Adding high-dose celecoxib to increase effectiveness of standard glioblastoma chemoirradiation.

Over one hundred clinical trials since 2005 have failed to significantly improve the prognosis of glioblastoma. Since 2005, the standard of care has been maximal resection followed by 60Gy irradiation over six weeks with daily temozolomide. With this, a median survival of 2 years can be expected. This short paper reviewed how the pharmacodynamic attributes of an EMA/FDA approved, cheap, generic drug to treat pain, celecoxib, intersect with pathophysiological elements driving glioblastoma growth, such that growth drive inhibition can be expected from celecoxib. The two main attributes of celecoxib are carbonic anhydrase inhibition and cyclooxygenase-2 inhibition. Both attributes individually have been in active study as adjuncts during current cancer treatment, including that of glioblastoma. That research is briefly reviewed here. This paper concludes from the collected data, that starting celecoxib, 600 to 800mg twice daily before surgery and continuing it through the chemoirradiation phase of treatment would be a low-risk intervention with sound rationale.

Dapsone as treatment adjunct in ARDS.

Multiple pharmacological interventions tested over the last decades have failed to reduce ARDS mortality. This short note recounts past data indicating that (i) neutrophils home along an IL-8 gradient, (ii) in ARDS, massive neutrophil accumulation and degranulation in and along bronchoalveolar spaces contributes to damage and hypoxia, (iii) large increases in IL-8 are one of the chemotaxic signals drawing neutrophils to the ARDS lung, and (iv) old data from dermatology and glioblastoma research showed that the old drug against Hansen's disease, dapsone, inhibits neutrophils' chemotaxis to IL-8. Therefore dapsone might lower neutrophils' contributions to ARDS lung pathology. Dapsone can create methemoglobinemia that although rarely problematic it would be particularly undesirable in ARDS. The common antacid drug cimetidine lowers risk of dapsone related methemoglobinemia and should be given concomitantly.

Simultaneous Interference with HER1/EGFR and RAC1 Signaling Drives Cytostasis and Suppression of Survivin in Human Glioma Cells in Vitro.

We have previously reported that combined inhibition of the epidermal growth factor receptor by erlotinib and of RAC1 by NSC23766 yielded a synergistic antiproliferative effect on established and primary cultured glioblastoma cells. The current study aimed at identifying the molecular mechanism. Staining for annexin V/PI or carboxyfluorescein succinimidyl ester was performed in order to determine the induction of apoptosis, necrosis or cytostasis in established and primary cultured glioblastoma cells. Moreover, expression of Ki-67 was determined by immunofluorescence, and the expression of cell cycle proteins was analysed by Western blot. Our data show that combined treatment with erlotinib and NSC23766 resulted in a reduced number of cell divisions, a significantly decreased Ki-67 expression, increased apoptosis and autophagy when compared to single agent treatments. On the molecular level, concomitant treatment with both agents resulted in a pronounced downregulation of cyclin D1, cyclin-dependent kinases 2, 4 and 6, as well as of survivin when compared to treatments with either agent alone. In conclusion, we demonstrate that combined treatment of human glioma cell lines in vitro with erlotinib and NSC23766 markedly inhibits cell division, induces apoptosis independent of caspase-3 activation and induces autophagy concomitant with suppression of survivin.

Glioblastoma treatment using perphenazine to block the subventricular zone's tumor trophic functions.

We present here a potential new treatment adjunct for glioblastoma. Building on murine studies, a series of papers appeared recently showing that therapeutic irradiation of the ipsilateral subventricular zone (SVZ) retards growth of more peripherally growing cortical glioblastomas in humans, suggesting a tumor trophic function for the SVZ. Further studies showed that SVZ cells migrate out towards a peripheral glioblastoma. Dopamine signaling through D3 subtype receptor indirectly drives this centrifugal migration in humans. Since psychiatry has several drugs with good D3 blocking attributes, such as fluphenazine, or perphenazine, we suggest that adding one of these D3 blocking drugs to current standard treatment of resection followed by temozolomide and irradiation might prolong survival by depriving glioblastoma of the trophic functions previously subserved by dopaminergic signaling on SVZ cells.

Why dapsone stops seizures and may stop neutrophils' delivery of VEGF to glioblastoma.

Lopez-Gomez et al. recently published remarkable but mechanistically unexplained empirical evidence that the old antibiotic dapsone has antiepileptic activity. We addressed the question "Why should a sulfone antibiotic reduce seizures?". We report here our conclusions based on data from past studies that seizures are associated with elevated interleukin-8 (IL-8) and that dapsone inhibits IL-8 release and function in several different clinical and experimental contexts. Diverse CNS insults cause an increase in CNS IL-8. Thus, the pro-inflammatory environment generated by increase IL-8 leads to a lower seizure threshold. Together this evidence indicates dapsone exerts anti-seizure activity by diminishing IL-8 signalling. Since IL-8 is clearly upregulated in glioblastoma and contributes to the florid angiogenesis of that disease, and since interference with IL-8 function has been shown to inhibit glioblastoma invasion and growth in several experimental models, and dapsone has been repeatedly been shown to clinically inhibit IL-8 function when used to treat human neutrophilic dermatoses, we believe that dapsone thereby reduces seizures by countering IL-8 function and may similarly retard glioblastoma growth by such anti-IL-8 function.

Short review of SEC, a potential dexamethasone-sparing regimen for glioblastoma: Spironolactone, ecallantide, clotrimazole.

This paper presents a short review of data supporting a dexamethasone sparing regimen, SEC, to reduce glioblastoma related brain edema. The conclusion of the reviewed data is that the rationale and risk/benefit ratio favors a pilot study to determine if the three drug regimen of SEC can reduce need for corticosteroid use during the course of glioblastoma. Details of how selected pathophysiological aspects of brain edema occurring during the course of glioblastoma and its treatment intersect with the established action of the three old drugs of SEC indicate that they can be repurposed to reduce that edema. Current first-line treatment of this edema is dexamethasone or related corticosteroids. There are multiple negative prognostic implications of both the edema itself and of dexamethasone, prime among them shortened survival, making a dexamethasone sparing regimen highly desirable. SEC uses spironolactone, an antihypertensive potassium-sparing diuretic acting by mineralocorticoid receptor inhibition, ecallantide acting to inhibit kallikrein activation marketed to treat hereditary angioedema, and clotrimazole, an old antifungal drug that inhibits intermediate conductance Ca++ activated K+ channel (KCa3.1). These three old drugs are well known to most clinicians, have a well-tolerated safety history, and have a robust preclinical database showing their potential to reduce the specific edema of glioblastoma. Additionally, these three drugs were chosen by virtue of each having preclinical evidence of glioblastoma growth and/or migration inhibition independent of their edema reduction action. A clinical study of SEC is being planned.

Glioblastoma: synergy of growth promotion between CCL5 and NK-1R can be thwarted by blocking CCL5 with miraviroc, an FDA approved anti-HIV drug and blocking NK-1R with aprepitant, an FDA approved anti-nausea drug.

WHAT IS KNOWN AND BACKGROUND: Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion- that of CCR5 and neurokinin (NK)-1R- have small molecule inhibitors that are FDA approved and marketed to treat other conditions. The anti-HIV drug, maraviroc, inhibits human CCR5's ligand from binding, and hence blocks CCR5 stimulation. The anti-nausea drug aprepitant blocks substance P signaling at NK-1R. AIMS AND OBJECTIVE: We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma. COMMENT: After stimulation by their respective ligands both CCR5 and NK-1R, through intermediaries, phosphorylate and thereby activate ERK1/2, triggering in turn migratory and mitotic events. Neurokinin-1R second messenger signaling also happens to serine phosphorylate CCR5. Phosphorylated CCR5 exhibits amplified activity after agonist ligation. Therefore, aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma. Inhibiting an amplifier is equivalent to amplifying an inhibitor. Since the two suggested drugs are non-cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide, radiation, and bevacizumab, all to be used after debulking primary resection. WHAT IS NEW AND CONCLUSION: Our analysis makes the case for a well-designed trial of the proposed combination in the treatment of glioblastoma.

Use of FDA approved methamphetamine to allow adjunctive use of methylnaltrexone to mediate core anti-growth factor signaling effects in glioblastoma.

Methylnaltrexone (MNTX) was recently FDA approved to treat opiate induced constipation. It happens to also indirectly reduce Src activity. Src is a 54 kDa tyrosine kinase, crucial in signaling of, and link between, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). Glioblastomas use both EGF and VEGF signaling to enhance growth and neo-angiogenesis. Stem cell sub-fractions of glioblastomas are enriched for high VEGF synthesizing cells so this is a particularly valuable adjunctive target during cytotoxic treatment with drugs like temozolomide. MNTX does not cross the blood-brain barrier (BBB). Methamphetamine (MA) temporarily opens the BBB and therefore may allow methylnaltrexone entry into glioblastoma tissue. MA is FDA approved, marketed to treat attention problems in children. MA-MNTX combination should be tested as glioblastoma treatment adjunct. Temozolomide CSF levels are 10-20% of blood levels. Thus MA may also allow greater brain tissue temozolomide levels yet with lower systemic exposure.

Endothelin-1 inhibition by ambrisentan as a potential treatment adjunct after debulking surgery in epithelial ovarian cancer.

The 21 amino acid signaling peptide endothelin-1 is commonly elevated in epithelial ovarian cancer, and it mediates or facilitates much of this cancer's aggressive behavior. Ambrisentan (Letairis; Gilead Sciences Inc.) is an antagonist of endothelin-1 at its cognate receptor that has just been approved to treat pulmonary hypertension. Ambrisentan is a well-tolerated pill taken once daily. In theory, it should retard and inhibit lodgement and establishment of disseminated peritoneal micrometastases after debulking surgery.

How lithium treatment generates neutrophilia by enhancing phosphorylation of GSK-3, increasing HIF-1 levels and how this path is important during engraftment.

Lithium is commonly used in psychiatry for mood stabilization. Lithium treatment results in neutrophilia, increased platelets and increased circulating CD34+ haematopoietic stem cells, HSC. This paper outlines the newly discovered mechanism by which this occurs. Glycogen synthase kinase-3, GSK-3, phosphorylates and thereby inactivates hypoxia-induced factor-1, HIF-1. HIF-1 is a transcription factor triggering transcription of multiple genes related to adaptation to hypoxia, among which is CXCL12. CXCL12 forms the primary homing gradient for CD34+ HSCs towards the hypoxic, trophic bone marrow niche to which they must go to thrive. Lithium inhibits GSK-3 thereby increasing active HIF-1 that results in a stronger CXCL12 homing gradient. Trophic niche function is enhanced, ultimately resulting in increased production of neutrophils, platelets and CD34+ cells. Sitagliptin is a new drug to treat diabetes that coincidentally inhibits destruction of CXCL12. Thus, lithium and sitagliptin enhance CXCL12 by different paths, potentially increasing trophic niche function. Awareness of this path is important in HSC transplantation.

Melanoma inhibition by cyclooxygenase inhibitors: role of interleukin-6 suppression, a putative mechanism of action, and clinical implications.

Melanoma progression is often associated with supranormal levels of interleukin-6 (IL-6). Il-6 is an important growth factor for many cases of melanoma. A recent case report by Lejeune et al. [Melanoma Res 2006;16:263-265] of remission of an advanced melanoma during treatment with the cyclooxygenase, (COX) inhibitor rofecoxib can be explained by rofcoxib-mediated lowering of tumor-produced Il-6. Several examples of rofecoxib's ability to lower Il-6 in humans have been published recently in other settings, and many reports indicate that other commonly used COX inhibitors like aspirin, diclofenac, etodolac, indomethacin, naproxen, and many others, also lower Il-6 in humans. These studies are reviewed. The likely mechanism of COX inhibition leading to Il-6 lowering is due to the tendency for Il-6 levels to be controlled by intracellular cyclic adenosine monophosphate (cAMP). Adenylate cyclase is the rate-limiting enzyme in cAMP synthesis. Because adenylate cyclase activity is allosterically enhanced when it binds prostaglandin E, the latter increases Il-6. COX inhibition lowers prostaglandin E levels. This lowers intracellular cAMP levels. Lower cAMP results in lower Il-6 synthesis, lower levels of a required growth factor. Controlled studies are needed to define the role of COX inhibitors in melanoma treatment.

Some fibrocystic breast change may be caused by sexually transmitted H. pylori during oral nipple contact: supporting literature and case report of resolution after gut H. pylori eradication treatment.

OBJECTIVES: To briefly review previously published evidence for Helicobacter pylori (Hp), colonization of extra-intestinal sites and suggest an hypothesis that breast acini and ducts be added to this list, concluding such breast colonization is not rare and is a sexually transmitted infection. METHODS: PubMed literature search and review with a case report. CONCLUSIONS: (1) Evidence indicates oral Hp is common and can remain in the mouth after successful eradication in stomach and duodenum. (2) Evidence indicates that the breast is also occasionally colonized by Hp. (3) Hp may be injected retrograde up into ducts of the breast during oral nipple stimulation during sexual activity and this Hp may give rise to some cases of fibrocystic breast change. (4) A case of painful fibrocystic change that had been present for two years in a 27 year old female, resolved after gastrointestinal Hp treatment.

A new chapter opens in anti-inflammatory treatments: the antidepressant bupropion lowers production of tumor necrosis factor-alpha and interferon-gamma in mice.

In a wide range of human diseases of inflammatory nature like Crohn's disease, pathology is mediated in part by pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF) or interferon-gamma. We show here that a commonly used generic antidepressant bupropion, in wide use worldwide to treat depression in humans for a decade now, profoundly lowers levels of TNF, interferon-gamma, and interleukin-1 beta in vivo, in a mouse lipopolysaccharide (LPS) induced inflammation model. Mice challenged with an otherwise lethal dose of LPS were protected by bupropion and levels of the anti-inflammatory cytokine interleukin-10 were increased. Previous data in rodents and humans indicate antidepressant effects of bupropion are mediated by its weak reuptake inhibition of norepinephrine and dopamine. Concordant with this, TNF suppression by bupropion in our mouse LPS model was largely abrogated by beta-adrenergic or dopamine D1 receptor antagonists but not by a D2 antagonist. TNF synthesis is controlled by an inverse relationship with intracellular cyclic adenosine monophosphate (cAMP) and stimulation of either beta-adrenoreceptors or D1 dopaminergic receptors result in increased cAMP but stimulation of D2 receptors lowers cAMP. We conclude that bupropion may suppress TNF synthesis by mediating increased signaling at beta-adrenoreceptors and D1 receptors, resulting in increased cAMP that inhibits TNF synthesis. Bupropion is well tolerated also in non-psychiatric populations and has less risk with long term use than current anti-inflammatory, immunosuppressive or TNF suppressive treatments such as prednisone, azathioprine, infliximab, or methotrexate. New anti-inflammatory treatments are needed. We believe a new chapter in antiinflammatory, TNF lowering treatment of disease has been opened. Bupropion's use for this in humans should be explored.

Evidence of a mechanism by which etanercept increased TNF-alpha in multiple myeloma: new insights into the biology of TNF-alpha giving new treatment opportunities--the role of bupropion.

Etanercept is a commercially available pharmaceutical protein approved for treatment of rheumatoid arthritis, RA. Given subcutaneously, etanercept binds and inactivates soluble tumor necrosis factor-alpha, TNF. Etanercept has a good safety record and is of benefit in lowering pain, inflammation, and joint destruction in RA. RA is mediated by many factors, TNF among them. Malignant myeloma, MM, is a malignant clonal expansion of a post-germinal center B lymphocyte. Since TNF is a necessary growth factor for expansion and maintenance of MM cells, and etanercept binds soluble TNF and is of clinical benefit in RA, etanercept was tried experimentally in MM. Contrary to expectations, etanercept resulted in increased levels of TNF and possibly shortened survival. This paper presents an hypothesis of how this happened. There are two cognate receptors for TNF, termed R1 and R2 and two forms of TNF, soluble and transmembrane. Soluble TNF has greater affinity for TNF-R1 than for TNF-R2. Transmembrane TNF has equal affinity for the two receptors. Since TNF-R2 signaling tends to be more anti-apoptotic and activating of nuclear factor kappa B, NFkB, than is TNF-R1, and TNF-R1 tends to be more pro-apoptotic than is TNF-R2, by inactivating soluble TNF while leaving transmembrane TNF signaling relatively unchanged, etanercept changed the balance in TNF signaling from TNF-R1 towards TNF-R2 weighting. Anti-apoptosis and TNF synthesis would have been up-regulated by that shift. Early data indicates that the common generic antidepressant bupropion may ameliorate Crohn's disease course by down regulating TNF synthesis, maybe it will slow the course of MM as well.

Tenofovir, COX inhibitors and zileuton during cancer immunotherapies: up-regulated TNF-alpha increases antigen driven lymphocyte proliferation.

Current attempts at active immunization of patients to their adenocarcinomas have heretofore met with a curiously little success. The carrier antigens, viral vector proteins, and other co-administered antigens typically elicit strong cell-mediated or humoral responses while the relevant cancer antigen elicits undetectable or feeble responses and often minimal if any retardation of malignant tissue growth is seen. There are exceptions but clearly more effective cancer antigen immunization strategies are needed. Adenylate cyclase, AC, catalyses the conversion of ATP to cyclic adenosine monophosphate (cAMP). Increased cAMP down regulates tumor necrosis factor-alpha, TNF, and decreased cAMP reliably up-regulates synthesis and release of TNF. TNF enhances dendritic cell (DC) maturation processes started by other stimuli. TNF promotes antigen responding CD4+ and CD8+ lymphocytes' proliferation, and suppresses suppressor T cells during primary immunization. Tenofovir is an oral antiviral drug currently used in anti-HIV treatments. It is an acyclic nucleoside analogue of adenosine monophosphate that also happens to increase TNF. The mechanism has not been established but antagonism of cAMP's inhibition of TNF is the likely path. Prostaglandin E (PGE) is a stimulatory allosteric modifier of AC and thus suppresses TNF via the resultant increase of cAMP. Since cyclooxygenase, COX, is the rate-controlling enzyme in PGE production, COX inhibitors, otherwise known as non-steroidal anti-inflammatory drugs (NSAID), increase TNF synthesis and release by depriving AC of PGE. Indomethacin, diclofenac and ketorolac are COX inhibitors that have been on the market for many years that would be well suited for use to increase TNF levels. This paper reviews the data on TNF up-regulation by tenofovir and COX inhibitors and the consequent augmented antigen driven lymphocyte proliferation secondary to increased TNF and suggests exploration of tenofovir and COX inhibitors like indomethacin, diclofenac or ketorolac in augmentation of current cancer immunotherapy attempts. Profound COX inhibition can lead to a compensatory leukotriene increase and leukotrienes have been identified as growth and survival factors in various gastrointestinal cancers. Therefore, zileuton, an orally active 5-lipooxygenase inhibitor that prevents leukotriene synthesis, should be added whenever profound COX inhibition is undertaken in cancer immunotherapies.

Tiagabine may reduce bruxism and associated temporomandibular joint pain.

Tiagabine is an anticonvulsant gamma-aminobutyric acid reuptake inhibitor commonly used as an add-on treatment of refractory partial seizures in persons over 12 years old. Four of the 5 cases reported here indicate that tiagabine might also be remarkably effective in suppressing nocturnal bruxism, trismus, and consequent morning pain in the teeth, masticatory musculature, jaw, and temporomandibular joint areas. Tiagabine has a benign adverse-effect profile, is easily tolerated, and retains effectiveness over time. Bed partners of these patients report that grinding noises have stopped; therefore, the tiagabine effect is probably not simply antinociceptive. The doses used to suppress nocturnal bruxism at bedtime (4-8 mg) are lower than those used to treat seizures.

Erlotinib augmentation with dapsone for rash mitigation and increased anti-cancer effectiveness.

BACKGROUND: The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib has failed in many ways to be as potent in the anti-cancer role as pre-clinical studies would have suggested. This paper traces some aspects of this failure to a compensatory erlotinib-mediated increase in interleukin-8. Many other-but not all- cancer chemotherapeutic cytotoxic drugs also provoke a compensatory increase in a malignant clone's interleukin-8 synthesis. Untreated glioblastoma and other cancer cells themselves natively synthesize interleukin-8. Interleukin-8 has tumor growth promoting, mobility and metastasis formation enhancing, effects as well as pro-angiogenesis effects. FINDINGS: The old sulfone antibiotic dapsone- one of the very first antibiotics in clinical use- has demonstrated several interleukin-8 system inhibiting actions. Review of these indicates dapsone has potential to augment erlotinib effectiveness. Erlotinib typically gives a rash that has recently been proven to come about via an erlotinib triggered up-regulated keratinocyte interleukin-8 synthesis. The erlotinib rash shares histological features reminiscent of typical neutrophilic dermatoses. Dapsone has an established therapeutic role in current treatment of other neutrophilic dermatoses. CONCLUSION: Thus, dapsone has potential to both improve the quality of life in erlotinib treated patients by amelioration of rash as well as to short-circuit a growth-enhancing aspect of erlotinib when used in the anti-cancer role.

Ribavirin in cancer immunotherapies: controlling nitric oxide helps generate cytotoxic lymphocyte.

Either ribavirin, RBV, or cyclophosphamide, CY, can shift an immune response from Th2 towards a Th1 cytokine profile. CY is used in this role in various current cancer immunotherapy attempts but with mixed success. More potent and reliable immunoadjuvants and Th 1 response biasing methods are needed. RBV is used today mainly to augment interferon-alpha treatment of hepatitis C. RBV shifts an immune response from Th2 towards Th1 more effectively than CY and may be a safe and useful adjuvant for current cancer immunotherapeutic efforts. RBV is thought to act by inhibition of tetrahydrobiopterin synthesis. Tetrahydrobiopterin is an essential co-factor for all known isoforms of nitric oxide synthase. Lowered nitric oxide favors Th1 development as high levels favor Th2 weighting.

Borage oil reduction of rheumatoid arthritis activity may be mediated by increased cAMP that suppresses tumor necrosis factor-alpha.

Recent double blind studies have shown some benefit of borage oil in treatment of rheumatoid arthritis. Tumor necrosis factor-alpha has been shown to be a central mediator of inflammatory and joint destructive processes in rheumatoid arthritis. In this paper, evidence from published research is reviewed that indicates gamma linolenic acid component of borage oil increases prostaglandin E levels that increase cAMP levels that in turn suppress tumor necrosis factor-alpha synthesis. If this biochemical path of borage oil is correct then (1) concomitant non-steroidal anti-inflammatory drug use would tend to undermine borage oil effects, and (2) borage oil would be contraindicated in pregnancy given the teratogenic and labor inducing effects of prostaglandin E agonists.