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1.
Biochem J ; 478(6): 1199-1225, 2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33740047

RESUMO

PI3Ks are important lipid kinases that produce phosphoinositides phosphorylated in position 3 of the inositol ring. There are three classes of PI3Ks: class I PI3Ks produce PIP3 at plasma membrane level. Although D. melanogaster and C. elegans have only one form of class I PI3K, vertebrates have four class I PI3Ks called isoforms despite being encoded by four different genes. Hence, duplication of these genes coincides with the acquisition of coordinated multi-organ development. Of the class I PI3Ks, PI3Kα and PI3Kß, encoded by PIK3CA and PIK3CB, are ubiquitously expressed. They present similar putative protein domains and share PI(4,5)P2 lipid substrate specificity. Fifteen years after publication of their first isoform-selective pharmacological inhibitors and genetically engineered mouse models (GEMMs) that mimic their complete and specific pharmacological inhibition, we review the knowledge gathered in relation to the redundant and selective roles of PI3Kα and PI3Kß. Recent data suggest that, further to their redundancy, they cooperate for the integration of organ-specific and context-specific signal cues, to orchestrate organ development, physiology, and disease. This knowledge reinforces the importance of isoform-selective inhibitors in clinical settings.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositóis/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Humanos , Fosforilação , Transdução de Sinais , Especificidade por Substrato
2.
Int J Mol Sci ; 22(17)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34502481

RESUMO

The median-effect principle proposed by Chou and Talalay is the most effective approach to parameterize interactions between several agents in combination. However, this method cannot be used to evaluate the effectiveness of equimolar drug combinations, which are comparative references for dual-targeting molecular design. Here, using data acquired through the development of "combi-molecules" blocking two kinases (e.g., EGFR-c-Src and EGFR-c-Met), we established potency indices for equimolar and dual-targeted inhibitors. If the fold difference (κ) between the IC50 of the two individual kinase inhibitors was >6, the IC50 of their equimolar combination resembled that of the more potent inhibitor. Hence, the "combi-targeting" of the two kinases was considered "imbalanced" and the combination ineffective. However, if κ ≤ 6, the IC50 of the combination fell below that of each individual drug and the combi-targeting was considered "balanced" and the combination effective. We also showed that combi-molecules should be compared with equimolar combinations only under balanced conditions and propose a new parameter Ω for validating their effectiveness. A multi-targeted drug is effective if Ω < 1, where Ω is defined as the IC50 of the drug divided by that of the corresponding equimolar combination. Our study provides a methodology to determine the in vitro potency of equimolar two-drug combinations as well as combi-/hybrid molecules inhibiting two different kinase targets.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sistemas de Liberação de Medicamentos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Células A549 , Animais , Cricetulus , Feminino , Humanos , Masculino , Camundongos , Células NIH 3T3 , Neoplasias/metabolismo , Células PC-3
3.
Cancer Metastasis Rev ; 33(1): 17-39, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24357056

RESUMO

Ovarian adenocarcinoma is characterized by a late detection, dissemination of cancer cells into the whole peritoneum, and the frequent acquisition of chemoresistance. If these particularities can be explained in part by intrinsic properties of ovarian cancer cells, an increased number of studies show the importance of the tumor microenvironment in tumor progression. Ovarian cancer cells can regulate the composition of their stroma in promoting the formation of ascitic fluid, rich in cytokines and bioactive lipids, and in stimulating the differentiation of stromal cells into a pro-tumoral phenotype. In return, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, tumor-associated macrophages, or other peritoneal cells, such as adipocytes and mesothelial cells can regulate tumor growth, angiogenesis, dissemination, and chemoresistance. This review focuses on the current knowledge about the roles of stromal cells and the associated secreted factors on tumor progression. We also summarize the different studies showing that targeting the microenvironment represents a great potential for improving the prognosis of patients with ovarian adenocarcinoma.


Assuntos
Adenocarcinoma/patologia , Neoplasias Ovarianas/patologia , Microambiente Tumoral , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Antineoplásicos/uso terapêutico , Citocinas/metabolismo , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Células Estromais/metabolismo , Células Estromais/patologia
4.
Cancers (Basel) ; 15(3)2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36765741

RESUMO

Phosphatidylinositol-3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways. PI3K is a family of eight enzymes divided into three classes with various functions in physiology and largely deregulated in cancer. Here, we will review the recent evidence obtained during the last 5 years on the roles of PI3K class I, II and III isoforms in tumor biology and on the anti-tumoral action of PI3K inhibitors in preclinical cancer models. The dependency of tumors to PI3K isoforms is dictated by both genetics and context (e.g., the microenvironment). The understanding of class II/III isoforms in cancer development and progression remains scarce. Nonetheless, the limited available data are consistent and reveal that there is an interdependency between the pathways controlled by all PI3K class members in their role to promote cancer cell proliferation, survival, growth, migration and metabolism. It is unknown whether this feature contributes to partial treatment failure with isoform-selective PI3K inhibitors. Hence, a better understanding of class II/III functions to efficiently inhibit their positive and negative interactions with class I PI3Ks is needed. This research will provide the proof-of-concept to develop combination treatment strategies targeting several PI3K isoforms simultaneously.

5.
Int J Mol Sci ; 13(8): 9545-9571, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22949815

RESUMO

Tumor development principally occurs following the accumulation of genetic and epigenetic alterations in tumor cells. These changes pave the way for the transformation of chemosensitive cells to chemoresistant ones by influencing the uptake, metabolism, or export of drugs at the cellular level. Numerous reports have revealed the complexity of tumors and their microenvironment with tumor cells located within a heterogeneous population of stromal cells. These stromal cells (fibroblasts, endothelial or mesothelial cells, adipocytes or adipose tissue-derived stromal cells, immune cells and bone marrow-derived stem cells) could be involved in the chemoresistance that is acquired by tumor cells via several mechanisms: (i) cell-cell and cell-matrix interactions influencing the cancer cell sensitivity to apoptosis; (ii) local release of soluble factors promoting survival and tumor growth (crosstalk between stromal and tumor cells); (iii) direct cell-cell interactions with tumor cells (crosstalk or oncologic trogocytosis); (iv) generation of specific niches within the tumor microenvironment that facilitate the acquisition of drug resistance; or (v) conversion of the cancer cells to cancer-initiating cells or cancer stem cells. This review will focus on the implication of each member of the heterogeneous population of stromal cells in conferring resistance to cytotoxins and physiological mediators of cell death.


Assuntos
Morte Celular , Resistencia a Medicamentos Antineoplásicos , Neoplasias/patologia , Células Estromais/patologia , Microambiente Tumoral , Animais , Humanos , Neoplasias/tratamento farmacológico , Transdução de Sinais , Células Estromais/efeitos dos fármacos , Células Tumorais Cultivadas
6.
Mol Cancer Ther ; 20(12): 2433-2445, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34552006

RESUMO

The PI3K pathway is highly active in human cancers. The four class I isoforms of PI3K are activated by distinct mechanisms leading to a common downstream signaling. Their downstream redundancy is thought to be responsible for treatment failures of PI3K inhibitors. We challenged this concept, by mapping the differential phosphoproteome evolution in response to PI3K inhibitors with different isoform-selectivity patterns in pancreatic cancer, a disease currently without effective therapy. In this cancer, the PI3K signal was shown to control cell proliferation. We compared the effects of LY294002 that inhibit with equal potency all class I isoenzymes and downstream mTOR with the action of inhibitors with higher isoform selectivity toward PI3Kα, PI3Kß, or PI3Kγ (namely, A66, TGX-221 and AS-252424). A bioinformatics global pathway analysis of phosphoproteomics data allowed us to identify common and specific signals activated by PI3K inhibitors supported by the biological data. AS-252424 was the most effective treatment and induced apoptotic pathway activation as well as the highest changes in global phosphorylation-regulated cell signal. However, AS-252424 treatment induced reactivation of Akt, therefore decreasing the treatment outcome on cell survival. Reversely, AS-252424 and A66 combination treatment prevented p-Akt reactivation and led to synergistic action in cell lines and patient organoids. The combination of clinically approved α-selective BYL-719 with γ-selective IPI-549 was more efficient than single-molecule treatment on xenograft growth. Mapping unique adaptive signaling responses to isoform-selective PI3K inhibition will help to design better combinative treatments that prevent the induction of selective compensatory signals.


Assuntos
Neoplasias Pancreáticas/tratamento farmacológico , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Proteômica/métodos , Animais , Linhagem Celular Tumoral , Resistência a Medicamentos , Humanos , Camundongos , Neoplasias Pancreáticas/patologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia
7.
EMBO Mol Med ; 13(7): e13502, 2021 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-34033220

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micro-metastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We searched for a gene signature that discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. An unbiased approach identified, amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3Kα activation signature as predictive of PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3Kα-selective inhibition prevented macro-metastatic evolution by hindering tumoural cell migratory behaviour independently of genetic alterations. We found that PI3Kα inhibition altered the quantity and the species composition of the produced lipid second messenger PIP3 , with a selective decrease of C36:2 PI-3,4,5-P3 . Tumoural PI3Kα inactivation prevented the accumulation of pro-tumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour cell-intrinsic PI3Kα promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Carcinoma Ductal Pancreático/genética , Humanos , Macrófagos , Neoplasias Pancreáticas/genética , Fosfatidilinositol 3-Quinases/genética
8.
J Mol Cell Biol ; 12(3): 202-215, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-31504643

RESUMO

Factors released by surrounding cells such as cancer-associated mesenchymal stromal cells (CA-MSCs) are involved in tumor progression and chemoresistance. In this study, we characterize the mechanisms by which naïve mesenchymal stromal cells (MSCs) can acquire a CA-MSCs phenotype. Ovarian tumor cells trigger the transformation of MSCs to CA-MSCs by expressing pro-tumoral genes implicated in the chemoresistance of cancer cells, resulting in the secretion of high levels of CXC chemokine receptors 1 and 2 (CXCR1/2) ligands such as chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL2, and interleukin 8 (IL-8). CXCR1/2 ligands can also inhibit the immune response against ovarian tumor cells. Indeed, through their released factors, CA-MSCs promote the differentiation of monocytes towards M2 macrophages, which favors tumor progression. When CXCR1/2 receptors are inhibited, these CA-MSC-activated macrophages lose their M2 properties and acquire an anti-tumoral phenotype. Both ex vivo and in vivo, we used a CXCR1/2 inhibitor to sensitize ovarian tumor cells to carboplatin and circumvent the pro-tumoral effects of CA-MSCs. Since high concentrations of CXCR1/2 ligands in patients' blood are associated with chemoresistance, CXCR1/2 inhibition could be a potential therapeutic strategy to revert carboplatin resistance.


Assuntos
Comunicação Celular , Resistencia a Medicamentos Antineoplásicos , Fatores Imunológicos/biossíntese , Células-Tronco Mesenquimais/metabolismo , Neoplasias/metabolismo , Animais , Antineoplásicos/farmacologia , Biomarcadores , Biópsia , Diferenciação Celular , Linhagem Celular Tumoral , Biologia Computacional , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Imunomodulação , Macrófagos/imunologia , Macrófagos/metabolismo , Células-Tronco Mesenquimais/citologia , Camundongos , Modelos Biológicos , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Receptores CXCR/genética , Receptores CXCR/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
9.
Cancers (Basel) ; 10(6)2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29865155

RESUMO

For patients with metastatic pancreatic cancer that are not eligible for surgery, signal-targeted therapies have so far failed to significantly improve survival. These therapeutic options have been tested in phase II/III clinical trials mostly in combination with the reference treatment gemcitabine. Innovative therapies aim to annihilate oncogenic dependency, or to normalize the tumoural stroma to allow immune cells to function and/or re-vascularisation to occur. Large scale transcriptomic and genomic analysis revealed that pancreatic cancers display great heterogeneity but failed to clearly delineate specific oncogene dependency, besides oncogenic Kras. Beyond these approaches, proteomics appears to be an appropriate approach to classify signal dependency and to identify specific alterations at the targetable level. However, due to difficulties in sampling, proteomic data for this pathology are scarce. In this review, we will discuss the current state of clinical trials for targeted therapies against pancreatic cancer. We will then highlight the most recent proteomic data for pancreatic tumours and their metastasis, which could help to identify major oncogenic signalling dependencies, as well as provide future leads to explain why pancreatic tumours are intrinsically resistant to signal-targeted therapies. We will finally discuss how studies on phosphatidylinositol-3-kinase (PI3K) signalling, as the paradigmatic pro-tumoural signal downstream of oncogenic Kras in pancreatic cancer, would benefit from exploratory proteomics to increase the efficiency of targeted therapies.

10.
Sci Rep ; 8(1): 17862, 2018 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-30552344

RESUMO

The poor prognosis of ovarian cancer (it is the leading cause of death from gynecological cancers) is mainly due to the acquisition of resistance to carboplatin. Among the possible resistance pathways, resistance to apoptosis and especially the overexpression of inhibitor of apoptosis proteins (IAP) cIAP1 and X-linked IAP (XIAP), have been implicated. DEBIO 1143, a SMAC (second mitochondria-derived activator of caspase) mimetic, belongs to a new class of targeted agents currently being evaluated in clinical trials, which activate apoptotic cell death and block pro-survival signaling in cancer cells. Here, we demonstrate that DEBIO 1143 in vitro inhibits the cell viability of two carboplatin-sensitive cell lines (IGROV-1 and A2780S) as well as three carboplatin-resistant cell lines (A2780R, SKOV-3 and EFO-21). Of note, DEBIO 1143 is able to reverse resistance to carboplatin by inducing cell death either by apoptosis or necroptosis depending on the cell lines. To identify a biomarker able to predict the sensitivity of the cell lines to DEBIO 1143 treatment we analyzed the expression of the DEBIO 1143 targets cIAP1 and XIAP, and one of their downstream targets, caspase 9. These proteins did not constitute a marker of DEBIO 1143 sensitivity/resistance. Importantly, we confirmed these findings in vivo in SKOV-3 xenograft models where DEBIO 1143 highly potentiated carboplatin treatment.


Assuntos
Antineoplásicos/farmacologia , Azocinas/farmacologia , Compostos Benzidrílicos/farmacologia , Carboplatina/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Inibidoras de Apoptose/antagonistas & inibidores , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/antagonistas & inibidores , Animais , Antineoplásicos/administração & dosagem , Azocinas/administração & dosagem , Compostos Benzidrílicos/administração & dosagem , Carboplatina/administração & dosagem , Caspase 9/análise , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Proteínas Inibidoras de Apoptose/análise , Camundongos , Camundongos Nus , Transplante de Neoplasias , Neoplasias Ovarianas/tratamento farmacológico , Resultado do Tratamento , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/análise
11.
Oncotarget ; 9(43): 27220-27232, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29930760

RESUMO

BACKGROUND: Ovarian cancer is associated with poor prognostic outcome due to late diagnosis and to intrinsic and acquired resistance to platinum-based chemotherapy in a large number of patients. This chemoresistance is acquired through the peritoneal and ascites microenvironment by several released factors, such as IL-6,. Preclinical studies have implicated the activation of PI3K pathway in chemoresistance, showing it to extend tumor cell survival and modulate multidrug resistance. We aimed to evaluate the implication of the p110 alpha PI3K subunit in ovarian cancer chemoresistance acquisition, and to evaluate whether the STAT3 pathway can mediate resistance to PI3K inhibitors through secretion of IL6. RESULTS: Human ovarian adenocarcinoma IGROV-1 and JHOC-5 cells cultured in ascites showed an increase in carboplatinum-based resistance. Level of chemoresistance was associated to IL6 concentration in ascites. Activation of PI3K/Akt, STAT and MAPK pathways was observed after IGROV-1 incubation with ascites and treatment with carboplatin. Neither IGROV-1 nor JHOC-5 cells exposed to ascites treated with additional IL-6 directed antibody showed any reversion of the chemoresistance. CONCLUSION: IL6-related resistance was not abolished by the selective inhibition of PI3K alpha subunit coupled with the anti-IL6-receptor antibody tocilizumab. This dual inhibition requires further exploration in other ovarian cancer models such as clear cell carcinoma.

12.
J Ovarian Res ; 10(1): 31, 2017 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-28446239

RESUMO

BACKGROUND: Ovarian cancer is the leading cause of death for gynecological cancers and the 6th cause of women cancer death in developed countries. The late stage detection, the peritoneal dissemination and the acquisition of resistance against carboplatin are the main reasons to explain this poor prognosis and strengthen the need of alternative treatments to improve the management of ovarian cancer and/or to sensitize tumors to platinum salts. Epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (Met) and cellular Src kinase (c-Src) are crucial kinases implied in ovarian tumor growth, survival, invasion and resistance to carboplatin. Their expression is increased in advanced ovarian cancers and is correlated with poor prognosis. Despite a clear potential in inhibiting these proteins in ovarian cancer, as a single agent or in combination with a carboplatin treatment, we need to target kinases in tandem because of their capacity to trigger compensatory pathways that synergize to promote drug resistance. METHODS: Here we target EGFR, c-Src and Met individually or in combination with carboplatin, using Gefitinib, Dasatinib and Crizotinib respectively, in a panel of carboplatin-sensitive (OVCAR-3, IGROV-1 and A2780) and carboplatin-resistant cells (SKOV-3 and EFO-21). We studied the ability of the most potent combination to induce apoptosis, regulate migration, invasion and to modulate the activation of proliferation and survival proteins. RESULTS: Crizotinib, Dasatinib and Gefitinib, alone or in combination with carboplatin, showed a cell-specific cytotoxic synergy in ovarian cancer cells. The Dasatinib plus Gefitinib combination was synergistic in OVCAR-3, SKOV-3 and, in IGROV-1 cells (high concentrations). This combination was unable to induce apoptosis but suppressed cell migration, invasion and the activation of EGFR, Erk, c-Src and Akt compared to single treatments. CONCLUSIONS: Combining carboplatin with kinase inhibitors lead to synergistic interactions in a cell-specific manner. Unlike platinum-based combinations, mixing Dasatinib with Gefitinib led to cytotoxic activity, inhibition of cell migration and invasion. Thus, the Dasatinib + Gefitinib combination presents anti-tumour properties that are superior to those of platinum-based combinations, indicating that it may well represent a promising new treatment modality to be tested in the clinic.


Assuntos
Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/patologia , Adenocarcinoma/enzimologia , Apoptose/efeitos dos fármacos , Carboplatina/administração & dosagem , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dasatinibe/administração & dosagem , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Feminino , Gefitinibe , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Invasividade Neoplásica , Neoplasias Ovarianas/enzimologia , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinazolinas/administração & dosagem , Células Tumorais Cultivadas , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
13.
Trends Cancer ; 3(6): 454-469, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28718419

RESUMO

Targeting upstream phosphatidylinositol-3-kinases (PI3Ks) in the PI3K/Akt/mTOR pathway appears to be a promising therapy in solid cancers; however, first early clinical trials with PI3K inhibitors in monotherapy have been disappointing. A massive array of preclinical and clinical trials are currently evaluating combinations of PI3K inhibitors in targeted therapies. These combinations include co-treatments with drugs directed against other intra-/extracellular signaling molecules, nuclear hormone receptors, DNA damage repair enzymes, and immune modulators. We review the literature and pinpoint mechanisms of action in different genomic and organ contexts. Combinatorial approaches are potentially superior to monotherapies and should become alternative clinical strategies to treat cancer patients.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos como Assunto , Humanos , Mutação , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/metabolismo , Mutações Sintéticas Letais , Serina-Treonina Quinases TOR/metabolismo
14.
Oncotarget ; 8(65): 109559-109574, 2017 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-29312629

RESUMO

Surgery is often the first treatment option for patients with cancer. Patient survival essentially depends on the completeness of tumor resection. This is a major challenge, particularly in cases of peritoneal carcinomatosis, where tumors are widely disseminated in the large peritoneal cavity. Any development to help surgeons visualize these residual cells would improve the completeness of the surgery. For non-disseminated tumors, imaging could be used to ensure that the tumor margins and the draining lymph nodes are free of tumor deposits. Near-infrared fluorescence imaging has been shown to be one of the most convenient imaging modalities. Our aim was to evaluate the efficacy of a near-infrared fluorescent probe targeting the αvß3 integrins (Angiostamp™) for intraoperative detection of tumors using the Fluobeam® device. We determined whether different human tumor nodules from various origins could be detected in xenograft mouse models using both cancer cell lines and patient-derived tumor cells. We found that xenografts could be imaged by fluorescent staining irrespective of their integrin expression levels. This suggests imaging of the associated angiogenesis of the tumor and a broader potential utilization of Angiostamp™. We therefore performed a veterinary clinical trial in cats and dogs with local tumors or with spontaneous disseminated peritoneal carcinomatosis. Our results demonstrate that the probe can specifically visualize both breast and ovarian nodules, and suggest that Angiostamp™ is a powerful fluorescent contrast agent that could be used in both human and veterinary clinical trials for intraoperative detection of tumors.

15.
Cancer Lett ; 370(1): 10-8, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-26404751

RESUMO

Epithelial ovarian cancer is the fourth cause of death among cancer-bearing women and frequently associated with carboplatin resistance, underlining the need for more efficient and targeted therapies. F14512 is an epipodophylotoxin-core linked to a spermine chain which enters cells via the polyamine transport system (PTS). Here, we investigate this novel concept of vectorization in ovarian cancer. We compared the effects of etoposide and F14512 on a panel of five carboplatin-sensitive or resistant ovarian cancer models. We assessed the incorporation of F17073, a spermine-linked fluorescent probe, in these cells and in 18 clinical samples. We then showed that F14512 exhibits a high anti-proliferative and pro-apoptotic activity, particularly in cells with high levels of F17073 incorporation. Consistently, F14512 significantly inhibited tumor growth compared to etoposide, in a cisplatin-resistant A2780R subcutaneous model, at a dose of 1.25 mg/kg. In addition, ex vivo analysis indicated that 15 out of 18 patients presented a higher F17073 incorporation into tumor cells compared to normal cells. Overall, our data suggest that F14512, a targeted drug with a potent anti-tumor efficacy, constitutes a potential new therapy for highly PTS-positive and platinum-resistant ovarian cancer-bearing patients.


Assuntos
Antineoplásicos/farmacologia , Poliaminas Biogênicas/metabolismo , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Podofilotoxina/análogos & derivados , Inibidores da Topoisomerase II/farmacologia , Animais , Apoptose/efeitos dos fármacos , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Feminino , Humanos , Camundongos , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Epiteliais e Glandulares/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Podofilotoxina/farmacologia
16.
J Ovarian Res ; 7: 40, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24739440

RESUMO

BACKGROUND: Hyaluronic acid is a prognostic factor in ovarian cancers. It is also a component of Hyaluronic Acid-Carboxymethyl Cellulose (HA-CMC) barrier, an anti-adhesion membrane widely used during abdominal surgeries in particular for ovarian carcinosis. 70% of patients who undergo ovarian surgery will relapse due to the persistence of cancer cells. This study's objective was to determine the oncological risk from use of this material, in the presence of residual disease, despite the benefit gained by it decreasing post-surgical adhesions in order to provide an unambiguous assessment of its appropriateness for use in ovarian surgical management. METHODS: We assessed the effects of HA-CMC barrier on the in vitro proliferation of human ovarian tumor cell lines (OVCAR-3, IGROV-1 and SKOV-3). We next evaluated, in vivo in nude mice, the capacity of this biomaterial to regulate the tumor progression of subcutaneous and intraperitoneal models of ovarian tumor xenografts. RESULTS: We showed that HA-CMC barrier does not increase in vitro proliferation of ovarian cancer cell lines compared to control. In vivo, HA-CMC barrier presence with subcutaneous xenografts induced neither an increase in tumor volume nor cell proliferation (Ki67 and mitotic index). With the exception of an increased murine carcinosis score in peritoneum, the presence of HA-CMC barrier with intraperitoneal xenografts modified neither macro nor microscopic tumor growth. Finally, protein analysis of survival (Akt), proliferation (ERK) and adhesion (FAK) pathways highlighted no activation on the xenografts imputable to HA-CMC barrier. CONCLUSIONS: For the most part, our results support the lack of tumor progression activation due to HA-CMC barrier. We conclude that the benefits gained from using HA-CMC barrier membrane during ovarian cancer surgeries seem to outweigh the potential oncological risks.


Assuntos
Implantes Absorvíveis , Carboximetilcelulose Sódica/uso terapêutico , Ácido Hialurônico/uso terapêutico , Neoplasias Ovarianas/cirurgia , Animais , Carboximetilcelulose Sódica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Estudos de Avaliação como Assunto , Proteínas da Matriz Extracelular/metabolismo , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Ácido Hialurônico/farmacologia , Camundongos Nus , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Transdução de Sinais , Aderências Teciduais/prevenção & controle
17.
Bull Cancer ; 100(4): 357-62, 2013 Apr 01.
Artigo em Francês | MEDLINE | ID: mdl-23559430

RESUMO

The high rate of recurrence after apparently complete surgery and/or complete clinical response to chemotherapy implies that most patients have undetected minimal residual disease. Novel techniques such as laparoscopic or laparotomic fluorescence may prove to be crucial in reassessing the definition of primary outcome in ovarian cancer management. For this purpose, the importance of fluorescence in the peroperative detection of human ovarian adenocarcinoma cells has to be validated in animal models prior to be used in clinic by determining its efficiency in detecting infra-millimetric tumor metastases. In the preclinical data presented, a fluorescent RAFT-(cRGD)4 tracer molecule (AngioStamp(®)) with a very high affinity for the αvß3 integrin was used. Infrared fluorescence was visualized with Fluobeam(®), an open fluorescent imaging system that could potentially be used in peroperative conditions in the future. We showed that this novel technique allowed the specific detection of residual tumor deposits and inframillimetric metastases in mice and dogs.


Assuntos
Adenocarcinoma/patologia , Integrina alfaVbeta3/análise , Micrometástase de Neoplasia/patologia , Proteínas de Neoplasias/análise , Neoplasias Ovarianas/patologia , Adenocarcinoma/química , Adenocarcinoma/cirurgia , Animais , Modelos Animais de Doenças , Cães , Feminino , Imunofluorescência/métodos , Humanos , Camundongos , Recidiva Local de Neoplasia , Neoplasia Residual , Neoplasias Ovarianas/química , Neoplasias Ovarianas/cirurgia , Sensibilidade e Especificidade , Espectrofotometria Infravermelho/métodos
18.
Cancer Lett ; 326(1): 59-68, 2012 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-22824244

RESUMO

Within the microenvironment, Carcinoma-associated mesenchymal stem cells (Hospicells) are able to influence ovarian tumor development via, among others, the facilitation of angiogenesis in the tumor site allowing an accelerated tumor growth. We demonstrate the presence of a chemotactism between endothelial cells and Hospicells, and a cell line specific increased secretion of pro-angiogenic cytokines such as IL-6, IL-8 and VEGF from ovarian adenocarcinoma cells. Hospicells are also able to attract and activate macrophages to a M2 phenotype and allow them to secrete a huge quantity of pro-angiogenic cytokines, favorable to tumor progression of all the associated ovarian adenocarcinoma cells tested.


Assuntos
Adenocarcinoma/patologia , Ascite/patologia , Macrófagos/fisiologia , Células-Tronco Mesenquimais/fisiologia , Células-Tronco Neoplásicas/fisiologia , Neovascularização Patológica , Neoplasias Ovarianas/patologia , Adenocarcinoma/metabolismo , Animais , Comunicação Celular , Linhagem Celular , Feminino , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Camundongos , Transplante de Neoplasias , Neoplasias Ovarianas/metabolismo , Esferoides Celulares , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/metabolismo
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