Suppression of Kynurenine 3-Monooxygenase as a Treatment for Triple-negative Breast Carcinoma.

Kynurenine 3-monooxygenase (KMO), a key enzyme within the kynurenine (KYN) pathway of tryptophan (TRY) metabolism, enables the excess production of toxic metabolites (such as 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid), and modulates the balance between these toxic molecules and the protective metabolite, kynurenic acid (KYNA). Despite its importance, KMO suppression as a treatment for cancer has not been fully explored. Instead, researchers have focused on prevention of KYN pathway activity by inhibition of enzymes indoleamine 2,3-dioxygenase (IDO1 and IDO2) or tryptophan 2,3-dioxygenase (TDO, also known as TDO2). However, studies using IDO/TDO inhibitors against cancer have not yet shown that this type of treatment can be successful. We argue that KMO suppression can be an effective strategy for treatment of cancer by 1) decreasing toxic metabolites within the KYN pathway and 2) increasing levels of KYNA, which has important protective and anticancer properties. This strategy may be beneficial in the treatment of aggressive breast cancer, particularly in patients with triple-negative breast cancer. A major challenge to this strategy, when searching for an effective treatment for tumors, especially tumors like breast carcinoma that often metastasize to the brain, is finding KMO inhibitors that adequately cross the blood-brain barrier.

The complex lipid, SPPCT-800, reduces lung damage, improves pulmonary function and decreases pro-inflammatory cytokines in the murine LPS-induced acute respiratory distress syndrome (ARDS) model.

CONTEXT: Acute respiratory distress syndrome (ARDS) is a highly fatal, inflammatory condition of lungs with multiple causes. There is no adequate treatment. OBJECTIVE: Using the murine LPS-induced ARDS model, we investigate SPPCT-800 (a complex lipid) as treatment for ARDS. MATERIALS AND METHODS: C57B16/N mice received 50 µg of Escherichia coli O111:B4 lipopolysaccharide (LPS). SPPCT-800 was given as either: (1) 20 or 200 mg/kg dose 3 h after LPS; (2) 200 mg/kg (prophylactically) 30 min before LPS; or (3) eight 200 mg/kg treatments over 72 h. Controls received saline installations. RESULTS: At 48 and 72 h, SpO2 was 94% and 90% in controls compared to 97% and 94% in treated animals. Expiration times, at 24 and 48 h, were 160 and 137 msec for controls, but 139 and 107 msec with SPPCT-800. In BALF (24 h), cell counts were 4.7 × 106 (controls) and 2.9 × 106 (treated); protein levels were 1.5 mg (controls) and 0.4 mg (treated); and IL-6 was 942 ± 194 pg/mL (controls) versus 850 ± 212 pg/mL (treated) [at 72 h, 4664 ± 2591 pg/mL (controls) versus 276 ± 151 pg/mL (treated)]. Weight losses, at 48 and 72 h, were 20% and 18% (controls), but 14% and 8% (treated). Lung injury scores, at 24 and 72 h, were 1.4 and 3.0 (controls) and 0.3 and 2.2 (treated). DISCUSSION AND CONCLUSIONS: SPPCT-800 was effective in reducing manifestations of ARDS. SPPCT-800 should be further investigated as therapy for ARDS, especially in longer duration or higher cumulative dose studies.

The Mystery of Chemotherapy Brain: Kynurenines, Tubulin and Biophoton Release.

The majority of patients receiving chemotherapy experience post-chemotherapy cognitive impairment, sometimes referred to as "chemo brain" or "chemo fog." The cognitive impairment associated with this syndrome can be severe, and can sometimes last for many years after therapy discontinuation. Despite extensive investigations, its etiology is unknown. We argue that chemo brain results from damage to tubulin within microtubules. This damage can occur directly from tubulin inhibitors such as taxanes, epothilones or vinca alkaloids. Other chemotherapies stimulate increased mitochondrial activity and biophoton release. This results in abnormal tryptophan metabolism and excess production of neurotoxic kynurenines, which, in turn, damage microtubules.

Pharmacokinetics of liposomal curcumin (Lipocurc™) infusion: effect of co-medication in cancer patients and comparison with healthy individuals.

PURPOSE: Investigation of the impact of co-medication on the plasma levels of curcumin and tetrahydrocurcumin (THC) in cancer patients and a comparison of the pharmacokinetics of curcumin and plasma levels of THC between cancer patients and healthy individuals following intravenous infusion of Lipocurc™ (liposomal curcumin). METHODS: Correlation analysis was used to determine the impact of co-medication on infusion rate normalized plasma levels of curcumin and THC in cancer patients and to compare the plasma levels of curcumin and THC at different infusion rates between cancer patients and healthy individuals. In vitro hepatocyte and red blood cell distribution experiments were conducted with Lipocurc™ to support clinical findings. Plasma concentration time data were analyzed by the non-compartmental method to determine and compare the pharmacokinetic parameters of curcumin in cancer patients and healthy individuals. RESULTS: Of 44 co-medications studied, three medications targeting the renin-angiotensin system, Lisinopril, Ramipril, and Valsartan elevated plasma levels of curcumin and THC in three cancer patients infused with Lipocurc™. Cell distribution experiments indicated that the disposition of curcumin in red blood cells may be a target for elevation of the plasma levels of curcumin. Plasma levels of curcumin in cancer patients increased to a greater extent with increased infusion rate compared to healthy individuals. Upon termination of infusion, the elimination phase for curcumin was shorter with a shorter terminal half-life and smaller volume of distribution for curcumin in cancer patients compared to healthy individuals. CONCLUSION: Either co-medications or health status, or both, can impact the pharmacokinetics of curcumin infusion (as Lipocurc™) in cancer patients.

A phase 1 dose-escalation study on the safety, tolerability and activity of liposomal curcumin (Lipocurc™) in patients with locally advanced or metastatic cancer.

PURPOSE: This study was conducted to investigate the safety and tolerability of increasing doses of liposomal curcumin in patients with metastatic cancer. Investigations of anti-tumor activity and of the pharmacokinetics of curcumin were secondary objectives. METHODS: In this phase I, single-center, open-label study in patients with metastatic tumors, liposomal curcumin was administered as a weekly intravenous infusion for 8 weeks. Dose escalation was started at 100 mg/m2 over 8 h and the dose increased to 300 mg/m2 over 6 h. RESULTS: 32 patients were treated. No dose-limiting toxicity was observed in 26 patients at doses between 100 and 300 mg/m2 over 8 h. Of six patients receiving 300 mg/m2 over 6 h, one patient developed hemolysis, and three other patients experienced hemoglobin decreases > 2 g/dL without signs of hemolysis. Pharmacokinetic analyses revealed stable curcumin plasma concentrations during infusion followed by rapid declines to undetectable levels after the infusion. Anti-tumor activity by RECIST V1.1 was not detected. Significant tumor marker responses and transient clinical benefit were observed in two patients. CONCLUSION: 300 mg/m2 liposomal curcumin over 6 h was the maximum tolerated dose in these heavily pretreated patients, and is the recommended starting dose for anti-cancer trials.

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. IDO and TDO also act as checkpoint molecules that suppress T-cell function. GBM is particularly associated with severe immunosuppression, and this tumor type might be thought to be the ideal candidate for checkpoint inhibitor therapy. However, treatment with checkpoint inhibitors now in clinical use for peripheral solid tumors, such as those inhibiting cytotoxic T-lymphocyte-associated protein-4 (CTLA4) or programmed cell death-1 (PD1) receptors, results in further abnormalities of tryptophan metabolism. This implies that to obtain optimal results in the treatment of GBM, one may need to add an inhibitor of the kynurenine pathway to therapy with a CTLA4 or PD1 inhibitor, or use agents which can suppress multiple checkpoint molecules.

Short wavelength infrared optical windows for evaluation of benign and malignant tissues.

There are three short wavelength infrared (SWIR) optical windows outside the conventionally used first near-infrared (NIR) window (650 to 950 nm). They occur in the 1000- to 2500-nm range and may be considered second, third, and fourth NIR windows. The second (1100 to 1350 nm) and third windows (1600 to 1870 nm) are now being explored through label-free linear and multiphoton imaging. The fourth window (2100 to 2350 nm) has been mostly ignored because of water absorption and the absence of sensitive detectors and ultrafast lasers. With the advent of new technology, use of window IV is now possible. Absorption and scattering properties of light through breast and prostate cancer, bone, lipids, and intralipid solutions at these windows were investigated. We found that breast and prostate cancer and bone have longer total attenuation lengths at NIR windows III and IV, whereas fatty tissues and intralipid have longest lengths at windows II and III. Since collagen is the major chromophore at 2100 and 2350 nm, window IV could be especially valuable in evaluating cancers and boney tissues, whereas windows II and III may be more useful for tissues with high lipid content. SWIR windows may be utilized as additional optical tools for the evaluation of collagen in tissues.

Vulnerable atherosclerotic plaque detection by resonance Raman spectroscopy.

A clear correlation has been observed between the resonance Raman (RR) spectra of plaques in the aortic tunica intimal wall of a human corpse and three states of plaque evolution: fibrolipid plaques, calcified and ossified plaques, and vulnerable atherosclerotic plaques (VPs). These three states of atherosclerotic plaque lesions demonstrated unique RR molecular fingerprints from key molecules, rendering their spectra unique with respect to one another. The vibrational modes of lipids, cholesterol, carotenoids, tryptophan and heme proteins, the amide I, II, III bands, and methyl/methylene groups from the intrinsic atherosclerotic VPs in tissues were studied. The salient outcome of the investigation was demonstrating the correlation between RR measurements of VPs and the thickness measurements of fibrous caps on VPs using standard histopathology methods, an important metric in evaluating the stability of a VP. The RR results show that VPs undergo a structural change when their caps thin to 66 ?? ? m , very close to the 65 - ? m empirical medical definition of a thin cap fibroatheroma plaque, the most unstable type of VP.

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)-1ß, 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. RESEARCH DESIGN: Narrative literature review. Outcome and conclusions: Strategies to control the levels of these pro-inflammatory cytokines and to reduce the cytokine-induced brain damage are discussed. There is extensive evidence from experiments in animal models that suppression of cytokines is effective in ameliorating neurologic damage after TBI. However, the efficacy of this approach remains to be proven in patient trials.

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. A shift in this balance toward S1P is seen in glioblastoma (GBM) and other cancers, and results in tumor cell survival and resistance to chemotherapy. Sphingosine kinase (SK), the enzyme responsible for transforming sphingosine into S1P, plays the critical role in modulating the balance between S1P and ceramides. Chemotherapeutic agents or radiation therapy may induce short-term responses in GBM patients by increasing ceramide levels. However, we believe that the enzyme SK may cause the increased ceramide to be metabolized to S1P, restoring the abnormally high S1P to ceramide balance, and that this may be part of the reason for the near-100% recurrence rate of GBM. The use of maintenance therapy with an SK inhibitor, in patients with GBM who have tumor reduction or stable disease after therapy, should be investigated.

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. The reported activity of curcumin against cancer stem cells, a major cause of glioblastoma resistance to therapy, and its ability to augment the apoptotic effects of ceramides, suggest it would have a synergistic effect with cytotoxic chemotherapy agents currently used in second-line therapy, such as lomustine.

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-1ß and 6. Studies in experimental models have shown that these cytokines act through stimulation of reactive oxygen species. Our review of data on phospholipidosis and on QT-shortening agents suggests a key role in QT prolongation for the ceramide/sphingosine-1-phosphate rheostat. We conclude that the cause of prolonged QT in inflammatory conditions is cytokine induction of reactive oxygen species and then ceramides, and believe that QT-prolonging agents bypass initial steps of this pathway and directly affect ceramides. Since both pro-inflammatory cytokines and numerous medications cause QT prolongation and ventricular arrhythmias by this mechanism, extra caution is needed when using these agents in patients with inflammatory conditions.

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). This may be due to curcumin's different effects on CSCs and 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. The suppression of cytokine release by curcumin correlates with clinical improvement in experimental models of disease conditions where a cytokine storm plays a significant role in mortality. CONCLUSION: The use of curcumin should be investigated in patients with Ebola and cytokine storm. Intravenous formulations may allow achievement of therapeutic blood levels of curcumin.

Differences in fluorescence profiles from breast cancer tissues due to changes in relative tryptophan content via energy transfer: tryptophan content correlates with histologic grade and tumor size but not with lymph node metastases.

The correlation between histologic grade, an increasingly important measure of prognosis for patients with breast cancer, and tryptophan levels from tissues of 15 breast carcinoma patients was investigated. Changes in the relative content of key native organic biomolecule tryptophan were seen from the fluorescence spectra of cancerous and paired normal tissues with excitation wavelengths of 280 and 300 nm. Due to a large spectral overlap and matching excitation­emission spectra, fluorescence resonance energy transfer from tryptophan-donor to reduced nicotinamide adenine dinucleotides-acceptor was noted. We used the ratios of fluorescence intensities at their spectral emission peaks, or spectral fingerprint peaks, at 340, 440, and 460 nm. Higher ratios correlated strongly with high histologic grade, while lower-grade tumors had low ratios. Large tumor size also correlated with high ratios, while the number of lymph node metastases, a major factor in staging, was not correlated with tryptophan levels. High histologic grade correlates strongly with increased content of tryptophan in breast cancer tissues and suggests that measurement of tryptophan content may be useful as a part of the evaluation of these patients.

Optical spectral fingerprints of tissues from patients with different breast cancer histologies using a novel fluorescence spectroscopic device.

The fluorescence of paired human breast malignant and normal tissue samples was investigated using a novel fluorescence spectroscopic (S3-LED) ratiometer unit with no moving parts. This device can measure the emission spectra of key native organic biomolecules such as tryptophan, tyrosine, collagen and elastin within tissues by using LED (light emitting diode) excitation sources coupled to an optical fiber. With this device, the spectral profiles of 11 paired breast cancerous and normal samples from 11 patients with breast carcinoma were obtained. In each of the 11 cases, marked increases in the tryptophan levels were found in the breast carcinoma samples when compared to the normal breast tissues. In the breast cancer samples, there were also consistently higher ratios of the 340 to 440 nm and the 340 to 460 nm intensity peaks after 280 nm excitation, likely representing an increased tryptophan to NADH ratio in the breast cancer samples. This difference was seen in the spectral profiles of the breast cancer patients regardless of whether they were HER2 positive or negative or hormone receptor positive or negative, and was found regardless of menopausal status, histology, stage, or tumor grade.

Splenic infarction in human babesiosis: two cases and discussion.

We describe 2 patients with Babesia infection who presented with fever and multiple splenic infarcts. There were no other conditions present that could potentially be causes of splenic infarction. Although retinal infarction has been described rarely in patients with babesiosis, splenic infarction has not been reported previously in association with this infection in humans.