DIOSPYROS MELANOXYLON ROXB IN CANCER PREVENTION: PHARMACOLOGICAL SCREENING, PHARMACOKINETICS AND CLINICAL STUDIES
HTML Full TextDIOSPYROS MELANOXYLON ROXB IN CANCER PREVENTION: PHARMACOLOGICAL SCREENING, PHARMACOKINETICS AND CLINICAL STUDIES
Md. Harun Al Rashid * 1, Vivekananda Mandal 2, Subhash C. Mandal 1 and Rajarajan Amirthalingam Thandavarayan 3
Pharmacognosy and Phytotherapy Research Laboratory 1, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata - 700032, West Bengal, India.
Institute of Pharmacy 2, Guru Ghasidas Central University, Bilaspur - 495009, Chattisgarh, India.
Department of Cardiovascular Sciences 3, Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, TX 77030, USA.
ABSTRACT: Plants contain a galaxy of phytoconstituents which accounts for their remedial worth. This plant has been used expansively for its medicinal value all over the world. Different plant parts have been used for its different pharmacological screening, including cancer therapy and leaves can be wrapped to create the “beedi” filled with tobacco which has outsold conventional cigarettes in India. Extraction of plant material with organic solvent and elucidation of pure compounds using a different technique with the different solvent system are an extremely imperative limitation. Elucidation of pentacyclic triterpenoid, ursolic acid from D. melanoxylon and molecular mechanisms has vast chances for the development of enhanced therapy for different diseases, including cancer, and clinical studies. Our extensive intention of this study is to give a general delineate on the thyme D. melanoxylon and its cancer prevention potential, diverse pharmacological action, ethnomedicinal uses, and chemical compounds. We also focus the extraction methodology, elucidation, pharmacokinetic and various clinical trials of ursolic acid chiefly obtained from D. melanoxylon.
Keywords: |
Diospyros melanoxylon Roxb, Pharmacological screening, Ursolic acid, Cancer, NF-kB, Clinical studies
INTRODUCTION: Diospyros melanoxylon Roxb. is numerically and economically the most important genus of Ebenaceae. Concerning 500 species are prevalent primarily of the family Ebenaceae in tropics and subtropics. D. melanoxylon is flowering tree known as Coromandel Ebony or East Indian Ebony. It is an inhabitant of India and Sri Lanka that has a hard, and dry bark.
In the vicinity, it is identified as temburini or tendu in Hindi. In Odisha, West Bengal and Jharkhand it is well-known as kendu. Kendu is a middle-sized tree, height up to 10 -15 feet, branchlets, and young leaves, inflorescence clothed with a soft grey or tawny tomentum. Leaves are mostly sub-opposite, coriaceous, 3 - 6 inches long but sometimes much longer up to 12 inches, when fully grown glabrous above, tomentose or pubescent beneath 1.
It is very famous for making ‘beedi’ which has considered conformist cigarettes in India 2. It is very well known as medicinal herbs which have been widespread in the world for diverse diseases having the less adverse effect and extra beneficial consequence 3-7. It is anticipated for 184 countries of the world exposed that there were 14.1 million fresh cancer cases, 8.2 million cancer deaths, and 32.6 million people existing with cancer (within 5 years of analysis) in 2012 globally according to The International Agency for Research on Cancer 8. Next, to 2030, it is expected that in attendance will be 26 million new cancer cases and 17 million cancer deaths per year 9.
At present, in spite of substantial labors, unmoving cancer ruins as a violent murderer globally. Furthermore, throughout the previous decade, new synthetic chemotherapeutic substances at present to utilizing clinically have not thrived in satisfying prospects in spite of the substantial price of their progress. Thus there is a stable insist on expanding novel, efficient, and reasonable anticancer medicines 10. Beginning the prehistoric drug, human diseases can be treated using chemical compounds obtained from plants. Herbal medicines have established rising awareness over the past 30 years for their possible as a new cancer preventive and healing mediators 11, 12. At the same time, there is rising proof for the possibility of plant-derived compounds as inhibitors of different phases of cancer and connected inflammatory progressions, underscoring the significance of these goods in cancer prevention and treatment.
About 60% of isolated drugs from herbal medicines presently utilized for cancer treatment and the plant kingdom are the mainly momentous foundation 13. Recently, 16 novel compounds from the plant being investigated in clinical trials. Out of them, 13 compounds are in phase I or II, and 3 compounds are in phase III. Out of these, one is flavopiridol, obtained from the Indian herb Dysoxylum binectariferum, and meiso indigo, obtained from the Chinese plant Indigofera tinctoria, have been revealed to demonstrate anticancer effects with minor toxicity compared to conventional drugs 14. 3000 herbs have been investigated for anticancer properties and its constitute a common alternative for cancer management in several countries globally 15, 16. In the world, about 10% to 40% of plant derived products for cancer treatment is utilizing recently and in Asiatic patients reaching about 50 % 17–19.
Kendu leaves contain valuable flavones and pentacyclic triterpene possessing antimicrobial properties 20. The kendu bark shows antihyper- glycemic activity 21 and has important anti-plasmodial property against Plasmodium falciparum, which causes malaria in human beings 22. The leaves contain ursolic acid having a beneficial effect in diverse diseases including cancer therapy. Preclinical studies of ursolic acid have plenty of proof that is naturally and synthetically occurring and having chemopreventive and therapeutic properties 23.
Our broad objective of this review is to give a general delineate on the thyme Diospyros melanoxylon Roxb. and their anticancer activity, ethnomedicinal uses, diverse pharmacological screening, and chemical compounds. We also converse the facts of extraction, elucidation and diverse mechanism of ursolic acid obtained from D. melanoxylon and its various preclinical and clinical studies.
Chemical Compounds: A chemical compound is one type of chemical substance having a distinctive chemical structure existing of two or more different chemical elements 24-26 that can be separated into simpler substances by chemical reactions 27. Fruits of D. melanoxylon contain flavonoids, saponins, tannins, terpenoids, and alkaloids. Kendu leaves contain valuable flavones and pentacyclic triterpenes viz., ursolic acid, lupeol, betulin, betulinic acid, α, and β amyrin, oleonic acid, and β-sitosterol. It is also posses ceryl alcohol, lupeol, betulin, sitosterol, triterpene alcohol, triterpene carboxylic acid, i.e. diospyric acid 1.
Extraction and Elucidation of Ursolic Acid: The main active compound of D. melanoxylon is ursolic acid, a pentacyclic triterpenoid, accomplished by a diversity of methods 28. Generally, the plant material is extracted with different solvents according to increasing the polarity using a suitable extraction method. N-hexane and petroleum ether mainly used for removing waxy and fatty materials that are not required for pharmacological activity. The solvent extract is concentrated using the vacuum dryer and kept in a flask with properly sealed and stored in the refrigerator. The common method of elucidation is with organic solvent using either column chromatography, partition chromatography, solid phase extraction method, high-pressure liquid chromatography (HPLC), or high-performance thin layer chromatography (HPTLC) after iodine derivatization 29. For elucidation and analysis of ursolic acid, some particular methods are used like gas chromatography including the essential silylation or methylation step, liquid chromatography coupled with UV and MS spectrometry 30-33. Then the bioactive fraction was taken for further fractionation, purification followed by elucidation. Pure ursolic acid appears in the forms of hair like needles having 284 °C melting point.
Another study was carried out with chloroform extract and subjected to column chromatography with chloroform fraction and increasing the solvent methanol. 18-20 fractions contained major compound out of 25 fractions and combined 18-20 fractions. The combined fractions were subjected for column chromatography with the solvent system ethyl acetate: chloroform (10:90) and collect fractions 4-7 (total 30 ml) having 45 mg compound which is a pale yellow powder and melting is 271-274 °C 34.
Mechanism of Action of Ursolic Acid: Formerly the compound ursolic acid has been revealed to stifle the proliferation of several tumor cells, encourage apoptosis35 and reduce tumor promotion, metastasis, and angiogenesis 36. It has been demonstrated to inhibit NF-κB activation induced by carcinogenic agents, like tumor necrosis factor (TNF), phorbol ester, okadaic acid, hydrogen peroxide, and cigarette smoke, through the suppression of IkBa kinase and p65/RelA phosphorylation. Besides, it suppresses constitutive and TNF-α- induced activation of NF-κB in DU145 and LNCaP cells in dose-dependent manner 37. It downregulates the expression of various NF-κB and STAT regulated gene products involved in proliferation, survival, and angiogenesis and induced apoptosis in both cell lines 38.
It has been demonstrated to prevent the development of lung cancer by suppressing cigarette smoke extract-induced human bronchial epithelial cell injury. It suppresses constitutive NF-κB activation and down-regulation of cell survival, proliferative, and metastatic (MMP-9) proteins and induce apoptosis in colorectal cancer cells. It also has been revealed to suppress growth and induce apoptosis in gemcitabine-resistant human pancreatic cancer cells (MIA PaCa-2, PAN-1, and Capan-1) via modulation of the JNK and PI3K/AK/ NF-κB pathway 39. At last, an enormous mainstream of these studies designates that ursolic acid can hinder tumor initiation, progression, and metastasis in an extensive assortment of preclinical cancer replicas.
Ethnomedicinal Uses: Day by day the demand of ethnomedicine is rising exponentially all over the world 40. Traditionally in India, leaves of D. melanoxylon have been extensively used as a diuretic, styptic, laxative, carminative and ophthalmic agent asan astringent lotion. Ethnically, the bark is used as urinary discharge. Flower of D. melanoxylon is used in skin disease, inflammation of spleen and enrichment of blood. The seed of D. melanoxylon is used as a germicide and in the treatment of dysentery 41-43.
Pharmacological Screening:
Analgesic Activity: Nonsteroidal anti-inflammatory drugs (NSAIDs) trim down pain with repressing the formation of prostaglandins, by hindering the action of the enzyme Cyclo-oxygenase (COX). So, containment of fusion of prostaglandins (PGs) by NSAIDs truly lessens the fight of the mucosa to damage as well as snooping with restore developments. Selective COX-2 inhibitors were thought to be the result of this puzzle as it is obligatory that NSAIDs repress prostaglandin synthesis at sites of inflammation. It has been reported that extracts of stems bark and root bark screening for their analgesic activity by an acetic acid-induced writhing method and hot plate method, albino mice were divided into four different groups (six animals each) 44, 45. Leaf of D. melanoxylon contains flavonoids having analgesic activity 46.
Anti-inflammatory Activity: Kendu leaves have valuable flavones, and pentacyclic triterpenes and flavonoids have anti-inflammatory activity 47. Flavonoids are incredibly imperative secondary metabolite mainly inhibit the enzyme prostaglandin synthetase, additional purposely the endo-peroxidase and accounted to produce anti-inflammatory property 48. This investigation observed that the flavonoids and pentacyclic triterpenoids of D. melanoxylon illustrated important anti-inflammatory activity in a dose-dependent way. This recommends that the further experiment is carried out on this plant and their lead compounds with the vision of characterizing the potential activities.
Antiulcer Activity: Inequity among aggressive and protective factors causing gastric ulcer which is the most prevalent disease 49. Medicine, healing of ulcers is embattled at either neutralizing aggressive factors (acid, pepsin, active oxidants, platelet aggravating factor “PAF”, leukotrienes, endothelins, bile or exogenous factors including NSAIDs) or motivating the mucosal defences (mucus, bicarbonate, normal blood flow, prostaglandins (PG), nitric oxide) 50. Pyloric ligation is one type of method mostly used for the evaluation of anti-ulcer drugs and increased the acid secretion, which in turn causes an increase in gastric volume, low pH, increased free and total acidity ensuing into an increase in ulcer index 51.
A recent investigation has been demonstrated that the anti-ulcer activity against pylorus ligation induced gastric ulcer model using a methanolic leaf extract of D. melanoxylon. The methanolic extract 200 mg/kg body weight reduces the ulcer index significantly (p<0.05) compared to control group 52. It also lessens the total Acidity, Acidity free, and pH of the gastric content and viewing protection index 32% and 58% at the dose of 100 mg/kg and 200 mg/kg. Correspondingly, the standard drug ranitidine (50 mg/kg) proved 85% of ulcer protection.
Antihyperglycemic Activity: It has been demonstrated that the extracts are showing significant anti-hyperglycemic activity as compared to the standard drug. Ethanolic extract (200 mg/kg) show beneficial effects on blood glucose and hyperlipidemia associated with diabetes, which might be due to the presence of steroids, tannins, alkaloids and triterpenoids in the extract. Ethanolic extract could serve as a good adjuvant to other oral hypoglycemic agents and seems to be promising for the development of phytomedicines for diabetes mellitus 53. Petroleum ether extract of D. melanoxylon leaves showed the antidiabetic effect at doses of 250 and 500 mg/kg in 1% v/v of Tween 80 (1 ml/kg p.o.) for 28 days to different groups of animals. It is proved that D. melanoxylon leaves effective for the treatment of both types of diabetes, i.e., Insulin Dependent Diabetes Mellitus (IDDM) and Non-insulin Dependent Diabetes Mellitus (NIDDM) with a hypolipidemic property when compared to other diabetic drugs available in the market 54. An additional study reported that the anti-hyperglycemic activity is D. melanoxylon Roxb. which was selected based on its abundant availability in Maharashtra state and based on ethnomedicinal information that the tribe of the Chotta Nagpur region (Orissa) use it extensively as antidiabetic 55.
Antimicrobial Activity: For the period of the previous few years, antimicrobial activities of plant extracts and natural products have been severely observed as they require for safe drugs which have augmented due to the abuse of antibiotics and an increase in immuno-deficiency disease 56.
The leaves of D. melanoxylon were explored for its antimicrobial activity and estimated by determining the zone of inhibition of S. areas (gram positive) and E. coli (gram negative) in different extracts like ethanolic and petroleum ether. Standard Ciprofloxacin was viewing zone of inhibition (mm) 24 and 30 for S. aureus and E. coli in that order. In the ethanolic extract, it was found 25 and 24 while in petroleum ether extract zone of inhibition was found with a value of 18 and 14 respectively. This revision demonstrated that the possibility of different extracts above microbes for the progress of novel antimicrobial mediator 57.
Anticancer Activity: It has been revealed that D. melanoxylon leaves contain ursolic acid (0.56%). Ursolic acid is a pentacyclic triterpenoid acts as a chemopreventive and chemotherapeutic agent in various types of cancer by inhibiting the initiation, promotion, and metastasis of cancer 20. Ursolic acid inhibits the cell proliferation of Hep G2 human liver cancer cells 58. It has been demonstrated the in-vitro anti-tumor activity in 2001 of ursolic acid 59. Ursolic acid lessens the cell proliferation of many tumor cell lines and mechanisms of action have been tackled. It has been showed an early G1cytostatic effect for ursolic acid in B16 cells and MCF-7 breast carcinoma cells 60, 61.
Clinical Studies of Ursolic Acid: Clinical studies of ursolic acid mainly determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics in healthy adult volunteers and patients with sophisticated tumors. It has been demonstrated that single dose ursolic acid liposomes (11, 22, 37, 56, 74, 98, and 130 mg/m2) were administered as 4 hours intravenous infusion in 63 subjects (4 patients, 35 healthy volunteers, and 24 adults). It has been revealed that liposomal ursolic acid had convenient toxicities with MTD of 98 mg/m2 for the first time. Mostly, the DLT was hepatotoxicity and diarrhea. Temporarily it has been demonstrated a linear pharmacokinetic profile of ursolic acid liposomal formulation 62.
Another study was carried out for 3 days of human subjects in the skin with incorporation of ursolic acid into the liposome and increased the ceramide content, with increases in hydroxyl ceramide. And also it has been revealed that increased the ceramide content in human skin after incorporation of ursolic acid into liposomes for 11 days 63. From these reviews, we can say that ursolic acid has fabulous perspective into a powerful anticancer drug.
CONCLUSION: Our present assessments of D. melanoxylon have been contributed to tremendous positive roles in various diseases. It is documented for the use of many important chemical constituents in various health problems including cancer. Although, this plant has been used for a long time and so many research works have been done. The pentacyclic triterpenoid ursolic acid chiefly obtained from D. melanoxylon revealed chemopreventive and therapeutic potential in different cancer replicas and countless research works had been done as it is ubiquitous. Clinical trials are imperative parameters to develop it’s reported worth for the prevention and treatment of assorted diseases. Still, there are opportunities to explore the different extract of the plant in the field of nano-technology mainly for cancer therapy 64, so that it can serve more effectively to the mankind.
ACKNOWLEDGEMENT: We are grateful to “Innovation in Science Pursuit for Inspire Research” (INSPIRE) implemented by the Department of Science and Technology (DST, Government of India, New Delhi, INSPIRE Reg. No. IF 130670) for financial support and the authority of Jadavpur University to carry out the work.
CONFLICT OF INTEREST: The authors have declared no conflict of interest.
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How to cite this article:
Rashid MHA, Mandal V, Mandal SC and Thandavarayan RA: Diospyros melanoxylon Roxb in cancer prevention: pharmacological screening, pharmacokinetics and clinical studies. Int J Pharmacognosy 2017; 4(7): 217-23. doi link: http://dx.doi.org/10.13040/IJPSR. 0975-8232.IJP.4(7).217-23.
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M. H. A. Rashid *, V. Mandal, S. C. Mandal and R. A. Thandavarayan
Pharmacognosy and Phytotherapy Research Laboratory, Division of Pharmacognosy, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, West Bengal, India.
mdharunalrashid15@gmail.com
31 March 2017
22 May 2017
30 May 2017
10.13040/IJPSR.0975-8232.IJP.4(7).217-23
01 July 2017