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New Anti-Cancer Compound Found

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A marine compound discovered off the coast of Key Largo in Florida inhibits cancer cell growth in lab tests and is likely to prompt the development of effective new drugs.

The University of Florida (UF)-patented compound, largazole, is derived from cyanobacteria that grow on coral reefs. It is being described as one of the most promising finds since the college’s marine lab was established three years ago.

The molecule’s natural chemical structure and its ability to inhibit cancer cell growth were first described in the Journal of American Chemical Society in February, and the lab synthesis and description of the molecular basis for its anti-cancer activity appeared on July 2.

“It’s exciting because we’ve found a compound in nature that may one day surpass a currently marketed drug or could become the structural template for rationally designed drugs with improved selectivity,” said Hendrik Luesch, assistant professor in UF’s Department of Medicinal Chemistry and the study’s principal investigator.

Largazole, discovered and named by Luesch for its Florida location and structural features, seeks out a family of enzymes called histone deacetylase, or HDAC. Overactivity of certain HDACs has been associated with several cancers such as prostate and colon tumours, and inhibition of HDACs can activate tumour-suppressor genes that have been silenced in these cancers.

Although scientists have been probing the depths of the ocean for marine products since the early 1960s, many pharmaceutical companies lost interest before researchers could deliver useful compounds because natural products were considered too costly and time-consuming to research and develop.

Many common medications, from pain relievers to cholesterol-reducing statins, stem from natural products that grow on the earth, but there is literally an ocean of compounds yet to be discovered in our seas.

Only 14 natural marine products developed are in clinical trials today, Luesch said, and one drug recently approved in Europe is the first-ever marine-derived anti-cancer agent.

“Marine study is in its infancy”, said William Fenical, professor of oceanography and pharmaceutical sciences at the University of California, San Diego. “The ocean is a genetically distinct environment and the single, most diverse source of new molecules to be discovered”.

HDACs are already targeted by a drug approved for cutaneous T-cell lymphoma manufactured by the global pharmaceutical company Merck & Co. Inc. However, UF’s compound does not inhibit all HDACs equally, meaning a largazole-based drug might result in improved therapies and fewer side effects, Luesch said.

Luesch said that, within the next few months, he plans to study whether largazole reduces or prevents tumour growth in mice. Luesch has several other anti-tumour natural products from Atlantic and Pacific cyanobacteria in the pipeline.

These results were presented on Thursday at an international natural products scientific meeting in Athens.

Sources: The Times Of Imdia

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Herbs & Plants

Kalmegh (Andrographis paniculata Nees.)

Botanical Name: Andrographis paniculata
Family:    Acanthaceae
Genus:    Andrographis
Species:    A. paniculata
Kingdom:    Plantae
Order:    Lamiales

Common Name(s): Kalmegh (Hindi), Chuanxinlian (Chinese), Kalupnath , Kiriat , Mahatita (“ King of Bitters ), Alui , Bhunimba , Yavatikta (Sanskrit), Sambiloto (Malay)

Habitat: Kalmegh or Andrographis paniculata is a herbaceous plant in the family Acanthaceae,  native to India, China, and Southeast Asia.

It is widely cultivated in southern Asia, where it is used to treat infections and some diseases, often being used before antibiotics were created. Mostly the leaves and roots were used for medicinal purposes .

Description of the plant:

A. paniculata is an erect annual herb. The square stem has wings on the angles of new growth and is enlarged at the nodes, while the small flowers are borne on a spreading panicle. It is widely cultivated in Asia. The above-ground parts are collected in the fall. The genetic variability of the species has been examined.
It grows erect to a height of 30-110 cm in moist shady places with glabrous leaves and white flowers with rose-purple spots on the petals. Stem dark green, 0.3 – 1.0 m in height, 2 – 6 mm in diameter, quadrangular with longitudinal furrows and wings on the angles of the younger parts, slightly enlarged at the nodes; leaves glabrous, up to 8.0 cm long and 2.5 cm broad, lanceolate, pinnate; flowers small, in lax spreading axillary and terminal racemes or panicles; capsules linear-oblong, acute at both ends, 1.9 cm x 0.3 cm; seeds numerous, sub quadrate, yellowish brown.

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Cultivation
It prefers a sunny situation. The seeds are sown during May-June. The seedlings are transplanted at a distance of 60 cm x 30 cm.

Pharmacology
Andrographis paniculata plant extract is known to possess a variety of pharmacological activities. Andrographolide, the major constituent of the extract is implicated towards its pharmacological activity. A study has been conducted on the cellular processes and targets modulated by andrographolide treatment in human cancer and immune cells. Andrographolide treatment inhibited the in vitro proliferation of different tumor cell lines, representing various types of cancers. The compound exerts direct anticancer activity on cancer cells by cell cycle arrest at G0/G1 phase through induction of cell cycle inhibitory protein and decreased expression of cyclin dependent kinase 4 (CDK4). Immunostimulatory activity of andrographolide is evidenced by increased proliferation of lymphocytes and production of interleukin 2. Andrographolide also enhanced the tumor necrosis factor α production and CD marker expression, resulting in increased cytotoxic activity of lymphocytes against cancer cells, which may contribute for its indirect anticancer activity. The in vivo anticancer activity of the compound is further substantiated against B16F0 melanoma syngenic and HT 29 xenograft models. These results suggest that andrographolide is an interesting pharmacophore with anticancer and immunomodulatory activities and hence has the potential for being developed as a cancer therapeutic agent.

The herb is the well-known drug Kalmegh ‘green chiretta’, and forms the principal ingredient of a reputed household medicine (‘alui’), used as a bitter tonic and febrifuge.
Clinical Overview

Andrographis paniculata Nees (Acanthaceae), the Kalmegh of Ayurveda is an erect annual herb extremely bitter in taste in each and every part of the plant body. The plant is known in north-eastern India as  Maha-tita, literally  king of bitters  and known by various vernacular names (Table below). It is also known as   Bhui-neemâ, since the plant, though much smaller in size, shows similar appearance and has bitter taste as that of Neem (Azadirachta indica). Incidentally, the genus Andrographis consists of 28 species of small annual shrubs essentially distributed in tropical Asia. Only a few species are medicinal, of which A. paniculata is the most popular.

Properties: Analgesic* Antiparasite* Antibacterial* Astringent* Febrifuge* Stomachic* Laxative* Antispasmodic* Immunostimulant* Tonic*

Uses of Kalmegh
Kalmegh has been used for liver complaints and fevers and as an anti-inflammatory and immunostimulant. In clinical trials, Andrographis extract shortened duration and reduced symptoms of colds.

Kalmegh Dosing
Kalmegh dosage in clinical studies has ranged from 3 to 6 g of the crude plant, 1.2 g daily, or 48 mg of andrographolide daily, for common cold, tonsilitis, and familial Mediterranean fever.

Contraindications
Contraindications have not yet been identified.

Pregnancy/Lactation
Documented adverse effects. Abortifacient. Avoid use.

Kalmegh Interactions

None well documented.

Kalmegh Adverse Reactions
No data.

Toxicology

Male reproductive side effects have been studied. In rats, kalmegh decreased sperm count and motility.

History
The herb has been used primarily for liver complaints and to reduce fevers in the traditional medicine of India and China, as well as for its bitter tonic properties. A large variety of Indian herbal patent medicines are available in which A. paniculata is a prominent ingredient.

Chemistry
The diterpene lactone andrographolide was first isolated as a major constituent and later characterized as a lactone. Its full structure was determined by Cava’s group in the 1960s, while x-ray crystallography later confirmed the structure. A number of related minor diterpenes and their glycosides have since been identified. Methods of analysis including high pressure liquid chromatography (HPLC), and nuclear magnetic resonance (NMR) have been published. A method for rapid isolation of andrographolide also is available. When callus cultures of the plant were investigated, it was found that andrographolide and the other diterpenes were not produced. Instead, the sesquiterpenes paniculides A-C were found. Other constituents of the plant include various flavones.

Kalmegh Uses and Pharmacology:

It is chiefly used in viral hepatitis, diminished appetite and drug induced liver damage. It is used in loss of appetite in infants.  Andrographis paniculata has been shown to reduce liver damage due to toxins such as alcohol.  It has been demonstrated that Andrographis paniculata can protect the liver from the effects of alcohol if taken prior to consumption.  Research has also linked Andrographis paniculata to increases in immune system activity.  When supplemented with Andrographis paniculata, animals had an increase activity of both their specific and non-specific immune systems.  Andrographis paniculata may be effective in both the prevention and treatment of ailments that range from the common cold to cancer. It has also been shown to help alleviate atherosclerotic narrowing of arteries induced by high cholesterol diets.  This can, in turn, reduce the risk of heart disease and heart attacks, as well as helping the recovery of patients who already suffer from these conditions.  It is useful in burning sensation, wounds, ulcers, chronic bronchitis, leprosy, pruritis, flatulence, colic and diarrhea.

Common Uses: Colds * Diarrhea * Digestion/Indigestion * Influenza *

Liver :The aqueous extract of A. paniculata protected mice from liver damage induced by hexachlorocyclohexane, while andrographolide protected rat hepatocytes from damage by acetaminophen. Several isolated Andrographis diterpenes protected mice from liver damage by carbon tetrachloride or tert-butylhydroperoxide. Both the extract and andrographolide induced hepatic drug metabolizing enzymes in rats, although the extract was more effective than the isolated compound. An increase in bile flow was noted with administration of andrographolide to rats and guinea pigs, while it blocked the decrease in bile flow induced by acetaminophen.

Animal data:  Both antigen-specific and nonspecific immune responses in mice were stimulated by andrographolide and an ethanolic extract, although the extract was more potent than andrographolide, suggesting that other constituents also were immunostimulants. 23 Inhibition of passive cutaneous anaphylaxis and mast cell stabilization was observed in studies of the purified diterpenes in rats.

Clinical data: Research reveals no clinical data regarding the use of kalmegh to treat liver complaints.Immunostimulant and anti-infective. A small clinical study found the extract to shorten the duration of common colds and to reduce symptoms. Extracts of Andrographis have shown modest activity in vitro against HIV; however, a phase Ι study of andrographolide showed no effect on viral replication, while adverse effects required interruption of the trial after 6 weeks. Succinoylated derivatives of andrographolide have been studied for their protease inhibitory properties, which were suggested to be involved in the anti-HIV activity in vitro. Activity in antimalarial screens has also been noted for Andrographis extracts.

Other uses

The extract of A. paniculata has been shown to block E. coli enterotoxin-induced secretion in rabbit and guinea pig models of diarrhea. Andrographolide and 3 other related diterpenes were responsible for this action. An ethanol extract of Andrographis reversed elevation in blood glucose caused by streptozotocin in rats. Two purified Andrographis diterpenes stimulated nitric oxide release from cultured human endothelial cells, an effect linked to their hypotensive effect in rats. Several fractions of Andrographis were shown to reduce mean arterial blood pressure in rats, although andrographolide was not active in this model.

A water soluble extract of the plant was reported to delay death from cobra venom in mice, in line with its folk use for snakebite in India. Andrographolide has demonstrated anti-inflammatory effects in several cellular systems, including prevention of phorbol ester-induced reactive oxygen species and N -formyl-methionyl-leucyl-phenylalanine (fMLP)-induced adhesion in rat neutrophils and inhibition of TNF-induced upregulation of intercellular adhesion molecule-1 (ICAM-1) expression and monocyte adhesion. Additionally, Andrographis extract blocked rat vas deferens voltage-gated calcium channels 41 and induced cell differentiation in mouse myeloid leukemia cells, as did several diterpenes from the extract. The diversity of pharmacologic activities observed for extracts of Andrographis and its diterpenes begs the question of pharmacologic specificity, which more studies will clarify.

Dosage
Kalmegh dosage in clinical studies has ranged from 3 to 6 g of the crude plant, 1.2 g daily, or 48 mg of andrographolide daily, for common cold, tonsilitis, and familial Mediterranean fever.

Pregnancy/Lactation
Documented adverse effects. Abortifacient. Avoid use. 46

Interactions
None well documented.

Adverse Reactions
Research reveals little or no information regarding adverse reactions with the use of this product.

Toxicology
Kalmegh extracts are not acutely toxic, but the male reproductive toxicology of Andrographis has been studied. Reported infertility in rats led to a subchronic 60-day study in male rats that showed no changes in testicular weight, histology, or testosterone levels. However, detailed studies with purified andrographolide in rats over 48 days have shown decreases in sperm counts and motility, linked to disruption of spermatogenesis.

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Medicinal Uses of Kalmegh

Disclaimer:
The information presented herein is intended for educational purposes only. Individual results may vary, and before using any supplements, it is always advisable to consult with your own health care provider.

Resources:

:http://www.drugs.com/npp/kalmegh.html

http://www.anniesremedy.com/herb_detail354.php

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