ABSTRACT
Eisai Co Ltd is developing eribulin, a simplified synthetic macrocyclic ketone analog of the tubulin inhibitor halichondrin B, for the potential treatment of cancer. Phase III trials are underway in the US and Europe for patients with breast cancer. Eribulin is currently in phase II trials for NSCLC and soft tissue sarcoma, and pancreatic, prostate, ovarian, fallopian tube, peritoneal and head and neck cancer, and phase I/II trials for urothelial cancers.
Subject(s)
Antineoplastic Agents , Ethers, Cyclic/antagonists & inhibitors , Furans/therapeutic use , Ketones/chemistry , Neoplasms/drug therapy , Tubulin Modulators/antagonists & inhibitors , Alopecia/chemically induced , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Line , Cell Line, Tumor , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Clinical Trials, Phase III as Topic , Drug Evaluation, Preclinical , Fatigue/chemically induced , Furans/chemistry , Humans , Hypoglycemia/chemically induced , Hypophosphatemia/chemically induced , Inhibitory Concentration 50 , Ketones/therapeutic use , Macrolides , Molecular Structure , Multicenter Studies as Topic , Nausea/chemically induced , Neoplasms/classification , Neutropenia/chemically induced , Peripheral Nervous System Diseases/chemically induced , Randomized Controlled Trials as Topic , Survival Analysis , Tubulin Modulators/adverse effects , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/metabolism , Tubulin Modulators/pharmacokinetics , Xenograft Model Antitumor AssaysABSTRACT
The effects of the non-phorbol ester type tumor promoter okadaic acid, a serine-threonine phosphatase inhibitor, on activator protein 1 (AP-1) DNA binding activity were studied in papilloma producing 308 mouse keratinocytes. Okadaic acid increased AP-1 binding to a consensus TPA responsive element (TRE) within 2 h; maximum stimulation was observed at 6 h followed by a gradual decrease to basal levels within 24 h. Jun B, Jun D and Fos B proteins were identified as the major components of the AP-1 complex binding to the TRE element at 6 h. Inhibition of transcription with actinomycin D and inhibition of protein synthesis with cycloheximide abrogated the okadaic acid effect on AP-1 DNA binding, indicating that transcription and translation are required for okadaic acid increased TRE binding activity. Northern and Western blot analyses revealed a correlation between increased AP-1 binding activity and accumulation of jun B, jun D and fos B mRNAs and proteins. These data suggest increased AP-1 expression as principal mechanism of okadaic acid stimulated AP-1 activation in the mouse keratinocytes studied.
Subject(s)
Carcinogens/pharmacology , DNA-Binding Proteins/metabolism , DNA/metabolism , Ethers, Cyclic/pharmacology , Nuclear Proteins/metabolism , RNA, Messenger/metabolism , Trans-Activators/metabolism , Transcription Factor AP-1/metabolism , Transcription Factors , Animals , Blotting, Northern , Blotting, Western , Carcinogens/antagonists & inhibitors , Cycloheximide/pharmacology , Dactinomycin/pharmacology , Dimethyl Sulfoxide/pharmacology , Ethers, Cyclic/antagonists & inhibitors , Keratinocytes , Mice , Okadaic Acid , Protein Biosynthesis/drug effects , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/metabolism , Regulatory Factor X Transcription Factors , Transcription, Genetic/drug effects , Tumor Cells, CulturedABSTRACT
Effects of okadai acid (OA) on contractile force in rat uterine uterine muscles permeabilized with alpha-toxin were examined. (1) Contractile force activated by Ca2+(10(-6.5) M to 10(-4.4) M) was suppressed by relatively low concentrations of OA (30 to 300 nM). The suppressed force was further decreased after washed out of OA. (2)Addition of 10 microM OA enhanced force. Whereas, the increased tension level fell to less than the control level after washed out of OA. (3)Okadaic acid methyl ester (methyl okadaate), an OA derivative without protein phosphatase inhibition, did not affect contraction. These results suggest that the force-inhibiting effect of OA is a result of interference with contractile elements through inhibition of protein phosphatases (PPs) activity.
Subject(s)
Enzyme Inhibitors/pharmacology , Ethers, Cyclic/pharmacology , Muscle, Smooth/drug effects , Phosphoprotein Phosphatases/antagonists & inhibitors , Type C Phospholipases/pharmacology , Uterus/drug effects , Animals , Calcium/pharmacology , Ethers, Cyclic/antagonists & inhibitors , Female , In Vitro Techniques , Muscle, Smooth/enzymology , Okadaic Acid , Rats , Rats, Wistar , Uterine Contraction/drug effects , Uterus/enzymologyABSTRACT
In isolated rat hepatocytes, the protein phosphatase inhibitor okadaic acid exerts a strong inhibitory effect on autophagy, which can be partially overcome by certain protein kinase inhibitors like the isoflavone genistein. To see if other, more specific okadaic acid antagonists could be found among the flavonoids, 55 different flavonoids were tested for their effect on okadaic acid-inhibited autophagy, measured as the sequestration of electroinjected [3H]raffinose. Naringin (naringenin 7-hesperidoside) and several other flavanone and flavone glycosides (prunin, neoeriocitrin, neohesperidin, apiin, rhoifolin, kaempferol 3-rutinoside) offered virtually complete protection against the autophagy-inhibitory effect of okadaic acid. Unlike genistein, these compounds had little or no autophagy-inhibitory effect of their own. Their innocuousness appeared to be related to glycosylation, because the corresponding aglycones (naringenin, eriodictyol, hesperetin, apigenin, kaempferol) were all inhibitory, in particular apigenin (80% inhibition at 100 microM). Naringin, the most potent okadaic acid-antagonistic flavonoid, gave half-maximal protection at 5 microM and maximal effect at 100 microM. Naringin also prevented the okadaic acid-induced inhibition of endogenous, autophagic lysosomal protein degradation and of receptor-mediated asialoglycoprotein uptake and degradation. Naringin and other okadaic acid-antagonistic flavonoids may be useful tools in the study of intracellular protein phosphorylation and could have potential therapeutic value as protectants against pathological hyperphosphorylations, environmental toxins, or side effects of chemotherapeutic drugs.
Subject(s)
Antioxidants/pharmacology , Autophagy/drug effects , Endocytosis/drug effects , Ethers, Cyclic/pharmacology , Flavanones , Flavonoids/pharmacology , Liver/cytology , Liver/physiology , Phosphoprotein Phosphatases/antagonists & inhibitors , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine , Animals , Cells, Cultured , Dose-Response Relationship, Drug , Ethers, Cyclic/antagonists & inhibitors , Genistein , Isoflavones/pharmacology , Isoquinolines/pharmacology , Kinetics , Liver/drug effects , Male , Okadaic Acid , Piperazines/pharmacology , Protein Kinase Inhibitors , Rats , Rats, WistarABSTRACT
The involvement of serine/threonine protein-phosphatases in the production of superoxide (respiratory burst) by human neutrophils was investigated using calyculin A, a potent inhibitor of both protein phosphatases type 1 and 2A, and okadaic acid, which preferentially inhibits protein phosphatase type 2A. Treatment of neutrophils with calyculin A (25-75 nM) or okadaic acid (1-4 microM) had no stimulatory effect but potently enhanced total superoxide production induced by an optimal fMLP (N-formyl-methionyl-leucyl-phenylalanine) concentration (0.1 microM). The maximum increase plateaued with 50-75 nM calyculin A and 2-4 microM okadaic acid, reaching approximately 120 and 200% of control values, respectively. Unlike calyculin A, okadaic acid also primed the initial rate of superoxide production, suggesting that protein phosphatases may down-regulate both initiation and termination of respiratory burst. Optimal stimulation of the respiratory burst by PMA (160 nM) was inhibited by calyculin A and okadaic acid, with an IC50 of 60 nM and 2 microM, respectively, although both drugs caused protein hyperphosphorylation. The inhibition was partially prevented by a nonstimulatory concentration of A23187, indicating a role of calcium in the inhibitory effects of the drugs. Unlike the optimal respiratory burst, suboptimal respiratory burst induced by PMA (1-7 nM) was enhanced by calyculin A and okadaic acid. Unprimed and primed respiratory bursts were depressed by a selective antagonist of protein kinase C (GF 109203X), indicating positive regulation of these responses by protein kinase C. Thus, the use of calyculin A and okadaic acid distinguishes two regulatory processes of superoxide production.(ABSTRACT TRUNCATED AT 250 WORDS)
Subject(s)
Ethers, Cyclic/pharmacology , Neutrophils/metabolism , Oxazoles/pharmacology , Phosphoprotein Phosphatases/antagonists & inhibitors , Respiratory Burst/drug effects , Amino Acid Sequence , Calcimycin/pharmacology , Ethers, Cyclic/antagonists & inhibitors , Humans , In Vitro Techniques , Marine Toxins , Molecular Sequence Data , N-Formylmethionine Leucyl-Phenylalanine/pharmacology , Neutrophils/drug effects , Okadaic Acid , Oxazoles/antagonists & inhibitors , Phosphorylation , Protein Kinase C/metabolism , Superoxides/metabolism , Tetradecanoylphorbol Acetate/pharmacologySubject(s)
Alkaloids/pharmacology , Caffeine/antagonists & inhibitors , Chromosomes/drug effects , Ethers, Cyclic/antagonists & inhibitors , Protein Kinase Inhibitors , Animals , Caffeine/pharmacology , Cells, Cultured , Cricetinae , Drug Interactions , Enzyme Activation , Ethers, Cyclic/pharmacology , Mitosis , Okadaic Acid , Protamine Kinase/metabolism , StaurosporineSubject(s)
Antibodies, Monoclonal/pharmacology , Ethers, Cyclic/antagonists & inhibitors , Starfish/embryology , Animals , Antibodies, Monoclonal/immunology , Antibody Specificity , Antigen-Antibody Reactions , Embryo, Mammalian/cytology , Embryo, Mammalian/drug effects , Embryo, Nonmammalian , Ethers, Cyclic/immunology , Ethers, Cyclic/pharmacology , Immunoglobulin G/pharmacology , Immunoglobulin kappa-Chains/pharmacology , Mice , Okadaic Acid , Starfish/drug effectsABSTRACT
This review article deals with significant effects of marine natural products in carcinogenesis, namely as chemical probes to understand the process of carcinogenesis and as possible cancer preventive agents in humans.
Subject(s)
Amphibian Proteins , Anticarcinogenic Agents/therapeutic use , Antimicrobial Cationic Peptides , Antineoplastic Agents/therapeutic use , Carcinogens/toxicity , Ethers, Cyclic/toxicity , Neoplasms, Experimental/prevention & control , Animals , Diterpenes/therapeutic use , Ethers, Cyclic/antagonists & inhibitors , Neoplasms, Experimental/chemically induced , Okadaic Acid , Peptides/therapeutic useABSTRACT
Okadaic acid, which is a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type tumor promoter and an inhibitor of protein phosphatases 1 and 2A, induced angiogenesis in the chorioallantoic membrane of the chick embryo. Its potent angiogenic activity was dose-dependent. The minimum effective dose was 5 fmol/egg and the effective dose for 50% induction was 90 fmol/egg. These results indicated that okadaic acid exhibits angiogenic activity one order of magnitude stronger than that of TPA (reported previously). Moreover, the time-course of angiogenesis induction by okadaic acid was much slower than that by TPA. The difference is consistent with the time-courses of other biochemical and biological activities and also various gene expressions induced by okadaic acid and TPA, indicating that the difference in the time-course is associated with their mechanisms of action. We conclude that okadaic acid induces angiogenesis through a different pathway than does TPA, indicating the existence of a new mechanism of angiogenesis induction.
