Pure Appl. Biol., 6(2): 748-761, June, 2017 http://dx.doi.org/10.19045/bspab.2017.60080

Review Article

A mini review on a tuberculata N. E. Br. uncommon and wild succulents but having exciting pharmacological attributes

Sobia Noreen* Department of Chemistry, University of Sargodha, Sargodha, 40100-Pakistan *Corresponding author’s email: [email protected] Citation Sobia Noreen. A mini review on a Caralluma tuberculata N. E. Br. uncommon and wild succulents but having exciting pharmacological attributes. Pure and Applied Biology. Vol. 6, Issue 2, pp748-761. http://dx.doi.org/10.19045/bspab.2017.60080 Received: 22/04/2017 Revised: 04/06/2017 Accepted: 13/06/2017 Online First: 15/06/2017 Abstract Caralluma tuberculata belongs to milky weed family which upholds 424 genera. This natural medicinal is widely distributed in South Asia, Africa, Middle East, and Spain etc. Overall phytochemistry of Caralluma tuberculata is endowed with flurry of pharmacologically active constituents like pregnane glycosides and aglycones, flavanoid, saponins and titerpenes etc. Caralluma tuberculata and its various other species of this genus have been explored for their anti-inflammatory action, strong hypoglycemic and weight reduction effect, quite effective for rheumatoid arthritis, paralysis stomach disorders, abdominal pain, migraine, fever wound healing and cardiac problems. Present review focuses on the comprehensive profile of Caralluma tuberculata with respect to its highly valuable phytoconstituent along with their available pharmacological characteristics and therapeutic prospective. Keywords: Caralluma tuberculata; Desert Succulents; Antidiabetic; Cancer; Obesity; Pharmacological Introduction certain physiological action in and Natural product term widely cover the human against different types of infectious natural bio source products i.e. plant, animal disease and metabolic disorders [2]. These and microbes. It may be in the form of a mix natural constituents can be classified into or single pure compound (secondary two groups on the basis of their role in metabolites) like alkaloids, limonoids, metabolism. Construction and maintenance steroid, flavonoid, lignana, terpenoids, of plant body is carried out by primary organosulfur, tannin, furyl, polylines, constituents. There was a thought in history chlorophyllins, thiophenes, saponins, that secondary constituents have no vital sulphides, coumarins, etc. [1]. The worth of role in building or continuance of body of a medicinal plants lies in these metabolites plant but at present their ecophysiological that are non-nutritive for plants but produce role has been established. They act as

Published by Bolan Society for Pure and Applied Biology 748 Noreen defensive tool and attract pollinators or symbionts towards plant. These are also Preface to genus Caralluma and involved in growth regulation, modulation Caralluma tuberculata N. E. Br. of genetic expression and transduction of Caralluma etymology considered to come signals. Some secondary components mimic from an Arabic word “qarh al-luhum” the body chemicals like signaling molecules, meaning of which is wound inside ligands, hormones, neurotransmitters and abscess/flesh probably relate with the milky may act as activators or inhibitors of target latex of stem [13]. Caralluma is considered cells. Above cited properties can be used to in family Apocynaceae that comprises three benefit human body such as cytotoxic subfamilies Rauvolfioideae, Apocynoideae secondary components for microbes can act and Asclepiadaceae holding 424 genera as effective antimicrobial agent in human [14]. Ornamental plants like Allamanda, body. Constituents used as defense by plants Frangipani, Oleander, Vinca of tropical area, against herbivores may affect Central large trees with special buttress roots of Nervous System of human being and act as rainforests and deciduous or evergreen trees, muscle relaxant, sedative, antidepressant or climbers or shrubs of world warm and anesthetic [3, 4]. temperate regions are included in these Phytotherapy history is as old as the history genera. Milky latex of most of the plants is of humankind itself [5]. People believe that considered important for medicinal purpose locally originated diseases can be cured by and rubber production. Later, in 1890 Robert local remedy [6]. Natural plant products are Brown separated Asclepiadaceae (milkweed considered to be in good health than family) from Apocynaceae. Recent advances artificial medicine [7].There are many side in genomic, molecular and morphological effects that are caused by the use of analysis merge the Asclepiadaceae and allopathic medicines [8]. The medicinal Periploceae into Apocynaceae family [15, efficacy of antibiotics existing today is 16]. Common members of this family are C. decreasing by the appearance of multidrug- tuberculata, C. edulis, C. negevensis, C. resistant microbes [9]. Unlike synthetic sinaica, C. russeliana, C. stalagmifera, C. medicines, phytomedicines may produce dalzielii N. E. Br, C. arabica etc. Among their positive effects by additive and these Caralluma tuberculata occupy a synergetic action of many chemical significant position. components that act on their target sites to Caralluma tuberculata is a member of produce a physiological change [10]. milkweed family Asclepiadaceae which Mostly the formulation schemes were kept include about 2500 species from 200 genera secret by traditional healers, herbalist and and widely distributed in Pakistan, shaman who pose as major obstacle to check Afghanistan, Africa, Middle East, Spain, the authenticity of these formulations on Saudia and India [17]. In Pakistan, scientific basis [11]. Despite of ever Asclepiadaceae is represented by increasing human knowledge regarding approximately 23 genera along with 40 conventional usage of natural products; species abundantly present in some tropical appropriate modern scientific approaches regions of Punjab, Khyber Pakhtunkhwa and have only been applied to a very little part of Blouchistan provinces. Caralluma species the world's flora. It is matter of grave have been used for centuries in semiarid concern to exploit the potential of those areas of Pakistan as emergency food. plant species that are in waiting line before Caralluma turbeculata vernacular name is they become endangered [12]. chunga or chung in Punjab. Plants belonging

749 Pure Appl. Biol., 6(2): 748-761, June, 2017 http://dx.doi.org/10.19045/bspab.2017.60080 to the genus Caralluma are normally leafless and each having pollen mass one. Glabrous [18]. This perennial herb has 15-45 cm Follicles with size about 9-11 cm are height with a succulent, fleshy leafless, erect progressively tapering to the tip. Flowering and 4 angled stem having grooves on it. season is June. It mostly grows widely on Quadrangular stem bear small flowers in rocks after rain but it is also cultivated in several varieties of dark colour [19]. Sessile some areas. Its stem and roots are not only single or many flowers in lateral cymes eaten raw as famine food but also cooked having ovate-lanceolate five sepals and due to its pharmacological potential. The deeply divided, glabrous, lobe lanceolate complete taxonomical classification of dark purple colour corolla of about 9 mm in Caralluma tuberculata is deciphered in diameter. Anthers are without appendages Figure 1.

Domain Eukaryota Kingdom Plantae Subkingdom Viridaeplantae Phylum Tracheophyta Subphylum Euphyllophytina Infraphylum Radiatopses Class Magnoliopsida

Subclass Asteridae Caralluma tuberculata: Whole plant & flower

Superorder Gentiananae Order Family Apocynaceae Subfamily: Tribe Ceropegieae Genus Caralluma Specific epithet tuberculata - N.E.Br.

Botanical Caralluma tuberculata N.E.Br. name

Figure 1. Taxonomy of Caralluma tuberculata N.E.Br. and whole plant along with flower

Phytochemistry Caralluma species, in general, are famous The succulent Cactus Caralluma contains for the presence of their key components i.e. glycosides, flavonoid, saponins and glycosides specifically pregnane glycosides triterpenes as major phytoconstituents. and aglycone steroid [19]. Pregnanes are the Genus Caralluma was 1st time explored for C-21 steroides having perhydro-1,2- its constituents in 1967 and two compounds cyclopentanophenanthrene ring as backbone (dihydrosarcostin, (20S)- that have β-oriented methyl group at two hexahydroxypregnane and tomentogenin position (C-10 and C-13) and two outside ((20S)-pentahydroxypregnane) were chains of carbon atoms at C-17. In extracted from C. dalzielii [20]. derrvitized form of pregnane the β

750 Noreen confirmation is present along with a glycosides were isolated from Caralluma hydroxyl group at C-14 [21]. tuberculata, in addition to a known one The literature survey indicates that the (russelioside E, 6). All these six compounds pregnane glycocydes were isolated from were checked for their action against various parts of the plant. With polar malarial and trypanosome. Moreover their solvents like ethylacetate, n-butanol, cytotoxic effect was also tested on the methanol, ethanol and water, the compounds growth human MRC5 embryonic cell line like C21 class of steroidal glycosides with [28]. Caratuberoside C (I), and D (II), two high molecular weight compounds were new pregnane glycosides were isolated from obtained but on other hand compounds Caralluma tuberculata [29]. A medicinal having low molecular weight like cumarin, herb, Caralluma tuberculata, furnished a sterol, steroid, terpenoid were obtained pregnane type compound, caratuberside A2. when the same parts were extracted with The sugar linkage was at C-14 which is a non-polar solvents like n-hexane, benzene rare site of substitution [30]. Glycone etc. moieties include different sugars like Some studies report the presence & glucose, digitalose, thevotose, quinvose etc. isolation of new pregnane glycosides Key phytochemical ingredients of carumbellosides I and II and a steroidal Caralluma umbellate include pregnane glycosides i.e. carumbellosides III-V were glycosides, flavone glycosides, bitter isolated from the extract of Caralluma principles, saponins and various flavonoids umbellate whole plant [22, 23]. New [31, 32]. Some acylated pregnane glycosides steroidal glycosides, stalagmosides I-V and like russeliosides E–H were obtained from indicosides I and II together with the known chloroform extract of Caralluma russeliana compounds Carumbelloside III, [28]. lasianthoside A and lasianthoside B were The aglycone pregnane (Pregnane-14β - isolated from whole plant of Caralluma formyl-5, 7-dien-20-one), with unusual stalagmifera. The genus is also formyl group at C-14, were extracted from characterized by the presence of flavones of the non polar (petroleum ether) extract glycosides [24]. Caralluma umbellate stem [33]. Similarly Two novel steroid glycosides were isolated two more aglycone steroids Crur I and Crur from Caralluma tuberculata that exhibited II were extracted from the nonpolar extract fairly in vitro cytotoxic activity on breast of the roots of same plant [22]. Furthermore, cancer cells even in micromolar in another study, one more compound i.e. st concentration. Pregnanes are C21 steroids 20S-epimer of boucerin was extracted 1 and often found in nature conjugated as time from the tolune extract of above said glycosides. A flurry of pregnane glycosides specie of Caralluma [34]. and esterified polyhydroxypregnane were Recently megastigmane glycosides also extracted from Caralluma and other family have been isolated from Caralluma member of Asclepiadaceae. Some of these negevensis with few flavones. Saponins and glycosides appear as novel potential flavonoids predominantly found in template for drug development against Caralluma are of great interest due to the cancer and tumor [25]. wide range of immunostimulating activities. Chemical investigation of Caralluma In Caralluma attenuata, the fresh whole tuberculata indicates that it was endowed plant contains luteolin-4-O- with the flavone glycosides and several neohesperidoside, a flavonoid (flavones pregnane glycosides [26, 27]. Five pregnane glycoside) identified as the major chemical

751 Pure Appl. Biol., 6(2): 748-761, June, 2017 http://dx.doi.org/10.19045/bspab.2017.60080 constituents of the plant. Caralluma acetate and guimarenol were extracted from adscendens is declared to contain saponin Caralluma buchardii [36]. glycosides, bitters, pregnane glycosides Pharmacological worth of Caralluma (caratubersides A and B and various tuberculata and other species of boucerosides) [35]. Caralluma Several members of the genus Caralluma Traditionally it was believed that Caralluma are rich in triterpenes, pregnane glycosides tuberculata has anti-inflammatory and or their esters which may have found strong hypoglycemic effect [37, 38]. It is medicinal uses. Triterpenes squalene, also reputed for the treatment of rheumatoid lupeol, lupenone, lupeol acetate, β -sitosterol arthritis, paralysis and fever [39].

Table 1. Global distribution and pharmacological activities of different species of Caralluma genus [40] Species of Distribution Pharmacological Activities Part Used in Citations Caralluma Genus traditional medicine System C. adscendens India Rheumatic Pain, Paralysis Plant Stem [41,42] C. attenuate Spain, India Anti-tumor, Pain, Hyperglycemia Whole Plant [43,28] C. edulis Pakistan, Iran Rheumatic Pain, Parasitic diseases, Whole Plant [44,45,46] Gastric problems, Leprosy, Hyperglycemia, Hypertension, Hypercholesterolemia C. umbellate India Gastric Ulcers & Pain Roots [47, 22] C. laciantha India Wound Healing, Veterinary Use Plant Stem [41] C. stalagmifera India Wound Healing, Malnutrition Plant Stem [41] C. sinaica Saudi Arabia Hyperglycemia, Leaves [48,49] Hypercholesterolemia C. diffusa India Organogenesis, Hyperglycemia, Whole Plant [50,51] C. penicillata Saudi Arabia Trypanosomacidal, Antivenom Whole Plant [40] C. russeliana Saudi Arabia Medicinal Whole Plant [40] C. bhupenderiana India Ethnoveternary uses Whole Plant [52] C. fimbriata India, Iran Obesity, Hyperglycemia, Plant Stem [41,53,54] Hypercholesterolemia C. europaea Italy Pharmaceutical Fruits & Stem [55] C. negevensis Africa, Spain Anti Cancer, Lung Diseases [56] C. diazielli Nigeria Obesity, Hyperglycemia, [57] Hypercholesterolemia C. nilagiriana India Infectious Diseases [58] C. wissmannii Egypt Medicinal Above Ground [18] Parts C. arabica UAE Vegetable, Liver Tonic, Obesity, Whole Plant [59] Hyperglycemia, Hypercholesterolemia, Wound Healing C. pauciflora India Vegetable Plant Stem [52] C. tuberculata N. Pakistan, Vegetable, Hepatitis B & C, Blood Whole Plant [38, 44, 46, E. Br. India, Iran, Purification, Gastric Problems, Liver 60-66,] Nigeria, Saudi Tonic, Obesity, Arabia Hyperglycemia,Hypercholesterolemia

Caralluma family members are rich with glycoside and its structure encomprises Pregnane that naturally conjugated with basic C21steroids backbone along with

752 Noreen sugar moiety. These molecules appear as rutin, Kaempferol, flavone glycoside and potential lead for drug development against hypolaetin-8-glucoside have been reported cancer and diabetes [20, 21]. Pregnane to have gastric ulcer protective effects. glycosides series has been extracted from its Similarly saponins, such as the derivatives organic extracts that explicit cytoxic effect of glycyrrhetinic acid and triterpenoid against cell line of Human diploid saponins were also reported to have embryonic cell like MRC5 [28]. antiulcer effects in rats. It therefore appears Antiproliferative potential of Caralluma responsible to suggest that flavonoids and tuberculata N. E. Br. was observed on the saponins in Caralluma tuberculata may be growth of estrogen-dependent (MCF-7), and totally or partially responsible for its estrogen-independent (MDA-MB-468) antigastric ulcer activity [69]. Pregnane breast cancer cells, U937 and Caco-2 glycosides, Penicilloside E showed the colonic cells [25]. Androstan and pregnane highest antitrypanosomal activity (IC50 1.01 glycosides stimulate caspase mediated µg/mL) followed by caratuberside C (IC50 apoptosis. Caspase enzyme, dependent on 1.85 µg/mL), which exhibited the highest Calcium, is activated via two possible selectivity index (SI 12.04). It was noticed pathways, intrinsic (e.g. mitochondria that acylation is required for the damage) and extrinsic (e.g. cell surface antitrypanosomal activity while death receptors ligation). This activated glycosylation at C-20 has no significant caspase along with caspase 3 trigger the effect on the activity. cleavage of poly-(ADP ribose) polymerase The methanolic extract of Caralluma (PARP) and DNA fragmentation. After tuberculata N. E. Br. as well as its PARP cleavage, cell irrevocably prone to petroleum ether, chloroform and n-butanol apoptosis. Due to structural homology of extract were also examined for Pregnane glycosides with estrogen agonist antitrypanosomal and antimalarial potential, inhibits Calcium exchangers, as a result additional to their cytotoxic potential against calcium concentration increased that diploid embryonic cell line (MRC5) of stimulate caspases and apoptosis [20]. Other human. Six compounds (1–6) were extracted possibility is activation of the xenobiotic and from the chloroform fraction and identified steroid receptors that also induce the by spectral means and were also tested for apoptosis process in cancerous cells of their antimalarial, antitrypanosomal and breast [67]. Mechanism of induction of antiprotozoal activity against malaria and apoptosis by the pregnane compound is trypanosomiasis. As for the anti-malarial shown in Figure 2. This process is not fully activity, only petroleum ether soluble cleared hence further research is mandatory fraction demonstrated moderate inhibitory to decipher the activation of xenobiotic effect (IC50 7.94 lg/mL), this fraction receptors. showed high cytotoxicity on MRC5 (IC50 Treatment with Caralluma tuberculata N. E. 0.8 l g/mL) [70]. As for the Br. extract induced complex biochemical antitrypanosomal activity, the methanolic and cytological changes in mice [68]. The extract was inactive, while the petroleum ethanolic extract of Caralluma tuberculata ether soluble fraction showed potent activity afforded potential protection against gastric (IC50 0.5 lg/mL) with a selectivity index of mucosa injuries caused by 80% ethanol, 0.2 1.6. On the other hand, the CHCl3 soluble M NaOH, hypertonic saline and fraction was moderately active (IC50 3.5 indomethacin in a dose-dependent manner lg/mL) with a selectivity index of 17.9. [26]. Many flavonoids such as Quercetin, Accordingly, the CHCl3 soluble fraction was

753 Pure Appl. Biol., 6(2): 748-761, June, 2017 http://dx.doi.org/10.19045/bspab.2017.60080 chosen for isolating the bioactive of wild Caralluma umbellata are used in compounds. Compounds 1–6 were isolated stomach disorders and abdominal pains [22]. from this fraction and their antimalarial and Caralluma adscendens is a thick, succulent antitrypanosomal activity were evaluated perennial herb found wild in Africa, the [28]. Canary Islands, India, Arabia, Southern Other members of this genus like Caralluma Europe, and Afghanistan. In India, it is fimbriata and Caralluma siniaca were found in the dry hills of Andhra Pradesh, considered to reduce body weight and blood Warangal and some other district. It is a glucose level respectively [49,54]. traditional food consumed in pickle form Caralluma fimbriata is listed in The Wealth and is also eaten during famines [35]. It is of India (1992) as medicinal plant used as an locally known as appetite suppressant and has also been used “Makadshenguli/Shengulmakad”. The local to treat diabetes, pain, fever, and people use it in raw form for treatment of inflammation [71]. Its pregnane glycosides diabetes and it is also utilized as a vegetable were thought to inhibit the action citrate [74]. Caralluma attenuata is eaten raw as a layase enzyme and malonyl coenzyme A cure for diabetes and the juice of the plant thus inhibiting the synthesis of fat cells. The along with black pepper is recommended in blockage of action by this plant extract the treatment of migraine. It also usually eventually stimulates the burning process of exhibits antinociceptive activity owing to its already stored fat reserves of body and luteolin-49-O-neohesperidoside components finally reduces circumference of muscles [43]. and body lose weight. Caralluma fimbriata Caralluma dalzielii N. E. Br. is a succulent extracts have also been found to be appetite herb growing wildly on the Sahelian region suppressant and is well known to Indian of West Africa from Senegal to Nigeria tribals and hunters. Indian folklore records where it was used in folk medicine as its use as a potent appetite suppressant and antispasmodic and analgesic remedy. Plant weight loss promoter [24]. latex, in Bandiagara area of Mali, is used for Caralluma edulis is also famous for its anti- wound healing, while the stems are diabetic potential [72]. Similarly grounded and eaten raw as tonic and for hypoglycemic synergistic effect was noticed cardiac problems. A previous phytochemical when C. edulis and C. attenuate were used study on this plant reported the isolation of in combination along with extract of two tomentogenin esters [75]. phlorizin for reducing blood and urine In short, worldwide distribution and glucose level in conjunction with weight pharmacological properties of some loss [73]. Figure 3 briefly explains the significant species of Caralluma genus are possible mechanisms of action of Caralluma represented in summarized form in Table 1 on the reduction of blood glucose in the and Figure 4. animal body. In Nepal and Sri Lanka, stem

754 Noreen

21 18 20 12 17 11 19 13 H 16 1 9 14

15 2 10 8 H OH 3 5 7 Intrinsic

HO 4 6 H pathway Pregnane glycosides

Extrinsic pathway Ca mediated ER Mitochondrial damage stress pathway e.g. BCl proteins, Death receptors e.g Cytochrome C, Caspase 9 HSP, Caspase 8 Xenobiotic and steroid receptor activation

Caspase 3 & caspase 7

Apoptosis

Figure 2. The proposed model of pregnane compound arbitrated apoptosis. Pregnane glycosides of Cralluma tuberculata N. E. Br. are considered in to stimulate the apoptosis process in cancer cell either through caspase dependent (Extrinsic & intrinsic pathways) or caspase indendent pathways (calcium mediated endoplasmic reticulumn stress pathway and stress & xenobiotic receptors activation.

755 Pure Appl. Biol., 6(2): 748-761, June, 2017 http://dx.doi.org/10.19045/bspab.2017.60080

Caralluma species Suppress appetite and decrease food intake

Free fatty acids from Insulin secretion adipose tissues Glucose uptake and its utilization

Level of glucose in blood Hepatic glucose Glucose absorption output by intestine

Figure 3. Possible mechanisms of action of Caralluma on the reduction of blood glucose in the animal body

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Figure 4. Graphical description of pharmacological features of different species of Genus Caralluma

Conclusion of neglected members from this genus on Most species of genus Caralluma grow in scientific basis. semiarid and desert area of Asia and Authors’ contributions Mediterranean region of the world. Key Conceived and designed the paper: S phytochemical ingredients of Caralluma Noreen, Wrote the paper: S Noreen. include pregnane glycosides, pregnane References aglycones, flavone glycosides, bitter 1. Naithani R, Huma LC, Holland LE, principles, saponins, triterpines and various Shukla D, McCormick DL, Mehta RG & flavonoids that were explored for various Moriarty RM (2008) Antiviral activity of therapeutic purposes against different phytochemicals: Mini-Rev Med Chem 8: infectious agents and metabolic disorders. In 1106-1133. folklore, Caralluma is famous for 2. Edeoga H, Okwu D & Mbaebie B (2005). hypoglycemic, anti-rheumatic and weight Phytochemical constituents of some reduction effects. Historically, Caralluma nigerian medicinal plants. Afr J Biotechnol members were also used as vegetable during 4: 685-688. famine but it is a neglected genus of 3. Kaufman PB, Cseke LJ, Warber S, Duke vegetable worldwide that is rarely cultivated JA & Brielmann HL (1998). Natural products from plants. CRC Press Inc. and very little efforts has been made to 4. Wink M (1998). Functions of plant conserve the species of this genus. Further secondary metabolites and their research on isolated compounds from this exploitation in biotechnology. CRC Press genus could improve their biological 1999. effectiveness along with future investigation 5. Ahmad I, Aqil F & Owais M (2006). Mdern phytomedicine: Turning medicinal

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