fenretinide and Brain-Neoplasms

Fenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas.. Twenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m(2) bid.. Six of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m(2) bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma C(max) for fenretinide was 832 +/- 360 ng/mL at the 600 mg/m(2) bid dosage and 1,213 +/- 261 ng/mL at the 900 mg/m(2) bid dosage.. Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Female; Fenretinide; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Survival Analysis; Treatment Outcome

Effective treatment of malignant glioma still remains a formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The antiglioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., antitumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.

Topics: Animals; Brain Neoplasms; Cell Line, Tumor; Drug Carriers; Drug Delivery Systems; Female; Fenretinide; Glioma; Humans; Lactoferrin; Macrophages; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Nanoparticles; Oxidative Stress; Simvastatin

Neuroblastoma is a common, frequently fatal, neural crest tumor of childhood. Chemotherapy-resistant neuroblastoma cells typically have Schwann cell-like ("S-type") morphology and express the p75 neurotrophin receptor (p75NTR). p75NTR has been previously shown to modulate the redox state of neural crest tumor cells. We, therefore, hypothesized that p75NTR expression level would influence the effects of the redox-active chemotherapeutic drug fenretinide on neuroblastoma cells.. Transfection and lentiviral transduction were used to manipulate p75NTR expression in these cell lines. Sensitivity to fenretinide was determined by concentration- and time-cell survival studies. Apoptosis incidence was determined by morphological assessment and examination of cleavage of poly-ADP ribose polymerase and caspase-3. Generation and subcellular localization of reactive oxygen species were quantified using species- and site-specific stains and by examining the effects of site-selective antioxidants on cell survival after fenretinide treatment. Studies of mitochondrial electron transport employed specific inhibitors of individual proteins in the electron transport chain.. Knockdown of p75NTR attenuates fenretinide-induced accumulation of mitochondrial superoxide and apoptosis. Overexpression of p75NTR has the opposite effects. Pretreatment of cells with 2-thenoyltrifluoroacetone or dehydroascorbic acid uniquely prevents mitochondrial superoxide accumulation and cell death after fenretinide treatment, indicating that mitochondrial complex II is the likely site of fenretinide-induced superoxide generation and p75NTR-induced potentiation of these phenomena.. Modification of expression of p75NTR in a particular neuroblastoma cell line modifies its susceptibility to fenretinide. Enhancers of p75NTR expression or signaling could be potential drugs for use as adjuncts to chemotherapy of neural tumors.

Topics: Antineoplastic Agents; Antioxidants; Apoptosis; Blotting, Western; Brain Neoplasms; Cell Line, Tumor; Cell Membrane; Cell Survival; Electron Transport; Fenretinide; Gene Expression Regulation, Neoplastic; Humans; Indicators and Reagents; Mitochondria; Nerve Tissue Proteins; Neuroblastoma; Oxidation-Reduction; Reactive Oxygen Species; Receptors, Nerve Growth Factor; RNA, Small Interfering; Signal Transduction

Lestaurtinib (CEP-701), a multi-kinase inhibitor with potent activity against the Trk family of receptor tyrosine kinases, has undergone early phase clinical evaluation in children with relapsed neuroblastoma. We studied the interaction of CEP-701 with isotretinoin (13cRA) and fenretinide (4HPR), two retinoids that have been studied in children with high-risk neuroblastoma.. In vitro growth inhibition was assessed following a 72-hour drug exposure using the sulforhodamine B (SRB) assay in eight neuroblastoma cell lines with variable TrkB expression. When appropriate, the combination index (CI) of Chou-Talalay was used to characterize the interaction of 13cRA (non-constant ratio) or 4HPR (constant ratio) with CEP-701.. The median (range) IC(50) of single-agent CEP-701 across all cell lines was 0.09 (0.08-0.3) μM. The combination of 13cRA and CEP-701 resulted in additive to synergistic interactions in four of the five cell lines studied. Addition of 1 or 5 μM of 13cRA decreased the median (range) CEP-701 IC(50) 1.5-fold (1.1-2.8-fold) and 1.7-fold (1.5-1.8-fold), respectively. With 10 μM 13cRA, less than 50% of cells survived when combined with various concentrations of CEP-701. The combination of 4HPR and CEP-701 trended toward being antagonistic, with a median (range) CI at the ED(50) of 1.3 (1.1-1.5).. The combination of 13cRA and CEP-701 was additive or synergistic in a spectrum of neuroblastoma cell lines, suggesting that these agents can be potentially studied together in the setting of minimal residual disease following intensive chemoradiotherapy for children with high-risk neuroblastoma.

Topics: Antineoplastic Agents; Brain Neoplasms; Carbazoles; Cell Line, Tumor; Drug Evaluation, Preclinical; Fenretinide; Furans; Humans; Isotretinoin; Neuroblastoma; Receptor, trkB

Survivin is highly expressed in most cancers, including glioblastoma, and it plays a significant role in inhibiting apoptosis and promoting tumor growth. Treatment of cancer cells with N-(4-hydroxyphenyl) retinamide (4-HPR) induces apoptosis through destabilization of mitochondrial membrane and activation of caspase-mediated apoptotic pathways. We studied the efficacy of a combination of survivin knockdown and 4-HPR treatment to induce apoptosis and inhibit invasion, angiogenesis, and growth of human glioblastomas in vitro and in vivo. Using a plasmid encoding survivin shRNA, we downregulated survivin in glioblastoma U251MG and U118MG cells and simultaneously treated with 1 µM 4-HPR for 48 hours. Cells following treatments were subjected to the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and invasion assays. In vivo angiogenesis and tumor regression studies were performed in nude mice. TUNEL assay demonstrated apoptosis in more than 80% of cells after survivin knockdown and 4-HPR treatment. Matrigel invasion assays demonstrated marked decreases in tumor cell invasion. In vivo angiogenesis studies depicted a remarkable inhibition of neovascularization due to the knockdown of survivin and 4-HPR treatment. Imaging of intracerebral tumorigenesis and longitudinal studies on subcutaneous solid tumor formation showed dramatic decreases in tumorigenesis and solid tumor progression, respectively, after treatment with the combination. Studies to elucidate the molecular mechanisms of the inhibition of angiogenesis and tumor regression demonstrated marked decreases in proliferating cell nuclear antigen, metalloproteinase-9, vascular endothelial growth factor, basic fibroblast growth factor, and CD31 in solid tumors. Our data demonstrated that survivin knockdown and concurrent 4-HPR treatment could be a novel therapeutic strategy for controlling growth of human glioblastomas.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Brain Neoplasms; Combined Modality Therapy; Fenretinide; Gene Knockdown Techniques; Genetic Therapy; Glioblastoma; Humans; In Situ Nick-End Labeling; Inhibitor of Apoptosis Proteins; Mice; Mice, Nude; Microtubule-Associated Proteins; Reverse Transcriptase Polymerase Chain Reaction; Survivin; Transfection; Xenograft Model Antitumor Assays

N-(4-Hydroxyphenyl) retinamide (4-HPR) is a synthetic retinoid that has shown biological activity against several malignant tumors and minimal side effects in humans. To explore the mechanisms underlying the chemotherapeutic effects of 4-HPR in glioblastoma, we used two human glioblastoma T98G and U87MG cell lines. In situ methylene blue staining showed the morphological features of astrocytic differentiation in glioblastoma cells following exposure to 1 microM and 2 microM 4-HPR for a short duration (24 h). Astrocytic differentiation was associated with an increase in expression of glial fibrillary acidic protein (GFAP) and downregulation of telomerase. Wright staining and ApopTag assay indicated appearance of apoptotic features in glioblastoma cells following exposure to 1 microM and 2 microM 4-HPR for a long duration (72 h). We found that 4-HPR caused apoptosis with activation of caspase-8 and cleavage of Bid to truncated Bid (tBid). Besides, apoptosis was associated with alterations in expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins resulting in an increase in Bax:Bcl-2 ratio, mitochondrial release of cytochrome c and Smac, downregulation of selective baculoviral inhibitor-of-apoptosis repeat containing (BIRC) molecules, an increase in intracellular free [Ca2+], and activation of calpain and caspase-3. Taken together, these results strongly suggested that 4-HPR could be used at low doses for induction of both differentiation and apoptosis in human glioblastoma cells.

Topics: Analysis of Variance; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Astrocytes; bcl-2-Associated X Protein; BH3 Interacting Domain Death Agonist Protein; Blotting, Western; Brain Neoplasms; Calpain; Caspase 3; Caspase 8; Cell Differentiation; Cell Line, Tumor; Cytochromes c; Dose-Response Relationship, Drug; Fenretinide; Glial Fibrillary Acidic Protein; Glioblastoma; Humans; Intracellular Signaling Peptides and Proteins; Mitochondria; Mitochondrial Proteins; Proto-Oncogene Proteins c-bcl-2; Reverse Transcriptase Polymerase Chain Reaction; Telomerase

The question whether chemotherapy-induced autophagy is causative to the demise of the cells or a part of the survival mechanism activated during cellular distress is unclear. Others and we have previously demonstrated apoptosis-inducing capacity of N-(4-hydroxyphenyl)retinamide (4-HPR) in malignant glioma cells. We provide evidences of 4-HPR-induced autophagy at a lower concentration (5 microM). Suboptimal dose of 4-HPR treatment of malignant glioma cell lines increased G(2)/M arrest, whereas cell accumulated in S phase at a higher concentration. 4-HPR-induced autophagy was associated with acidic vacuole [acidic vesicular organelle (AVO)] formation and recruitment of microtubule-associated protein light chain 3 (LC3). At a higher concentration of 10 microM of 4-HPR, glioma cells undergoing apoptosis manifested autophagic features indicated by autophagosome formation, AVO development and LC3 localization. Autophagy inhibition at an early stage by 3-methyl adenine inhibited the AVO formation and LC3 localization with an enhancement in cell death. Bafilomycin A1, a specific inhibitor of vacuolar type Hthorn-ATPase also prevented AVO formation without effecting LC-3 localization pattern and also enhanced the extent of 4-HPR-induced cell death. 4-HPR activated c-jun and P38(MAPK) at both 5 and 10 microM concentrations, whereas increased activation of extracellular signal-regulated kinase 1/2 and NF-kappaB was seen only at lower dose. Inhibiting phosphoinositide 3-kinase and mitogen-activated protein kinases pathways modulated 4-HPR-induced cell death. This is the first report that provides evidences that besides apoptosis induction 4-HPR can also induce autophagy. These results indicate that 4-HPR-induced autophagy in glioma cell may provide survival advantage and inhibition of autophagy may enhance the cytotoxicity to 4-HPR.

Topics: Autophagy; Brain Neoplasms; Cell Death; Cell Line, Tumor; Dose-Response Relationship, Drug; Fenretinide; Flow Cytometry; Glioma; Humans; Immunohistochemistry; Microscopy, Electron, Transmission; Protein Kinases