Pleiotropic Chemotherapy to Abrogate Glioblastoma Multiforme Migration/Invasion.

Current clinical failure to cure primary glioblastoma multiforme in virtually all adult patients is due to genetic aberrations, molecular heterogeneity, and clonal evolution of tumor stem and differentiated cells within the core tumor, leading to their migration, invasion and proliferation in normal surrounding and in distant cerebral tissue sites. These factors are the causes of targeted drug resistance, inadequate surgical removal, and inadequate radio-therapeutic interventions. Resolution of this clinical conundrum may be found in administration of Withaferin A alone or in combination with pleiotropic drugs which address aberrant molecules and pathways promoting tumor cell motility, migration, invasion and proliferation.

Radiation-induced Demyelination and Remyelination in the Central Nervous System: A Literature Review.

Therapeutic radiation applied to the central nervous system concomitant with or followed by surgery and chemotherapy induces significant pathologic demyelination depending upon tumor volume, dosage, field of treatment, and age of patient, with consequent exacerbation of significant impairment of mental function including personality change, memory deficiencies, confusion, learning difficulties and dementia. These adverse clinical events may be ameliorated by the application of remyelinating measures including nutrition, supplements and pharmaceuticals prophylactically, concomitant with radiation or post-radiation treatment.

Distribution and Metabolism of Lipocurc™ (Liposomal Curcumin) in Dog and Human Blood Cells: Species Selectivity and Pharmacokinetic Relevance.

Background/aim: The aim of this study was to investigate the distribution of curcumin (in the form of Lipocurc™) and its major metabolite tetrahydrocurcumin (THC) in Beagle dog and human red blood cells, peripheral blood mononuclear cells (PBMC) and hepatocytes.

Materials And Methods: Lipocurc™ was used as the source of curcumin for the cell distribution assays. In vitro findings with red blood cells were also compared to in vivo pharmacokinetic data available from preclinical studies in dogs and phase I clinical studies in humans.

The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma.

The failure of chemotherapy and radiation therapy to achieve long-term remission or cure in patients with glioblastoma (GBM) is, in a large part, due to the suppression of the immune system induced by the tumors themselves. These tumors adapt to treatment with chemotherapy or radiation therapy by stimulating secretion of molecules that cause tryptophan metabolism to be disrupted. Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are produced, accelerating metabolism along the kynurenine pathway and resulting in excess levels of quinolinic acid, 3-hydroxyanthranilic acid and other neurotoxic molecules.

In Vitro Study of a Liposomal Curcumin Formulation (Lipocurc™): Toxicity and Biological Activity in Synovial Fibroblasts and Macrophages.

Background/aim: The polyphenol curcumin is produced in the rhizome of Curcuma longa and exhibits potent anti-inflammatory, antioxidant, and chemopreventive activities. Due to the fact that curcumin is poorly soluble in water, many delivery systems have been developed to improve its solubility and bioavailability achieving optimum therapeutic application. In this study, we evaluated the biological effects of a liposomal curcumin formulation (Lipocurc™) on human synovial fibroblasts (SW982) and mouse macrophages (RAW264).

Use of basic mobile phase to improve chromatography and boost sensitivity for quantifying tetrahydrocurcumin in human plasma by LC-MS/MS.

Tetrahydrocurcumin (THC), a major metabolite of curcumin, is often quantified by LC-MS or LC-MS/MS using acidic mobile phases due to the concern of its instability in a basic medium. However, acidic mobile phases often lead to poor chromatography (e.g.

Curcumin-ER Prolonged Subcutaneous Delivery for the Treatment of Non-Small Cell Lung Cancer.

Non-small-cell lung cancer therapy is a challenge due to poor prognosis and low survival rate. There is an acute need for advanced therapies having higher drug efficacy, low immunogenicity and fewer side effects which will markedly improve patient compliance and quality of life of cancer patients. The purpose of this study was to develop a novel hybrid curcumin nanoformulation (Curcumin-ER) and evaluate the therapeutic efficacy of this formulation on a non-small cell lung cancer xenograft model.

Bifunctional role of pro-inflammatory cytokines after traumatic brain injury.

Background: Pro-inflammatory cytokines play an essential role in maintenance of normal brain function as well as in repair after traumatic brain injuries (TBI). However, massive and uncontrolled release of these cytokines, particularly interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF)-α, can also result in a great deal of additional brain damage. Levels of these cytokines may increase in the brain thousands of times more than do the corresponding levels in serum.

Sphingosine Kinase Inhibitors as Maintenance Therapy of Glioblastoma After Ceramide-Induced Response.

Ceramide and sphingosine 1-phosphate (S1P) are sphingolipid metabolites with important signaling functions. Ceramides promote apoptosis, whereas S1P favors proliferation, angiogenesis and cell survival. The balance between these opposing signaling functions is referred to as the sphingolipid rheostat.

Curcumin for the Treatment of Glioblastoma.

Glioblastoma multiforme is a highly aggressive primary cancer of the brain associated with a poor prognosis. Modest increases in survival can sometimes be achieved with the use of temozolomide and radiation therapy after surgery, but second-line therapy after recurrence has a limited efficacy. Curcumin has demonstrated promising results against this form of cancer in experimental models.

Review: The Prolonged QT Interval: Role of Pro-inflammatory Cytokines, Reactive Oxygen Species and the Ceramide and Sphingosine-1 Phosphate Pathways.

Patients with QT prolongation have delayed cardiac repolarization and may suffer fatal ventricular arrhythmias. To determine the role of cytokines in causing this syndrome, we reviewed reports on patients with rheumatoid arthritis, psoriasis and other inflammatory conditions. These patients frequently have prolonged QT, which correlates with increases in tumor necrosis factor alpha, and interleukin-1β and 6.

Curcumin and cancer stem cells: curcumin has asymmetrical effects on cancer and normal stem cells.

Curcumin has been shown to have numerous cytotoxic effects on cancer stem cells (CSCs). This is due to its suppression of the release of cytokines, particularly interleukin (IL)-6, IL-8 and IL-1, which stimulate CSCs, and also to its effects at multiple sites along CSC pathways, such as Wnt, Notch, Hedgehog and FAK. In spite of its multiple actions targeting CSCs, curcumin has little toxicity against normal stem cells (NSCs).

Curcumin suppression of cytokine release and cytokine storm. A potential therapy for patients with Ebola and other severe viral infections.

Background: The terminal stage of Ebola and other viral diseases is often the onset of a cytokine storm, the massive overproduction of cytokines by the body's immune system.

Materials And Methods: The actions of curcumin in suppressing cytokine release and cytokine storm are discussed.

Results: Curcumin blocks cytokine release, most importantly the key pro-inflammatory cytokines, interleukin-1, interleukin-6 and tumor necrosis factor-α.

Safety, tolerability and pharmacokinetics of liposomal curcumin in healthy humans.

Introduction: Experimental studies have shown that liposomal curcumin can exert a reduction in tumor growth in pancreatic and colorectal cancer. In this phase I clinical trial we investigated the pharmacokinetics, safety, and tolerability of intravenously administered liposomal curcumin in healthy subjects.

Material And Methods: 50 male and female participants were included in this randomized, placebo-controlled double-blind phase I dose escalation study.

Liposomes ameliorate Crizotinib- and Nilotinib-induced inhibition of the cardiac IKr channel and QTc prolongation.

Crizotinib (Xalkori®) and nilotinib (Tasigna®) are tyrosine kinase inhibitors approved for the treatment of non-small cell lung cancer and chronic myeloid leukemia, respectively. Both have been shown to result in electrocardiogram rate-corrected Q-wave T-wave interval (QTc) prolongation in humans and animals. Liposomes have been shown to ameliorate drug-induced effects on the cardiac-delayed rectifier K(+) current (IKr, KV11.

Mitigating prolonged QT interval in cancer nanodrug development for accelerated clinical translation.

Background: Cardiac toxicity is the foremost reason for drug discontinuation from development to clinical evaluation and post market surveillance [Fung 35:293-317, 2001; Piccini 158:317-326 2009]. The Food and Drug Administration (FDA) has rejected many potential pharmaceutical agents due to QT prolongation effects. Since drug development and FDA approval takes an enormous amount of time, money and effort with high failure rates, there is an increased focus on rescuing drugs that cause QT prolongation.

Effect of liposomal curcumin on red blood cells in vitro.

Background: The anti-inflammatory and antiproliferative agent curcumin has poor oral bioavailability and solubility in plasma. Liposomal formulations have therefore been developed, but the toxicity of these preparations is not yet established. We investigated the influence of free and liposomally formulated curcumin on human red blood cell (RBC) morphology in vitro.

Efficacy of liposomal curcumin in a human pancreatic tumor xenograft model: inhibition of tumor growth and angiogenesis.

Background: Liposome-based drug delivery has been successful in the past decade, with some formulations being Food and Drug Administration (FDA)-approved and others in clinical trials around the world. The major disadvantage associated with curcumin, a potent anticancer agent, is its poor aqueous solubility and hence low systemic bioavailability. However, curcumin can be encapsulated into liposomes to improve systemic bioavailability.

Polymeric curcumin nanoparticle pharmacokinetics and metabolism in bile duct cannulated rats.

The objective of this study was to compare the pharmacokinetics and metabolism of polymeric nanoparticle-encapsulated (nanocurcumin) and solvent-solubilized curcumin formulations in Sprague-Dawley (SD) rats. Nanocurcumin is currently under development for cancer therapy. Since free, unencapsulated curcumin is rapidly metabolized and excreted in rats, upon intravenous (i.

Curcumin (diferuloylmethane) delivery methods: a review.

Curcumin interacts with a large number of extra- and intracellular targets in a biphasic dose-dependent manner. It controls inflammation, oxidative stress, cell survival, cell secretion, homeostasis, and proliferation. Its mechanisms of action are generally directed toward cells that exhibit disordered physiology or blatant mutation-based abnormal states.

Infusion pharmacokinetics of Lipocurc™ (liposomal curcumin) and its metabolite tetrahydrocurcumin in Beagle dogs.

Curcumin's instability and its metabolite, tetrahydrocurcumin (THC) pose a major issue for the establishment of dependable pharmacokinetics and excretion profiles. Additional pharmacokinetic variances are associated with durations of intravenous infusions. We found that stabilizing curcumin with phosphoric acid allows accurate quantitative determinations of curcuminoids in the plasma and bile, by preventing degradation during the analytical processes.

Tissue distribution of (Lipocurc™) liposomal curcumin and tetrahydrocurcumin following two- and eight-hour infusions in Beagle dogs.

This study interrogated whether different durations of intravenous infusions of lipocurc™ would alter curcumin metabolism, tissue distribution and whether treating necropsied tissues of Beagle dogs with phosphoric acid prior to measuring curcumin and its metabolite, tetrahydrocurcumin (THC), would stabilize the compounds allowing for accurate analytic measurements. Two cohorts comprising two male and two female dogs were infused each intravenously with 10 mg/kg lipocurc™, either over two hours or over eight hours. Tissue data from each cohort was averaged from four dogs.

Scale up, optimization and stability analysis of Curcumin C3 complex-loaded nanoparticles for cancer therapy.

Background: Nanoparticle based delivery of anticancer drugs have been widely investigated. However, a very important process for Research & Development in any pharmaceutical industry is scaling nanoparticle formulation techniques so as to produce large batches for preclinical and clinical trials. This process is not only critical but also difficult as it involves various formulation parameters to be modulated all in the same process.

Differential distribution of intravenous curcumin formulations in the rat brain.

Background: The neuropathic side-effects of trauma, stroke or therapeutic radiation of the brain for life-threatening neoplastic diseases are the result of damage to normal tissues resulting in defects in cognition and memory. Based upon published preclinical data of curcumin activity application of parenteral curcumin formulations may prove to be to be promising chemotherapy for disorders following neuropathic insults. Studies in in vitro and animal models suggest curcumin may be an effective remediative agent for brain damage.

Anti-proliferative activity of the quassinoid NBT-272 in childhood medulloblastoma cells.

Background: With current treatment strategies, nearly half of all medulloblastoma (MB) patients die from progressive tumors. Accordingly, the identification of novel therapeutic strategies remains a major goal. Deregulation of c-MYC is evident in numerous human cancers.