Selective Late-Stage Functionalization of Tryptophan-Containing Peptides To Facilitate Bioorthogonal Tetrazine Ligation.

Site-selective modification of complex peptides and the functionalization of their C-H bonds hold great promise for expanding their use in therapeutics and biomedical research. Herein, we leverage the power of late-stage chemoenzymatic catalysis using an indole prenyltransferase (IPT) enzyme and alkyl diphosphates to specifically modify the indole ring of tryptophan in clinically relevant peptides. Furthermore, the installed handle enables bioorthogonal click chemistry through an inverse electron-demand Diels-Alder (IEDDA) reaction with a biotin-conjugated tetrazine probe.

Mating-induced analgesia is dependent of copulatory male pattern in high- and low- yawning male rats.

Mating behavior in rodents can modulate pain sensations in both sexes. In males, the execution of mounts, intromissions, and ejaculations induced a progressive increase in their vocalization thresholds induced by tail shocks and other types of noxious stimuli. We selectively inbred two sublines from Sprague-Dawley (SD) rats that differed in their spontaneous yawning frequency. The high-yawning (HY) subline had a mean of 20 yawns/h and a different pattern of sexual behavior characterized by longer interintromission intervals and more sexual bouts that delayed ejaculation. The low-yawning (LY) subline and SD rats yawned as a mean 2 and 1 yawns/h, respectively. So, we determine mating-induced analgesia in HY, LY, and SD male rats by measuring vocalization thresholds in response to noxious electric tail shocks. Our results showed that the magnitude of mating-induced analgesia was lower in HY and LY rats with respect to SD rats. When the rats performed different components of male sexual pattern, both sublines exhibited a significantly lower increase in their vocalization thresholds with respect to SD rats-being sublines less responsive regarding mating-induced analgesia. Pain modulation mechanisms depend on responses to stress, so the low levels of analgesia obtained in the yawning sublines may be due either to differences in their response to stress in other paradigms, or to atypical performance of male sexual behavior during mating, an event which as a stressful event in rats. Therefore, the yawning sublines are a suitable model for analyzing how a different temporal pattern in the display of male sexual behavior affects analgesia mechanisms. Our results concur with Wistar rats with different endophenotypes that could apply to humans as well.

Reacción acneiforme como efecto adverso del apremilast / Acneiform reaction as an adverse effect of apremilast

El apremilast es un fármaco inhibidor de la fosfodiesterasa-4 que modula, a nivel intracelular, la expresión de citoquinas involucradas en la patogenia inflamatoria de la psoriasis. Su uso está indicado en la psoriasis en placas moderada y severa, con buenos resultados clínicos. Los principales efectos adversos son gastrointestinales y, en menos del 2% de los pacientes, dermatológicos, con exantema y foliculitis. Se presenta el caso de un paciente de 42 años que, luego de tomar el apremilast, desarrolló lesiones faciales que correspondieron clínica e histopatológicamente a una reacción acneiforme, con evolución favorable y resolución total del cuadro posterior a la suspensión del medicamento.

Apremilast is a phosphodiesterase-4 inhibitor that modulates the intracellular expression of cytokines, which are involved in the pathogenesis of psoriasis. Apremilast is indicated in moderate to severe plaque psoriasis, and it has shown good clinical results. The main adverse effects occur at a gastrointestinal level, and in less than 2% at the dermatologic level with exanthema and folliculitis. We present a 42-year-old patient that developed facial lesions after taking apremilast. The facial lesions were clinically and histopathologically correspond to an acneiform eruption. The patient evolved favorably and fully recovered after suspending apremilast.

The Neural Signals of the Superior Ovarian Nerve Modulate in an Asymmetric Way the Ovarian Steroidogenic Response to the Vasoactive Intestinal Peptide.

The superior ovarian nerve (SON) provides neuropeptide-Y, norepinephrine and vasoactive intestinal peptide (VIP) to the ovaries. Ovarian steroidogenesis is modulated by the SON. In the cyclic rat, the acute steroidogenic response to ovarian microinjection of VIP is asymmetric and varies during the estrous cycle. In the present study, we analyze whether the differential effects of VIP in each ovary are modulated by the neural signals arriving through the SON. Cyclic female rats were submitted on diestrus-1, diestrus-2, proestrus, or estrus to a unilateral section of the SON, and immediately afterward, the denervated ovary was either microinjected or not with VIP. Animals were sacrificed 1 h after treatment. The injection of VIP into the left denervated ovary performed on diestrus-1 decreased progesterone levels in comparison with the left SON sectioning group; similar effects were observed on proestrus when VIP was injected into either of the denervated ovaries. Compared to the left SON sectioning group, VIP treatment into the left denervated ovary on diestrus-2 or proestrus decreased testosterone levels, whereas on diestrus-1, proestrus or estrus, the same treatment resulted in higher estradiol levels. Compared to the right SON sectioning group, VIP injected into the right denervated ovary yielded higher testosterone levels on diestrus-1 and estrus and lower testosterone levels on proestrus. VIP injection into the right denervated ovary increased estradiol levels on diestrus-2 or estrus while decreasing them on proestrus. Our results indicate that in the adult cyclic rat, the set neural signals arriving to the ovaries through the SON asymmetrically modulate the role of VIP on steroid hormone secretion, depending on the endocrine status of the animal. The results also support the hypothesis that the left and right ovary respond differently to the VIPergic stimulus.

Hemi-ovariectomies promote a decrease in the dendritic lengths of CA1 and CA3 neurons: A dimorphic effect of the cerebral hemispheres.

Certain structures of the central nervous system (CNS) are morphologically and functionally related to the ovaries. Ovariectomy has been used to study the functional role of the ovaries in the CNS, as well as the role of the CNS on the reproductive system. In the present study, the effects of left and right hemi-ovariectomy on the morphology of pyramidal neurons from the CA1 and CA3 regions of the ventral hippocampus were studied. During the estrus phase, female Long-Evans rats underwent either left and right hemi-ovariectomies or left and right sham surgeries. Three estrous cycles later, the animals were sacrificed, and their brains were processed in Golgi-Cox stain and analyzed by the Sholl method to calculate the dendritic length of the CA1 and CA3 neurons of the left and right hemispheres. The results indicate that the dendritic lengths of the basilar and apical arbors of the CA1 neurons from the left hemisphere were shorter after both left and right hemi-ovariectomy, while the CA1 neurons from the right hemisphere were not affected by either procedure. However, the basilar dendritic arbors of the CA3 neurons from both hemispheres were affected by right hemi-ovariectomy. The spine density only decreased in the apical arbors in the CA3 neurons from the left hemisphere of rats that underwent right hemi-ovariectomy. This study's results indicate that hemi-ovariectomy in adult rats changes in the morphology of the CA1 and CA3 pyramidal neurons in the ventral hippocampus and that there are dimorphic responses between the hemispheres.

Unilaterally blocking the muscarinic receptors in the suprachiasmatic nucleus in proestrus rats prevents pre-ovulatory LH secretion and ovulation.

BACKGROUND: The suprachiasmatic nucleus (SCN) and the cholinergic system of various regions of the hypothalamus participate in the regulation of gonadotropin-releasing hormone (GnRH) and gonadotropin secretion, which are necessary for the occurrence of ovulation. In the present study, our goal was to analyse the effects of unilaterally blocking the muscarinic receptors in the SCN on ovulation and steroid secretion. METHODS: Cyclic rats were randomly allotted to one of the experimental groups. Groups of 8-14 rats were anaesthetized and microinjected with 0.3 µl of saline or a solution of atropine (62.5 ng in 0.3 µl of saline) into the left or right SCN at 09.00 or 19.00 h during diestrus-1 or on the proestrus day. The rats were euthanized on the predicted day of oestrus, and evaluated ovulation and levels of progesterone and oestradiol. Other groups of 10 rats were microinjected with atropine into the left or right SCNs at 09.00 h on the proestrus day, were euthanized eight h later, and luteinizing hormone (LH) was measured. RESULTS: At 09.00 or 19.00 h during diestrus-1, atropine microinjections into the SCNs on either side did not modify ovulation. The atropine microinjections performed at 09.00 h of proestrus into either side of the SCN blocked ovulation (right SCN: 1/9 ovulated vs. 9/10 in the saline group; left SCN: 8/14 ovulated vs. 10/10 in the saline group). The LH levels at 17.00 h in the rats that were microinjected with atropine at 09.00 h of proestrus were lower than those of the controls. In the non-ovulating atropine-treated rats, the injection of synthetic LH-releasing hormone (LHRH) restored ovulation. Atropine treatment at 19.00 h of proestrus on either side of the SCN did not modify ovulation, while the progesterone and oestradiol levels were lower. CONCLUSION: Based on the present results, we suggest that the cholinergic neural information arriving on either side of the SCN is necessary for the pre-ovulatory secretion of LH to induce ovulation. Additionally, the regulation of progesterone and oestradiol secretion by the cholinergic innervation of the SCN varies with the time of day, the day of the cycle, and the affected SCN.

Multipotent adult progenitor cell-loaded demineralized bone matrix for bone tissue engineering.

Multipotent adult progenitor cells (MAPCs) from bone marrow have been shown to be capable of forming bone, cartilage and other connective tissues. In addition, MAPCs differentiate into lineages that are different from their germ layers of origin. Previous studies showed the ability of MAPCs to improve cardiac function and control allogenic-reactive responses associated with acute graft versus host disease. In the current study, we evaluated the ability of MAPCs to produce bone matrix on demineralized bone allograft substrates. Specifically, MAPCs expressed alkaline phosphatase, produced extracellular matrix proteins and deposited calcium-containing mineral on demineralized bone matrices. Furthermore, the addition of MAPCs on demineralized bone matrix (DBM) scaffolds enhanced osteoinductivity of the carrier in a rat ectopic pouch model. These results demonstrated the potential of MAPCs as a new approach for bone repair in tissue-engineering applications.

Endothelial cell derived angiocrine support of acute myeloid leukemia targeted by receptor tyrosine kinase inhibition.

In acute myeloid leukemia (AML), refractory disease is a major challenge and the leukemia microenvironment may harbor refractory disease. Human AML cell lines KG-1 and HL-60 expressed receptors also found on endothelial cells (ECs) such as VEGFRs, PDGFRs, and cKit. When human AML cells were co-cultured with human umbilical vein endothelial cells (HUVECs) and primary bone marrow endothelial cell (BMECs), the AML cells were more resistant to cytarabine chemotherapy, even in transwell co-culture suggesting angiocrine regulation. Primary BMECs secreted significantly increased levels of VEGF-A and PDGF-AB after exposure to cytarabine. Pazopanib, a receptor tyrosine kinase inhibitor (RTKI) of VEGFRs, PDGFRs, and cKit, removed EC protection of AML cells and enhanced AML cell sensitivity to cytarabine. Xenograft modeling showed significant regression of AML cells and abrogation of BM hypervascularity in RTKI treated cohorts. Together, these results show direct cytotoxicity of RTKIs on AML cells and reversal of EC protection. Combining RTKIs with chemotherapy may serve as promising therapeutic strategy for patients with AML.

In the pubertal rat, the regulation of ovarian function involves the synergic participation of the sensory and sympathetic innervations that arrive at the gonad.

BACKGROUND: The present study investigates sectioning the superior ovarian nerve (SON) in rats with functional sensorial denervation induced by capsaicin administration at birth and the effects on the establishment of puberty, ovulation, serum progesterone, and estradiol concentrations. METHODS: The animals were allotted randomly to one of the following experimental groups. Groups of 8-10 rats were injected at birth with capsaicin or vehicle, and on day 20 or 28 of life, they were submitted to a sham operation (SO). Other groups of 8-10 rats were injected at birth with capsaicin or vehicle, and on day 20 or 28 of life, they were submitted to the uni-or bilateral SON sectioning. The animals were killed at the first estrus. Serum concentration of progesterone (ng/ml) and estradiol (pg/ml) were measured using a radioimmunoassay. RESULTS: Animals treated with capsaicin and subjected at 20 days of life to the left or bilateral section of SON had a delayed age of vaginal opening. Furthermore, animals with a lack of sensory information and subjected to a SO at 28 days of life had the same delay in the age of vaginal opening. Animals with sensorial innervation intact, subjected to unilateral section of the SON at 20 or 28 days of age, showed diminished ovulation rate and number of ova shed by the denervated ovary. In animals with sensorial denervation, the uni-or bilateral sectioning of the SON did not result in changes in ovulation. Progesterone and estradiol levels were different depending on the age of the animal in which the SON section was performed. CONCLUSIONS: Based on the present results, we suggest that sympathetic innervation regulates ovulation and the secretion of steroid hormones and that the sensory fibers modulate the sympathetic innervation action on ovarian functions.

The effects of sensorial denervation on the ovarian function, by the local administration of capsaicin, depend on the day of the oestrous cycle when the treatment was performed.

There is evidence that sensory innervation plays a role in the regulation of puberty. The present study investigates the effects of functional sensorial desensitisation induced by capsaicin administration to adult female rats in the days of diestrus 1, diestrus 2, pro-oestrus or oestrus on ovulation and serum oestradiol and progesterone concentration. The animals were allotted at random to one of the following groups: (1) animals with capsaicin administration into the bursa ovarica (local administration) (2) animals with vehicle administration into the bursa ovarica and (3) untreated animals group. The animals treated were killed on the day of oestrus after three consecutive 4-day oestrous cycles. No differences were observed in oestrous cyclicity or the average number of ova shed between the sensorial desensitisation animals and the vehicle-treated groups. Capsaicin administration resulted in a significant increase in the intra-ovarian noradrenaline levels in the day of diestrus 2 and pro-oestrus. Serum oestradiol and progesterone concentrations were different, depending on the day of the oestrous cycle in which the treatment was performed. These results suggest that in adult normal female rats, ovarian sensorial innervations participate together with the sympathetic innervation in the ovarian function regulating the hormone secretion and this participation varies along the oestrous cycle.

Asymmetric steroidogenic response by the ovaries to the vasoactive intestinal peptide.

In vitro the vasoactive intestinal peptide (VIP) stimulates progesterone, androgens, and estradiol secretion, and the effects are time-dependent. The present study analyzed the acute (1 h) and sub-acute (24 h) effects of unilateral injection of VIP into the ovarian bursa on each day of the estrous cycle on progesterone, testosterone, and estradiol serum levels. Cyclic 60-day-old virgin female rats on diestrus-1, diestrus-2, proestrus, or estrus were injected with saline or VIP 10(-6) M into the left or right ovarian bursa. One hour after saline injection on each day of estrus cycle, progesterone levels were higher than in control animals. The acute effects of saline solution on testosterone and estradiol levels were asymmetric and varied during the estrous cycle. In comparison with saline groups, the effects of VIPergic stimulation on progesterone, testosterone, and estradiol serum levels depend on the time elapsed between treatment and autopsy and vary during the estrous cycle. An acute asymmetric response from the ovaries to the VIP was observed at diestrus-1, diestrus-2, and proestrus on progesterone and estradiol levels. The asymmetries on testosterone levels were observed at diestrus-1, diestrus-2, and estrus days. The present results suggest that in the cyclic rat, each ovary has different sensitivities to VIPergic stimulation which depends on the endocrine status of the animal.

Lack of sensorial innervation in the newborn female rats affects the activity of hypothalamic monoaminergic system and steroid hormone secretion during puberty.

There is evidence that sensory innervation plays a role regulating ovarian functions, including fertility.Since sensory denervation by means of capsaicin in newborn female rats results in a lower response togonadotropins, the present study analyzed the effects that sensory denervation by means of capsaicin in neonatal rats has on the concentration of monoamines in the anterior(AH) and medium (MH) hypothalamus, and on steroid hormone levels in serum. Groups of newborn female rats were injected subcutaneously with capsaicin and killed at 10, 20, and 30 days of age and on the first vaginal estrous.The concentrations of noradrenaline, dopamine, serotonin(5-HT), and their metabolites in the AH and MH were measured using HPLC, and the levels of estradiol (E),progesterone (P), testosterone (T), FSH, and luteinizing hormone using radioimmunoanalysis. The results show thatat 20 days of age, capsaicin-treated rats have lowernoradrenergic and serotonergic activities in the AH, and that the dopaminergic activity was lower in the MH. These results suggest that the sensorial system connections within the monoaminergic systems of the AH and MH are different.Capsaicin-treated animals had lower T, E, and P levels than in the control group, suggesting that the lower activity in the AH monoaminergic system and lower hormonesecretion could be explained by the blockade of information mediated by the sensory innervation (probably substance P), mainly between the ovary and the AH.

Effects on steroid hormones secretion resulting from the acute stimulation of sectioning the superior ovarian nerve to pre-pubertal rats.

In the adult rat, neural signals arriving to the ovary via the superior ovarian nerve (SON) modulate progesterone (P4), testosterone (T) and estradiol (E2) secretion. The aims of the present study were to analyze if the SON in the pre-pubertal rat also modulates ovarian hormone secretion and the release of follicle stimulating hormone (FSH) and luteinizing (LH) hormone. P4, T, E2, FSH and LH serum levels were measured 30 or 60 minutes after sectioning the SON of pre-pubertal female rats. Our results indicate that the effects on hormone levels resulting from unilaterally or bilaterally sectioning the SON depends on the analyzed hormone, and the time lapse between surgery and autopsy, and that the treatment yielded asymmetric results. The results also suggest that in the pre-pubertal rat the neural signals arriving to the ovaries via the SON regulate the enzymes participating in P4, T and E2 synthesis in a non-parallel way, indicating that the mechanisms regulating the synthesis of each hormone are not regulated by the same signals. Also, that the changes in the steroids hormones are not explained exclusively by the modifications in gonadotropins secretion. The observed differences in hormone levels between rats sacrificed 30 and 60 min after surgery reflect the onset of the compensatory systems regulating hormones secretion.

Angiogenesis in acute myeloid leukemia and opportunities for novel therapies.

Acute myeloid leukemia (AML) arises from neoplastic transformation of hematopoietic stem and progenitor cells, and relapsed disease remains one of the greater challenges in treating this hematologic malignancy. This paper focuses on angiogenic aspects of AML including the significance and prognostic value of bone marrow microvessel density and circulating cytokine levels. We show three general mechanisms whereby AML exploits angiogenic pathways, including direct induction of angiogenesis, paracrine regulation, and autocrine stimulation. We also present early evidence that leukemia cells contribute directly to vascular endothelia. Novel treatment strategies are proposed, and a review of relevant antiangiogenic clinical trials is presented. By understanding how blood vessels can serve as a reservoir for refractory and relapsed AML, new diagnostics and promising treatment strategies can be developed.

Effects of acute unilateral ovariectomy to pre-pubertal rats on steroid hormones secretion and compensatory ovarian responses.

In the present study we analyzed the existence of asymmetry in the secretion of steroid hormones in pre-pubertal female rats treated with unilateral ovariectomy (ULO) or unilateral perforation of the abdominal wall (sham-surgery). Treated rats were sacrificed at different times after surgery. Since sham-surgery had an apparent effect on the age of first vaginal estrous (FVE) and serum levels hormone, the results of the sham surgery groups were used to assess the effects of their respective surgery treatment groups. On the day of FVE, compensatory ovulation (CO) and compensatory ovarian hypertrophy (COH) were similar in animals with ULO, regardless of the ovary remaining in situ. In ULO treated animals, progesterone (P4) levels were higher than in animals with sham-surgery one hour after treatment but lower in rats sacrificed at FEV. Left-ULO resulted in lower testosterone (T) concentration 48 and 72 hours after surgery. In rats with Right-ULO lower T concentrations were observed in rats sacrificed one or 72 hours after surgery, and at FVE. ULO (left or right) resulted in lower estradiol (E2) concentrations one or 72 hours after treatment. In rats with Left-ULO, E2 levels were higher 48 hours after surgery and at FVE. Left-ULO resulted in higher levels of follicle stimulating hormone (FSH) five hours after surgery and at FVE. FSH levels were higher in rats with Right-ULO sacrificed on FVE. The present results suggest that in the pre-pubertal rat both ovaries have similar capacities to secrete P4, and that the right ovary has a higher capacity to secrete E2. Taken together, the present results support the idea that the effects of ULO result from the decrease in glandular tissue and changes in the neural information arising from the ovary.

Human adipose-derived side population stem cells cultured on demineralized bone matrix for bone tissue engineering.

BACKGROUND: Tissue engineering of new bone relies on the combination and application of osteoconductive, osteoinductive, and osteogenic elements. Natural scaffolds, such as demineralized bone matrix (DBM), contain collagenous networks with growth factors such as bone morphogenetic protein-2. Stem cells from readily available sources, including discarded adipose tissue, have the propensity to differentiate into bone. The present study examines a multi-component technique consisting of a novel side population of adipose stem cells cultured on DBM for tissue engineering applications. METHODS: Adipose-derived side population stem cells were cultured on DBM for up to 14 days. Cell proliferation, alkaline phosphatase activity, extracellular matrix protein production, and calcium-containing mineral deposit formation were assayed. Ectopic bone formation in a rat model was also evaluated. RESULTS: Side population stem cells attached to and proliferated on DBM while generating markers of new bone formation. When these cell/substrate composites were implanted into an ectopic model, newly formed bone was 30% greater than that of DBM alone. CONCLUSIONS: Novel populations of adipose-derived stem cells cultured on DBM compose a system that develops new bone matrix in vitro and in vivo. This strategy provides a novel approach using naturally occurring materials for bone repair in tissue engineering applications.

Inhibition of focal adhesion kinase decreases tumor growth in human neuroblastoma.

Neuroblastoma is the most common extracranial solid tumor of childhood. Focal adhesion kinase (FAK) is an intracellular kinase that regulates both cellular adhesion and apoptosis. FAK is overexpressed in a number of human tumors including neuroblastoma. Previously, we have shown that the MYCN oncogene, the primary adverse prognostic indicator in neuroblastoma, regulates the expression of FAK in neuroblastoma. In this study, we have examined the effects of FAK inhibition upon neuroblastoma using a small molecule [1,2,4,5-benzenetetraamine tetrahydrochloride (Y15)] to inhibit FAK expression and the phosphorylation of FAK at the Y397 site. Utilizing both non-isogenic and isogenic MYCN(+)/MYCN(-) neuroblastoma cell lines, we found that Y15 effectively diminished phosphorylation of the Y397 site of FAK. Treatment with Y15 resulted in increased detachment, decreased cell viability and increased apoptosis in the neuroblastoma cell lines. We also found that the cell lines with higher MYCN are more sensitive to Y15 treatment than their MYCN negative counterparts. In addition, we have shown that treatment with Y15 in vivo leads to less tumor growth in nude mouse xenograft models, again with the greatest effects seen in MYCN(+) tumor xenografts. The results of the current study suggest that FAK and phosphorylation at the Y397 site plays a role in neuroblastoma cell survival, and that the FAK Y397 phosphorylation site is a potential therapeutic target for this childhood tumor.

Inhibition of focal adhesion kinase and src increases detachment and apoptosis in human neuroblastoma cell lines.

Neuroblastoma is the most common extracranial solid tumor of childhood. Focal adhesion kinase (FAK) is an intracellular kinase that is overexpressed in a number of human tumors including neuroblastoma, and regulates both cellular adhesion and survival. We have studied the effects of FAK inhibition upon neuroblastoma using adenovirus-containing FAK-CD (AdFAK-CD). Utilizing an isogenic MYCN+/MYCN- neuroblastoma cell line, we found that the MYCN+ cells are more sensitive to FAK inhibition with AdFAK-CD than their MYCN negative counterparts. In addition, we have shown that phosphorylation of Src is increased in the untreated isogenic MYCN- neuroblastoma cells, and that the decreased sensitivity of the MYCN- neuroblastoma cells to FAK inhibition with AdFAK-CD is abrogated by the addition of the Src family kinase inhibitor, PP2. The results of the current study suggest that both FAK and Src play a role in protecting neuroblastoma cells from apoptosis, and that dual inhibition of these kinases may be important when designing therapeutic interventions for this tumor.

Ketone bodies inhibit the viability of human neuroblastoma cells.

PURPOSE: Recent studies have shown that brain tumor cells, unlike normal brain cells, are largely dependent upon glucose for energy and are not able to use ketone bodies as a primary energy source. These findings are thought to be because of decreased expression of succinyl-coenzyme A:3-oxoacid coenzyme A transferase (SCOT), a key enzyme involved in ketone body metabolism. Because of their neural crest origin, we hypothesized that neuroblastoma cells would also be unable to use ketone bodies as a primary energy source. METHODS: Human foreskin fibroblasts (control) and human neuroblastoma cells (SK-N-AS) were grown in standard media with glucose (glc+), standard media without glucose (glc-), glucose-free media with acetoacetate, or glucose-free media with beta-hydroxybutyrate. Cell viability was determined with MTT [3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide] assay and apoptosis with fluorescence-activated cell sorting analysis. Immunoblotting was performed to SCOT protein. RESULTS: Neuroblastoma cell viability was significantly decreased in the acetoacetate and hydroxybutyrate media by 52% and 61%, respectively, compared with control media. In addition, neuroblastoma cells showed significantly more apoptosis in the ketone media. Viability and apoptosis in the normal fibroblasts were not affected by the culture media. The expression of SCOT protein was significantly less in human neuroblastoma cells compared with the control fibroblasts. CONCLUSIONS: Unlike human fibroblasts, neuroblastoma cells were unable to use ketone bodies as an energy source, likely because of their decreased expression of SCOT protein. Dietary manipulation using ketone bodies in accordance with SCOT expression may be a novel therapeutic strategy for neuroblastoma.

TAE226 inhibits human neuroblastoma cell survival.

PURPOSE: Neuroblastoma is one of the most devastating pediatric solid tumors and is unresponsive to many interventions. TAE226 is a novel small molecule FAK inhibitor. We investigated the effects of TAE226 on neuroblastoma cells in vitro. MATERIALS AND METHODS: Human neuroblastoma cell lines were treated with varying concentrations of TAE226. Following treatment, cell viability, cell cycle, and apoptosis were evaluated. RESULTS: Treatment of human neuroblastoma cell lines with TAE226 resulted in a concentration dependent decrease in FAK phosphorylation, decrease in cellular viability, cell cycle arrest, and an increase in apoptosis. CONCLUSIONS: Targeting FAK provides potential therapeutic options for the treatment of neuroblastoma and deserves further investigation.