mobic and Neoplasms

The oxidative pentose phosphate pathway (PPP) contributes to tumour growth, but the precise contribution of 6-phosphogluconate dehydrogenase (6PGD), the third enzyme in this pathway, to tumorigenesis remains unclear. We found that suppression of 6PGD decreased lipogenesis and RNA biosynthesis and elevated ROS levels in cancer cells, attenuating cell proliferation and tumour growth. 6PGD-mediated production of ribulose-5-phosphate (Ru-5-P) inhibits AMPK activation by disrupting the active LKB1 complex, thereby activating acetyl-CoA carboxylase 1 and lipogenesis. Ru-5-P and NADPH are thought to be precursors in RNA biosynthesis and lipogenesis, respectively; thus, our findings provide an additional link between the oxidative PPP and lipogenesis through Ru-5-P-dependent inhibition of LKB1-AMPK signalling. Moreover, we identified and developed 6PGD inhibitors, physcion and its derivative S3, that effectively inhibited 6PGD, cancer cell proliferation and tumour growth in nude mice xenografts without obvious toxicity, suggesting that 6PGD could be an anticancer target.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Humans; Lipogenesis; Neoplasms; Oxidative Stress; Pentose Phosphate Pathway; Phosphogluconate Dehydrogenase; Protein Serine-Threonine Kinases; Ribulosephosphates; Signal Transduction

Among the most widely prescribed drugs worldwide, non-steroidal anti-inflammatory drugs (NSAIDs) are effective for relieving pain, but they are also associated with a high incidence of gastrointestinal (GI) adverse events. Both the beneficial and harmful effects of NSAIDs result from inhibition of the cyclo-oxygenase (COX) enzyme. Recognition of the two distinct COX isoforms prompted development of drugs that selectively block the activity of COX-2, thus providing pain relief and reducing inflammation while sparing COX-1, the enzyme apparently responsible for most protective prostaglandin synthesis in the mucosa of the stomach and duodenum. The results of preclinical and clinical studies indicate that COX-2 inhibitors exhibit high selectivity in inhibiting COX-2, provide excellent pain relief, and cause significantly less GI toxicity than do conventional nonselective NSAIDs. Although they represent a significant advance over nonselective NSAIDs, selective COX-2 inhibitors are not without limitations. They do not completely eliminate GI toxicity or the renal side effects associated with use of conventional NSAIDs. Moreover, in cases of inflammation or ulceration in the GI tract, COX-2 inhibition may delay ulcer healing. Finally, case reports and the results of animal experiments suggest that COX-2 inhibitors may adversely affect ovulation and cause a tendency towards prothrombotic events.

Topics: Alzheimer Disease; Anti-Inflammatory Agents, Non-Steroidal; Celecoxib; Cyclooxygenase Inhibitors; Humans; Lactones; Meloxicam; Neoplasms; Pyrazoles; Sulfonamides; Sulfones; Thiazines; Thiazoles

Non-steroidal anti-inflammatory drugs (NSAIDs) are infrequently utilized in cats due to concern for renal compromise; however, recent studies demonstrate tolerability of low dose meloxicam. Toceranib phosphate is used to treat several feline cancers and is well tolerated. This study aimed to determine the tolerability and adverse event profile of combined toceranib and low dose meloxicam in cancer-bearing cats. Secondary goals involved assessing anticancer tumor efficacy and impact upon quality of life and analgesia.. Cats with any cancer not involving the kidneys were eligible. The study adopted a conventional 3 + 3 dose escalation design. Toceranib was administered every other day at a standard dose with meloxicam administered in an escalating fashion in subsequent cohorts, at a starting dose of 0.01 mg/kg on opposite days to toceranib, up to a maximum of 0.02 mg/kg daily, based upon previous safety studies. Laboratory work, blood pressure, tumor measurements, pain score and client-completed quality-of-life surveys were recorded every 2-4 weeks during the 12-week study period.. Twenty-one cats were enrolled. When combined with toceranib, a meloxicam dose of 0.02 mg/kg q24h was safe and well tolerated, with no cats being withdrawn due to adverse events from the drug combination. The majority of cats demonstrated clinical benefit with stable to mildly improved tumor measurements, quality of life and pain scores.. Low dose meloxicam combined with toceranib is safe and well tolerated in cancer-bearing cats. Continued patient recruitment and data collection are needed to determine the maximum tolerated dose of meloxicam. The results of our study will guide further phase II/III trials.

Topics: Animals; Cat Diseases; Cats; Meloxicam; Neoplasms; Pain; Quality of Life

The objective of this work was to study the effect of the combined action of X-radiation and the cyclooxygenase-2 (COX-2) inhibitor on the level of vascular endothelial growth factor (VEGF) and prostaglandin E2 (PGE-2) in blood serum of rat-tumor carriers at irradiation in different doses.. 20 tumor-bearing rats of the Wistar population weighing 160-180 g, with transplanted Guerin carcinoma, fractionated irradiation (5 Gy + 5 Gy) and (0.5 Gy + 0.5 Gy) of the tumor growth zone on the RUM- 17 was carried out, with an interval between sessions of 24 hours. The drug «Meloxivet» - a selective inhibitor of cyclooxygenase-2 was administered 24 hours before irradiation and 2 hours before the second exposure (0.2 mg per 1 kg body weight). Blood sampling was performed by the method of life-time decapitation after 24 hours after the last fraction of irradiation. The content of VEGF in blood serum was determined by the method of enzyme immunoas- say using standardResults. After fractionated irradiation in a total dose of 1 Gy (0.5 Gy + 0.5 Gy), the level of VEGF was increased by 1.5 times compared with intact control, and in animals that were irradiated in a total dose of 10 Gy (5 Gy + 5 Gy ), the VEGF level was reduced by 1.92 times. That is, there was a difference in the content of VEGF in blood serum of rat tumor carriers, depending on the dose of irradiation: in a total dose of 1 Gy - stimulation of angiogenesis, and in the total dose of 10 Gy - a significant slowdown in this process. In the case of combined exposure to radiation (10 Gy) and the COX-2 inhibitor, meloxivet, the potential decrease in VEGF levels was 3.49 times compared to con- trol and 1.8 times with isolated exposure. At the same time, the level of PGE-2 also decreased with respect to iso- lated exposure by 1.5 times, indicating COX-2 inhibition. With a combined low dose (1 Gy) irradiation and COX-2- meloxivet inhibitor, VEGF levels were reduced by 1.1 times compared to control and 1.7 times relative to isolated exposure. At the same time, the level of PGE-2 also decreased in comparison with isolated radiation in 1,1 times. The obtained results indicate the influence of the combined act of irradiation and meloxivet on the level of VEGF and PGE-2, which causes the antiangiogenic effect.Сonclusions. It has been shown that low doses of ionizing radiation (1 Gy) and high doses (10 Gy) have a different effect on VEGF expression, and thus on angiogenesis processes. The combined effect of ionizing radiation and the COX-2 inhibitor (meloxivet) affects the level of PGE-2, VEGF, ie, the slowing of angiogenesis. In the case of large doses of exposure, this effect is even more expressed.. Meta: vyvchennia vplyvu kombinovanoï diï Kh-vyprominennia ta ingibitora tsyklooksygenazy-2 (TsOG-2) na riven' faktora rostu endoteliiu sudyn (VEGF) i prostaglandynu E-2 (PGE-2)-2 v syrovattsi krovi shchuriv z perevytoiu pukh- lynoiu Gerena pry oprominenni v riznykh dozakh.Materialy i metody. 20 shchuram-samytsiam populiatsiï Vistar masoiu 160–180 g z pereshcheplenoiu kartsynomoiu Gere- na provodyly fraktsionovane oprominennia (5 Gr + 5 Gr) ta (0,5 Gr + 0,5 Gr) zony rostu pukhlyny na aparati RUM-17 z intervalom mizh seansamy 24 god. Preparat «Meloksyvet» – selektyvnyy̆ ingibitor TsOG-2 vvodyly za dobu do oprominennia ta za 2 godyny pered drugym oprominenniam (0,2 mg na 1kg masy tila). Zabir krovi provodyly meto- dom pryzhyttievoï dekapitatsiï cherez 24 god pislia ostann'oï fraktsiï oprominennia. Vmist VEGF ta PGE-2 v syrovattsi krovi vyznachaly metodom imunofermentnogo analizu z vykorystanniam standartnykh naboriv.Rezul'taty. Pislia fraktsionovanogo oprominennia u sumarniy̆ dozi 1 Gr (0,5 Gr + 0,5 Gr) riven' VEGF pidvyshchuvav- sia u 1,5 raza porivniano z intaktnym kontrolem, a u tvaryn, oprominenykh u sumarniy̆ dozi 10 Gr (5 Gr + 5 Gr), riven' VEGF virogidno znyzhuvavsia u 1,92 raza. Tobto, sposterigaly riznytsiu vmistu VEGF v syrovattsi krovi shchuriv-pukhly- nonosiïv zalezhno vid doz oprominennia: pislia oprominennia sumarniy̆ dozi 1 Gr – stymuliatsiia angiogenezu, 10 Gr – znachne upovil'nennia ts'ogo protsesu. U razi poiednanoï diï oprominennia (10 Gr) ta ingibitora TsOG-2 – meloksyve- tu vidmichaly virogidne znyzhennia rivnia VEGF u 3,49 raza porivniano z kontrolem ta u 1,8 raza z izol'ovanym op- rominenniam. Pry ts'omu riven' PGE-2 takozh znyzhuvavsia vidnosno izol'ovanogo oprominennia u 1,5 raza, shcho vka- zuie na ingibuvannia TsOG-2. Pry poiednaniy̆ diï oprominennia v nyz'kykh dozakh (1 Gr) ta ingibitora TsOG-2 – meloksy- vetu sposterigaly znyzhennia rivnia VEGF u 1,1 raza porivniano z kontrolem ta u 1,7 raza vidnosno izol'ovanogo op- rominennia. Pry ts'omu riven' PGE-2 takozh znyzhuvavsia porivniano z izol'ovanym oprominenniam u 1,1 raza. Otry- mani rezul'taty svidchat' pro vplyv poiednanoï diï oprominennia i meloksyvetu na riven' VEGF ta PGE -2, shcho zumov- liuie antyangiogennyy̆ efekt.Vysnovky. Dovedeno, shcho nyz'ki dozy ionizuiuchoï radiatsiï (1 Gr) ta vysoki dozy (10 Gr) po-riznomu vplyvaiut' na ekspresiiu VEGF, i tym samym na protsesy angiogenezu. Poiednana diia ionizuiuchoï radiatsiï ta ingibitora TsOG-2 (me- loksyvetu) vplyvaie na znyzhe

Topics: Animals; Combined Modality Therapy; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dinoprostone; Female; Meloxicam; Neoplasms; Rats; Rats, Wistar; Vascular Endothelial Growth Factor A; X-Ray Therapy

Doxorubicin-induced renal toxicity overshadows its anticancer effectiveness. This study is aimed at assessing the possible modulator effects of meloxicam, a cyclooxigenase-2 inhibitor, on doxorubicin-induced nephrotoxicity in mice and exploring some of the modulator mechanisms. Forty male mice were divided for treatment, for 2 weeks, with saline, meloxicam (daily), doxorubicin (twice/week), or both meloxicam and doxorubicin. Doxorubicin induced a significant increase in relative kidney weight to body weight, kidney lipid perooxidation, plasma levels of interleukin-6 and tumor necrosis factor-α, kidney caspase-3 activity, and kidney prostaglandin E2 (PGE2) content. Doxorubicin disturbed kidney histology, abrogated renal function tests (serum creatinine, uric acid, and blood urea nitrogen), induced a significant decrease in antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and catalase) and reduced glutathione (GSH) content. The administration of meloxicam with doxorubicin mitigated all doxorubicin-disturbed parameters. Meloxicam ameliorated doxorubicin-induced renal injury via inhibition of inflammatory PGE2, inflammatory cytokines, caspase-3 activity, antioxidant effect, and free radical scavenging activity.

Topics: Animals; Caspase 3; Dinoprostone; Doxorubicin; Humans; Interleukin-6; Lipid Peroxidation; Male; Meloxicam; Mice; Neoplasms; Oxidative Stress; Renal Insufficiency; Thiazines; Thiazoles; Tumor Necrosis Factor-alpha

The reaction of aqueous cis-[Pt(NH(3))(2)(H(2)O)(2)](NO(3))(2) with Na(+)HMEL(-) (H(2)MEL, meloxicam, 4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide), and Na(+)HISO(-) (H(2)ISO, isoxicam, 4-hydroxy-2-methyl-N-(5-methylisoxazol-3-yl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide) at pH 7 produced micro-crystalline cis-[Pt(NH(3))(2)(N(1')-HMEL)(2)], 5 and cis-[Pt(NH(3))(2)(N(1')-HISO)(2)], 6. The X-ray diffraction structure of 5 shows two HMEL(-) anions donating through the thiazole nitrogen atoms and adopting a head-to-tail (HT) conformation. The (1)H NMR spectrum for 5 from DMSO-d(6) shows inertness of the complex up to at least 24h. Delivery studies for 5 and 6 from vinyl hydrogel based on L-phenylalanine (pH 6.5, 25 degrees C) show that concentrations of complexes ranging between 2.5 and 5 microM can be reached after a day. Compounds 5 and 6 show strong anti-proliferative effects on CH1 cells (ovarian carcinoma, human) in vitro, IC(50) values being 0.60 and 0.37 microM, respectively (0.16 microM for reference, cis-diamminodichloridoplatinum(II), cisplatin). ESI-MS measurements clearly documented that both 5 and 6 form adducts with the three model proteins ubiquitin (UBI), cytochrome c (CYT C) and superoxide dismutase (SOD), the HISO(-) complex being significantly more effective than the HMEL(-) one. Density functional methods help in finding rationale for the easiest dissociation of Pt-H(2)ISO/HISO bonds when compared to the Pt-N(1)(')-H(2)MEL/N(1)(')-HMEL linkages.

Topics: Antineoplastic Agents; Cell Proliferation; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Hydrogels; Meloxicam; Neoplasm Proteins; Neoplasms; Platinum; Thiazines; Thiazoles

Patients with a malignant glioma have a very poor prognosis. Cyclooxygenase-2 (COX-2) protein is regularly upregulated in gliomas and might be a potential therapeutic target. The effects of three selective COX-2 inhibitors were studied on three human glioma cell lines.. The selective COX-2 inhibitors NS-398, Celecoxib and Meloxicam and three human glioma cell lines (D384, U251 and U87) were used. Cell growth was assessed by a proliferation assay, the interaction with radiation (0 - 6 Gy) was studied using the clonogenic assay and cell cycle distribution was determined by FACS (fluorescence-activated cell sorting) analysis.. All COX-2 inhibitors reduced proliferation of the glioma cell lines irrespective of their COX-2 expression level. Incubation with 200 microM NS-398 24 h before radiation enhanced radiation-induced cell death of D384 cells and 750 microM Meloxicam resulted in radiosensitization of D384 and U87 cells. No radiosensitization was observed with COX-2 inhibitor administration after radiotherapy. Treatment of D384 with NS-398 (200 microM) or Celecoxib (50 microM) and U87 with NS-398 (200 microM) after radiation resulted even in radioprotection.. Effectiveness of COX-2 inhibitors on cell proliferation and radio-enhancement was independent of COX-2 protein expression. The sequence of COX-2 inhibitor addition and irradiation is very important.

Topics: Celecoxib; Cell Line, Tumor; Cell Proliferation; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Radiation; Flow Cytometry; Gene Expression Regulation, Neoplastic; Glioma; Humans; Meloxicam; Neoplasms; Nitrobenzenes; Pyrazoles; Radiation-Protective Agents; Sulfonamides; Thiazines; Thiazoles