Bryostatin
Encyclopedia
Bryostatins are a group of macrolide
lactone
s first isolated in the 1960s by George Pettit from extracts of a species of bryozoan, Bugula neritina. The structure of bryostatin 1 was determined in 1982. Until today 20 different bryostatins have been isolated. Bryostatins are a potent modulators of protein kinase C
. They are currently under investigation as anti-cancer
agents and as a memory enhancing agent.
(PKC). Short-term effects of bryostatin 1 include activation of classical or conventional PKCs and novel PKCs, whereas prolonged presence leads to lowered PKC activation. Bryostatin 1 effects on different isoforms of PKC vary. In in vitro tests bryostatin 1 was able to inhibit cell growth and angiogenesis
and to excite cell differentiation and apoptosis
. Bryostatin also shows immunomodulatry properties.
In in vitro
trials bryostatin 1 was able to induce apoptosis in HL-60 chronic lymphocytic leukaemia. It could be shown that bryostatin 1 acts synergistically
in combination with other anti-cancer drugs. Drug combination was effective against a large variety of tumor
cells including lung, prostate and non-Hodgkin's lymphoma tumor cells. Although animal studies were promising, bryostatin 1 as a single drug has failed to demonstrate significant activity in tumor patients in phase II trials in a wide range of tumor types, including melanoma
and colorectal cancer. Additionally severe side-effects, mainly myalgia
, were observed after bryostatin administration. As a consequence research focus has shifted to an investigation of combination therapy with other chemotherapeutic
antitumor agents such as gemcitabine, vincristine
, cisplatin
, and paclitaxel
.
Bryostatin 1 has appeared very promising in enhancing memory in animal models. It was able to increase the duration of memory retention of the marine slug Hermissenda crassicornis
by over 500 %. Additionally it also increased the rate of learning in rats. This makes it a possible drug candidate for the treatment of Alzheimer’s disease. Currently bryostatin 1 is in clinical trial phase II for the treatment against Alzheimer's disease.
The ability of bryostain 1 to alleviate brain damage in ischaemically brain-injured rats also seems promising and may open another therapeutic field for bryostatins.
A number of structurally simpler synthetic analogs also have been prepared which exhibit similar biological profile and in some cases greater potency, which may provide a practical supply for clinical use.
Investigations on how bryostatin 1 behaves in a unique fashion are ongoing in several laboratories. The latest structure and activity relationship studies show that the northern hemisphere of bryostatin 1 plays a unique role.
Macrolide
The macrolides are a group of drugs whose activity stems from the presence of a macrolide ring, a large macrocyclic lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, may be attached. The lactone rings are usually 14-, 15-, or 16-membered...
lactone
Lactone
In chemistry, a lactone is a cyclic ester which can be seen as the condensation product of an alcohol group -OH and a carboxylic acid group -COOH in the same molecule...
s first isolated in the 1960s by George Pettit from extracts of a species of bryozoan, Bugula neritina. The structure of bryostatin 1 was determined in 1982. Until today 20 different bryostatins have been isolated. Bryostatins are a potent modulators of protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
. They are currently under investigation as anti-cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
agents and as a memory enhancing agent.
Biological effects
Bryostatin 1 is a potent modulator of protein kinase CProtein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC). Short-term effects of bryostatin 1 include activation of classical or conventional PKCs and novel PKCs, whereas prolonged presence leads to lowered PKC activation. Bryostatin 1 effects on different isoforms of PKC vary. In in vitro tests bryostatin 1 was able to inhibit cell growth and angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
and to excite cell differentiation and apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Bryostatin also shows immunomodulatry properties.
In in vitro
In vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
trials bryostatin 1 was able to induce apoptosis in HL-60 chronic lymphocytic leukaemia. It could be shown that bryostatin 1 acts synergistically
Synergy
Synergy may be defined as two or more things functioning together to produce a result not independently obtainable.The term synergy comes from the Greek word from , , meaning "working together".-Definitions and usages:...
in combination with other anti-cancer drugs. Drug combination was effective against a large variety of tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
cells including lung, prostate and non-Hodgkin's lymphoma tumor cells. Although animal studies were promising, bryostatin 1 as a single drug has failed to demonstrate significant activity in tumor patients in phase II trials in a wide range of tumor types, including melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
and colorectal cancer. Additionally severe side-effects, mainly myalgia
Myalgia
Myalgia means "muscle pain" and is a symptom of many diseases and disorders. The most common causes are the overuse or over-stretching of a muscle or group of muscles. Myalgia without a traumatic history is often due to viral infections...
, were observed after bryostatin administration. As a consequence research focus has shifted to an investigation of combination therapy with other chemotherapeutic
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
antitumor agents such as gemcitabine, vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
, cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
, and paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
.
Bryostatin 1 has appeared very promising in enhancing memory in animal models. It was able to increase the duration of memory retention of the marine slug Hermissenda crassicornis
Hermissenda crassicornis
Hermissenda crassicornis is a species of small, brightly-colored, sea slug or nudibranch, a marine gastropod mollusk in the family Glaucidae.This species is also commonly known as the "opalescent sea slug."-Distribution:...
by over 500 %. Additionally it also increased the rate of learning in rats. This makes it a possible drug candidate for the treatment of Alzheimer’s disease. Currently bryostatin 1 is in clinical trial phase II for the treatment against Alzheimer's disease.
The ability of bryostain 1 to alleviate brain damage in ischaemically brain-injured rats also seems promising and may open another therapeutic field for bryostatins.
Synthesis
The low concentration in bryozoans (to extract one gram of bryostatin, roughly one tonne of the raw bryozoans is needed) makes extraction unviable for large scale production. Due to the structural complexity, total synthesis has proved difficult, with only a few total syntheses reported so far. Total syntheses have been published for bryostatin 1, 2, 3, 7 and 16.A number of structurally simpler synthetic analogs also have been prepared which exhibit similar biological profile and in some cases greater potency, which may provide a practical supply for clinical use.
Investigations on how bryostatin 1 behaves in a unique fashion are ongoing in several laboratories. The latest structure and activity relationship studies show that the northern hemisphere of bryostatin 1 plays a unique role.
External links
- Drugs from the seas – current status and microbiological implications, Proksch P, Edrada RA, Ebel R, Appl Microbiol Biotechnol. 2002 Jul;59(2-3):125-34.
- http://health.foxnews.mobi/quickPage.html?page=31737&content=60866907&pageNum=-1, story from Fox news.
- Bryostatin 1 Aphios report
- Bryostatins 1-3 QXHealth summary