sequence to sequences coding for domains II and III of Pseudomonas exotoxin A. Purified immunotoxin had a Kd of 22 nM for peptide and a Kd of 11 nM for cell-surface EGFRvIII. The immunotoxin was very cytotoxic to cells expressing EGFRvIII, with an IC50 of 1 ng/ml (16 pM) on mouse fibroblasts transfected with EGFRvIII and an IC50 of 7–10 ng/ml (110–160 pM) on transfected glioblastoma cells. There was no cytotoxic activity at 1000 ng/ml on the untransfected parent glioblastoma cell line. The immunotoxin was completely stable upon incubation at 37°C for 24 h in human serum. The combination of good affinity, cytotoxicity and stability make this immunotoxin a candidate for further preclinical evaluation.

Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway

PTEN/MMAC1 is a tumor suppressor gene located on chromosome 10q23. Inherited PTEN/MMAC1 mutations are associated with a cancer predisposition syndrome known as Cowden’s disease. Somatic mutation of PTEN has been found in a number of malignancies, including glioblastoma, melanoma, and carcinoma of the prostate and endometrium. The protein product (PTEN) encodes a dual-specificity protein phosphatase and in addition can dephosphorylate certain lipid substrates. Herein, we show that PTEN protein induces a G1 block when reconstituted in PTEN-null cells. A PTEN mutant associated with Cowden’s disease (PTEN;G129E) has protein phosphatase activity yet is defective in dephosphorylating inositol 1,3,4,5-tetrakisphosphate in vitro and fails to arrest cells in G1. These data suggest a link between induction of a cell-cycle block by PTEN and its ability to dephosphorylate, in vivo, phosphatidylinositol 3,4,5-trisphosphate. In keeping with this notion, PTEN can inhibit the phosphatidylinositol 3,4,5-trisphosphate-dependent Akt kinase, a downstream target of phosphatidylinositol 3-kinase, and constitutively active, but not wild-type, Akt overrides a PTEN G1 arrest. Finally, tumor cells lacking PTEN contain high levels of activated Akt, suggesting that PTEN is necessary for the appropriate regulation of the phosphatidylinositol 3-kinase/Akt pathway.

Conversion of a radioresistant phenotype to a more sensitive one by disabling erbB receptor signaling in human cancer cells

Inhibition of cell growth and transformation can be achieved in transformed glial cells by disabling erbB receptor signaling. However, recent evidence indicates that the induction of apoptosis may underlie successful therapy of human cancers. In these studies, we examined whether disabling oncoproteins of the erbB receptor family would sensitize transformed human glial cells to the induction of genomic damage by γ-irradiation. Radioresistant human glioblastoma cells in which erbB receptor signaling was inhibited exhibited increased growth arrest and apoptosis in response to DNA damage. Apoptosis was observed after radiation in human glioma cells containing either a wild-type or mutated p53 gene product and suggested that both p53-dependent and -independent mechanisms may be responsible for the more radiosensitive phenotype. Because cells exhibiting increased radiation-induced apoptosis were also capable of growth arrest in serum-deprived conditions and in response to DNA damage, apoptotic cell death was not induced simply as a result of impaired growth arrest pathways. Notably, inhibition of erbB signaling was a more potent stimulus for the induction of apoptosis than prolonged serum deprivation. Proximal receptor interactions between erbB receptor members thus influence cell cycle checkpoint pathways activated in response to DNA damage. Disabling erbB receptors may improve the response to γ-irradiation and other cytotoxic therapies, and this approach suggests that present anticancer strategies could be optimized.

Connexins regulate calcium signaling by controlling ATP release

Forced expression of gap junction proteins, connexins, enables gap junction-deficient cell lines to propagate intercellular calcium waves. Here, we show that ATP secretion from the poorly coupled cell lines, C6 glioma, HeLa, and U373 glioblastoma, is potentiated 5- to 15-fold by connexin expression. ATP release required purinergic receptor-activated intracellular Ca2+ mobilization and was inhibited by Cl− channel blockers. Calcium wave propagation also was reduced by purinergic receptor antagonists and by Cl− channel blockers but insensitive to gap junction inhibitors. These observations suggest that cell-to-cell signaling associated with connexin expression results from enhanced ATP release and not, as previously believed, from an increase in intercellular coupling.

ARF-GEP100, a guanine nucleotide-exchange protein for ADP-ribosylation factor 6

A human cDNA encoding an 841-aa guanine nucleotide-exchange protein (GEP) for ADP-ribosylation factors (ARFs), named ARF-GEP100, which contains a Sec7 domain, a pleckstrin homology (PH)-like domain, and an incomplete IQ-motif, was identified. On Northern blot analysis of human tissues, a ≈8-kb mRNA that hybridized with an ARF-GEP100 cDNA was abundant in peripheral blood leukocytes, brain, and spleen. ARF-GEP100 accelerated [35S]GTPγS binding to ARF1 (class I) and ARF5 (class II) 2- to 3-fold, and to ARF6 (class III) ca. 12-fold. The ARF-GEP100 Sec7 domain contains Asp543 and Met555, corresponding to residues associated with sensitivity to the inhibitory effect of the fungal metabolite brefeldin A (BFA) in yeast Sec7, but also Phe535 and Ala536, associated with BFA-insensitivity. The PH-like domain differs greatly from those of other ARF GEPs in regions involved in phospholipid binding. Consistent with its structure, ARF-GEP100 activity was not affected by BFA or phospholipids. After subcellular fractionation of cultured T98G human glioblastoma cells, ARF6 was almost entirely in the crude membrane fraction, whereas ARF-GEP100, a 100-kDa protein detected with antipeptide antibodies, was cytosolic. On immunofluorescence microscopy, both proteins had a punctate pattern of distribution throughout the cells, with apparent colocalization only in peripheral areas. The coarse punctate distribution of EEA-1 in regions nearer the nucleus appeared to coincide with that of ARF-GEP100 in those areas. No similar coincidence of ARF-GEP100 with AP-1, AP-2, catenin, LAMP-1, or 58K was observed. The new human BFA-insensitive GEP may function with ARF6 in specific endocytic processes.

Expression of hyaluronidase by tumor cells induces angiogenesis in vivo.

Hyaluronic acid is a proteoglycan present in the extracellular matrix and is important for the maintenance of tissue architecture. Depolymerization of hyaluronic acid may facilitate tumor invasion. In addition, oligosaccharides of hyaluronic acid have been reported to induce angiogenesis. We report here that a hyaluronidase similar to the one on human sperm is expressed by metastatic human melanoma, colon carcinoma, and glioblastoma cell lines and by tumor biopsies from patients with colorectal carcinomas, but not by tissues from normal colon. Moreover, angiogenesis is induced by hyaluronidase+ tumor cells but not hyaluronidase- tumor cells and can be blocked by an inhibitor of hyaluronidase. Tumor cells thus use hyaluronidase as one of the "molecular saboteurs" to depolymerize hyaluronic acid to facilitate invasion. As a consequence, breakdown products of hyaluronic acid can further promote tumor establishment by inducing angiogenesis. Hyaluronidase on tumor cells may provide a target for anti-neoplastic drugs.

Qualidade de vida relacionada à saude em mulheres com reações adversas após tratamento com quimioterapia para câncer de mama

Trata-se de estudo descritivo, exploratório, transversal, quantitativo, realizado com mulheres em tratamento quimioterápico para neoplasias de mama, em Aracaju-Sergipe-Brasil. O objetivo foi avaliar a qualidade de vida relacionada à saúde (QVRS) destas mulheres que apresentaram reações adversas pós quimioterapia. Foram utilizados instrumentos contendo dados sócio demográficos, clínicos e terapêuticos, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 e formulário de registro de toxicidades dos antineoplásicos. Na análise dos dados, foram utilizados análise descritiva, cálculos de percentual, teste de Shapiro-Wilk, coeficiente de correlação de Pearson ou de Spearman, teste de ANOVA ou Kruskal-Wallis. Os resultados mostraram dados de 206 mulheres, a partir da segunda sessão de quimioterapia, com média de idade de 53,1 anos, maioria procedente de Sergipe, com Carcinoma Ductal Infiltrante, estadiamento III. A maioria realizou cirurgia oncológica, não realizaram radioterapia devido à grande fila de espera, o protocolo de quimioterapia mais comum foi TAC (docetaxel, doxorrubicina e ciclofosfamida). Quanto às reações adversas, a maioria não apresentou alterações hematológicas e metabólicas no momento da coleta das informações, nas alterações funcionais, a fadiga foi presente em 80,8% dos casos, de forma moderada. Nas alterações gastrintestinais, diarreia, constipação, mucosite, náusea, vômito e dor abdominal foram citadas pela maioria. Nas alterações dermatológicas, a alopecia, hiperpigmentação na pele, alterações nas unhas, prurido na pele, descamação e eritema multiforme foram citadas pelas entrevistadas. Nas alterações cardiovasculares, hipotensão e HAS sobressaíram-se. Nas alterações neurológicas, neuropatia periférica, perda da audição e zumbido foram comuns. Os resultados da avaliação da QVRS foram analisadas à luz do referencial teórico de Ferrel et al. (1995) com os seguintes resultados: média do escore 76,01; escalas funcionais apresentaram escore baixo, com aspectos físico, emocional, cognitivo, funcional e social bastante afetados após o tratamento, o desempenho de papéis e função emocional foram os mais prejudicados; na escala de sintomas, os domínios mais prejudicados foram: dificuldades financeiras, fadiga e insônia. Na análise de correlação, o escore geral da QVRS apresentou correlação estatisticamente significante com a quantidade de reações adversas na medula óssea. Em todos os casos estatisticamente significantes o domínio emocional apresentou correlações positivas e o domínio dor, correlações negativas. A idade apresentou correlação estatisticamente significante e negativa com os domínios físico e dificuldades financeiras e positiva com perda de apetite. Pelo procedimento de comparações múltiplas, as diferenças ocorreram entre os estados civis casado e separado e também casado e solteiro, entre as religiões católica e evangélica, entre os ensinos fundamental e médio e entre médio e superior; para a extensão da doença os domínios dor e insônia apresentaram diferenças estatisticamente significantes entre as categorias de extensão. Para renda mensal, os domínios fisico, desempenho de papel, emocional, constipação e dificuldades financeiras apresentaram diferenças estatisticamente significantes entre as categorias de renda. Nos domínios fisico, desempenho de papel e emocional as diferenças ocorreram entre as faixas de 1 a 3 e mais de 6 salários. Concluiu-se que as reações adversas causadas pelo tratamento antineoplásico com quimioterapia afetaram de algum modo as pacientes, causando déficits em vários domínios, prejudicando assim sua QVRS

Ação da proteína amiloide sérica A em melanomas

Concentrações séricas basais da proteína amiloide sérica A (SAA) estão significativamente aumentadas em pacientes com câncer e alguns autores sugerem uma relação causal. Trabalho anterior do grupo mostrou que a SAA induz a proliferação de duas linhagens de glioblastoma humano e afeta os processos de invasividade in vitro, sustentando um papel pró-tumoral para esta proteína. Com base nesse trabalho, investigamos a abrangência dos efeitos de SAA para outro tipo de célula tumoral e para isso escolhemos um painel de linhagens de melanoma humano e uma linhagem primária obtida a partir de aspirado de linfonodo de paciente com melanoma, por nós isolada. Observamos que apesar da célula precursora de melanomas, isto é, melanócito, não produzir SAA, todas as linhagens de melanoma produziram a proteína e expressaram alguns dos seus receptores. Além disso, quando estas células foram estimuladas com SAA houve uma inibição da proliferação em tempos curtos de exposição (48 horas) e efeitos citotóxicos após um tempo maior (7 dias). A SAA também afetou processos de invasividade e a produção das citocinas IL-6, IL-8 e TNF-α. Aos avaliarmos o efeito da SAA na interação das células de melanoma com células do sistema imune, vimos que a SAA ativou uma resposta imune anti-tumoral aumentando a expressão de moléculas co-estumolatórias, como CD69 e HLA-DR, e sua função citotóxica. Ainda, vimos que a produção de TNF-α, IFN-γ, IL-10, IL-1β e IL-8 estimuladas por SAA podem contribuir com os efeitos desta. De forma geral estes resultados nos levam a crer que a SAA tem atividade anti-tumoral em melanomas. Finalizando, com base na importância do desenvolvimento da resistência às terapias atuais para o melanoma, observamos que em células resistentes ao PLX4032, um inibidor de BRAF, os efeitos imunomodulatórios induzidos pela SAA estão abolidos, possivelmente identificando um novo componente da resistência.

A novel and rational approach towards designing aluminium chelators

Aluminium (Al) is known to be neurotoxic and has been associated with the aetiology of Alzheimer's Disease. To date, only desferrioxamine (DFO), a trihydroxamic acid siderophore has been used in the clinical environment for the removal of Al from the body. However, this drug is expensive, orally inactive and is associated with many side effects. These studies employed a theoretical approach, with the use of quantum mechanics (QM) via semi-empirical molecular orbital (MO) calculations, and a practical approach using U87-MG glioblastoma cells as a model for evaluating the influence of potential chelators on the passage of aluminium into cells. Preliminary studies involving the Cambridge Structural Database (CSD) identified that Al prefers binding to bidentate ligands in a 3:1 manner, whereby oxygen was the exclusive donating atom. Statistically significant differences in M-O bond lengths when compared to other trivalent metal ions such as Fe3+ were established and used as an acceptance criterion for subsequent MO calculations. Of the semi-empirical methods parameterised for Al, the PM3 Hamiltonian was found to give the most reliable final optimised geometries of simple 3:1 Al complexes. Consequently the PM3 Hamiltonian was used for evaluating the Hf of 3:1 complexes with more complicated ligands. No correlation exists between published stability constants and individual parameters calculated via PM3 optimisations, although investigation of the dicarboxylates reveals a correlation of 0.961 showing promise for affinity prediction of closely related ligands. A simple and inexpensive morin spectrofluorescence assay has been developed and optimised producing results comparable to atomic absorption spectroscopy methods for the quantitative analysis of Al. This assay was used in subsequent in vitro models, initially on E. coli, which indicated that Al inhibits the antimicrobial action of ciprofloxacin, a potent quinolone antibiotic. Ensuing studies using the second model, U87-MG cells, investigated the influence of chelators on the transmembrane transport of Al, identifying 1,2-diethylhydroxypyridin-4-one as a ligand showing greatest potential for chelating Al in the clinical situation. In conclusion, these studies have explored semi-empirical MO Hamiltonians and an in-vitro U87-MG cell line, both as possible methods for predicting effective chelators of Al.

Evaluation of biodegradable polymer microspheres and an anionic dendrimer for the potential delivery of antisense oligonucleotides

Antisense oligonucleotides (AODNs) can selectively inhibit individual gene expression by binding specifically to rnRNA. The over-expression of the epidermal growth factor receptor (EGFR) has been observed in human breast and glioblastoma tumours and therefore AODNs designed to target the EGFR would be a logical approach to treat such tumours. However, poor pharmacokinetic/pharmacodynamic and cellular uptake properties of AODNs have limited their potential to become successful therapeutic agents. Biodegradable polymeric poly (lactide-co-glycolide) (P(LA-GA)) and dendrimer delivery systems may allow us to overcome these problems. The use of combination therapy of AODNs and cytotoxic agents such as 5-fluorouracil (5-FU) in biodegradable polymeric formulations may further improve therapeutic efficacy. AODN and 5-FU were either co-entrapped in a single microsphere formulation or individually entrapped in two separate microsphere formulations (double emulsion method) and release profiles determined in vitro. The release rates (biphasic) of the two agents were significantly slower when co-entrapped as a single microsphere formulation compared to those obtained with the separate formulations. Sustained release over 35 days was observed in both types of formulation. Naked and microsphere-loaded AODN and 5-FU (in separate formulations) were tested on an A431 vulval carcinoma cell line. Combining naked or encapsulated drugs produced a greater reduction in viable cell number as compared with either agent alone. However, controls and Western blotting indicated that non-sequence specific cytotoxic effects were responsible for the differences in viable cell number. The uptake properties of an anionic dendrimer based on a pentaerythritol structure covalently linked to AODNs (targeting the EGFR) have been characterised. The cellular uptake of AODN linked to the dendrimer was up to 3.5-fold higher in A431 cells as compared to naked AODN. Mechanistic studies suggested that receptor-mediated and adsorptive (binding protein-mediated) endocytosis were the predominant uptake mechanisms for the dendrimer-AODN. RNase H cleavage assay suggested that the dendrimer-AODN was able to bind and cleave the target site. A reduction of 20%, 28% and 45% in EGFR expression was observed with 0.05μM, 0.1μM and 0.5μM dendrimer-AODN treatments respectively with a reduction in viable cell number. These results indicated that the dendrimer delivery system may reduce viable cell number by an antisense specific mechanism.

Iniciação docente na educação infantil: cenários de uma cultura profissional

This paper focalizes the initial teacher socialization in the Infantile Education from the acknowledgement about that as a phase of a professional life cycle on distinguish of other steps in the teachers’ carrier. It is based on the studies of sociological and anthropological mark with the comprehension that the professional reality is equally constructed by daily practices of social interactions in the work environment. It aims understanding how the initial process of professional culture building of beginners in the infantile education occurs under a view toward to the organizational and dynamics aspects of the teacher activity (events, interactions, practices, wisdoms, tensions and dilemmas). This investigation assuming the orientations of an ethnographic type approach has been developed in a Municipal Center of Infantile Education (Centro Municipal de Educação Infantil) in the city of Natal, with daycare and pre-school. The participant subjects are four female teachers with less than five years in Infantile Education career. It has used a participant observation and a semi-structured interview in the data building that had interpreted through a content analysis and sources triangulation. It delineates three dimensions to the professional culture scenarios: the personal and formative profile of the subjects, the school daily and the teacher work management. The multiform character of the finds evidences that the professional culture of the novice teachers has been constituted from the confrontation with different situations of unpredictably in their emotions, routines and pedagogical and administrative difficulties, simultaneously to the dilemmas of child care and educate. The solitude feeling has been generating from the institutional and scholar organization, which offers no material and pedagogical conditions to the peers collaboration and discussion. Finally it means that teaching in the Infantile Education must been based on an expanding network relations, been indispensable to the beginners the support and orientation related to doubts, wistfulness and expectations as means of socializing and redefining their teaching practice

Reacções adversas a fármacos com manifestações na mucosa oral

Existe uma grande quantidade de fármacos que provocam reacções adversas na mucosa oral. Os efeitos que causam são variados, nomeadamente angioedema, língua pilosa nigra, bruxismo, síndrome da boca ardente, candidose, queilite, xerostomia, eritema multiforme, hiperplasia gengival, glossite, halitose, hiperpigmentação das mucosas, hipersalivação, reações liquenóides, lupóides, penfigóides e tipo pênfigo, osteonecrose, tumefação das glandulas salivares, alterações do paladar, ulcerações, mucosite e lesões potencialmente malignas, entre outras. Com o presente trabalho pretende-se criar uma base de dados que facilite a pesquisa dos diferentes efeitos adversos e relação com a terapêutica prescrita ao paciente, de modo a auxiliar a vida ao Médico Dentista no contexto da prestação de serviços aos seus Utentes.

Une éthique de responsabilité en quête de fondement - Réflexion à partir d'un contexte africain de crise

Sur quoi fonder une éthique de responsabilité et quelle place accorder aux cultures et aux traditions dans un contexte nouveau caractérisé par la mondialisation? Pour répondre à cette question, posée à partir de l’Afrique, nous avons pris un long chemin de réflexion. À partir de l’évaluation faite par Fabien Eboussi de la crise multiforme actuelle qui frappe l’Afrique, où l’auteur cherche et désigne les coupables et les responsables que sont, selon lui, les cultures africaines, la colonisation européenne et le christianisme, nous nous sommes concentré sur le sujet humain comme tel. La responsabilité est d’abord, à nos yeux, une question de conscience morale. Les approches anthropologiques utilisées dans leurs théories éthiques par Xavier Thévenot, Paul Ricoeur et Emmanuel Levinas nous ont permis de bâtir une définition du sujet comme une « liberté précédée ». L’antécédence est à la fois un principe anthropologique et éthique dans la relation et dans l’existence. Nous avons appliqué ce principe de précédence à la notion africaine d’ancestralité conçue comme le temps éthique hiérarchisé et orienté. Pour échapper à l’étroitesse tribale ou ethnique dans laquelle se vit cette ancestralité africaine, nous l’avons étendue aux dimensions de l’humanité, comme le fondement d’une éthique de responsabilité universelle. On est ancêtre de l’humanité. Sous le néologisme d’ancestrogenèse, nous avons proposé une éthique fondée sur le recrutement de ces ancêtres ou bienfaiteurs de l’humanité. L’ancestrogenèse est donc la construction d’une communauté humaine où chaque membre soit responsable de ses actes devant sa communauté locale – naturelle ou historique – en lien avec toute la communauté humaine dont la facilité de la communication accélère la convergence. À la suite de Bénezet Bujo, et pour fonder cette communauté sur le roc et la faire survivre aux fluctuations de l’esprit humain, nous avons placé le Christ à la tête des ancêtres, comme proto-ancêtre. En lui, nous avons le Verbe créateur unique, le sauveur unique et le rassembleur unique de l’humanité de tous lieux et de tous temps. Voilà qui suscite une multitude de questions d’ordre pédagogique, biblique, christologique, ecclésiologique, éthique, anthropologique, politique et sociologique, questions relatives à la formation morale du sujet-ancêtre telle qu’ébauchée dans le cadre limité de cette recherche.

The Role of PME-1 in Cancer: Therapeutic Implication

Protein phosphatase 2A (PP2A) plays a major role in maintaining cellular signaling homeostasis in human cells by reversibly affecting the phosphorylation of a variety of proteins. Protein phosphatase methylesterase-1 (PME-1) negatively regulates PP2A activity by reversible demethylation and active site binding. Thus far, it is known that overexpression of PME-1 in human gliomas contributes to ERK pathway signaling, cell proliferation, and malignant progression. Whether PME-1-mediated PP2A inhibition promotes therapy resistance in gliomas is unknown. Specific PP2A targets regulated by PME-1 in cancers also remain elusive. Additionally, whether oncogenic function of PME-1 can be generalized to various human cancers needs to be investigated. This study demonstrated that PME-1 expression promotes kinase inhibitor resistance in glioblastoma (GBM). PME-1 silencing sensitized GBM cells to a group of clinically used indolocarbazole multikinase inhibitors (MKIs). To facilitate the quantitative evaluation of MKIs by cancer-cell specific colony formation assay, Image-J software-plugin ‘ColonyArea’ was developed. PME-1-silencing was found to reactivate specific PP2A complexes and affect PP2A-target histone deacetylase HDAC4 activity. The HDAC4 inhibition induced synthetic lethality with MKIs similar to PME-1 depletion. However, synthetic lethality by both approaches required co-expression of a pro-apoptotic protein BAD. In gliomas, PME-1 and HDAC4 expression was associated with malignant progression. Using tumor PME-1, HDAC4 and BAD expression based stratification signatures this study defined patient subgroups that are likely to respond to MKI alone or in combination with HDAC4 inhibitor therapies. In contrast to the oncogenic role of PME-1 in certain cancer types, this study established that colorectal cancer (CRC) patients with high tumor PME-1 expression display favorable prognosis. Interestingly, PME-1 regulated survival signaling did not operate in CRC cells. Summarily, this study potentiates the candidacy of PME-1 as a therapy target in gliomas, but argues against generalization of these findings to other cancers, especially CRC.