Phytochemical and Pharmacological Studies of the Genus Tacca : A Review

Tacca is an important genus comprising of approximately 15 species of the medicinal plants (Taccaceae). The plants are used in traditional medicine to relieve pains of the body and stomach, as an antidote for food poisoning as well as for their analgesic, antipyretic and anti-inflammatory activities. Chemical studies have underlined more than 120 constituents have been isolated from Tacca, including steroidals, diarylheptanoids, phenolics, flavonoids, sesquitepenoids, triterpenoids and starch. Steroidals and diarylheptanoids showed potent bioactivities, such as cytotoxic, microtubule-stabilizing, NF-κB activation and PPAR transcriptional and insecticidal activities. The starch from T. leontopetaloides and T. involucrata have high amylase content and showed potential use in food and drug system.


INTRODUCTION
Tacca comprises of approximately 15 species of acaulescent forest understory herbs and is included in the family Taccaceae. With Southeast Asia as their current distribution center, such species are primarily paleotropical in distribution with 6 occurring in China [1,2]. T. chantriers Andre is an indigenous perennial in the tropics which is used by local healers to relieve pains of the body and stomach, and as an antidote for food poisoning as well. Keardrit et al found it showed analgesic, antipyretic and antiinflammatory activities as claimed in traditional medicine [3]. In China, its rhizome has been used in Chinese medicines for the treatment of various diseases including high blood pressure, burns, gastric ulcers, enteritis, and hepatitis [4].
T. integrifolia is mutagenic and its combined extracts from the medicinal plants are highly cytotoxic to the human cell lines, Hep2 and HFL1 [5]. Kitjaroennirut et al found that the hypotensive and negative chronotropic effect of Tacca extracts exists in rat [6].
In the early 1960s Professor Paul Scheuer investigated the "bitter principle" of the tubers of T. leontopetaloides, a starchy food source. Scheuer and his colleagues purified a compound they named taccalin in 1963 as an intensely bitter, light yellow powder with a probable tetracyclic structure [7]. The actual structure of taccalonolides was later found to be much larger, and this pioneering work laid groundwork for the elucidation of their structures in 1987. Then, much attention has been paid to Tacca species due to their cytotoxic, microtubule-stabilizing activities and as a starch source. The potency of taccalonolides, withanolides and their direct interaction with tubulin, together with their previous in vivo antitumor activities, reveal the potential of taccalonolides as new anticancer agents [8][9][10][11][12].
In this survey, we have explored the phytochemistry and pharmacological activities of the Tacca species in order to collate existing information on these plants as well as highlight its multi-activity properties as a medicinal agent and a potential source of industrial starch.

PHYTOCHEMICAL CONSTITUENTS
The chemical constituents of Tacca include steroidals, diarylheptanoids and their glucosides, terpenoids, flavonoids, and some other compounds . By February 2013, their structures are shown below (compounds 1-122), and their names and the corresponding plant sources are collated in Table 1-8. Of all these compounds, one hundred steroidals are the predominant constituents have been isolated from the Genus Tacca .

Starch
Starch is a natural biodegradable biopolymer which is in high demand recently for use in many industrial products. Search for more new sources of starch from plants, however, has also greatly increased. Tacca starch from T. leontopetaloides is found to have higher amylose content than maize starch but a lower content than potato starch. Its features in the formation of compacts (tablets) were comparable to those of maize starch with tacca starch being more resistant to deformation [54]. Maneka et al found lower gelatinization temperature and the narrow gelatinization range demonstrated an energy efficient cooking process. It has an implication for the food industry. The weak associative forces stabilizing tacca starch granules could be explored for its potential use as a disintegrant in the pharmaceutical sector [55]. The physicochemical properties of tacca starch showed potential usefulness of the starch in aqueous and hydrophobic food and drug systems [56].
The plant of T. involucrata is a wild plant that contains starch which is eaten when the flour is being cooked with almost 0% fat, usually by the villagers or rural dwellers in the Northern Nigeria as their food. The morphology of the granules was the same for both starches but they differed in granule size distribution: white tacca (6.13-18.12 μm), yellow tacca (4.19-11.98 μm), which were isolated from white and yellow T. involucrata tubers [57]. The gelatin at 52-65 o C has an amylase content of 36% [58]. It exhibits high water binding capacity, solubility and limited swelling power behavior which are dependent on temperature [59]. The properties are good data sources useful in processing, storage and handling for Tacca tubers [60]. Adebiyi et al reported that physicochemical properties of starch citrate derivative from T. involucrata might be a better disintegrant than native tacca starch in tablet formulations [61]. It shows better swelling and water absorption properties over the native starch, indicating that T. involucrata is a potential source of industrial starch and a promising pharmaceutical excipient [62].
In summary, the type of starch from a nonconventional source T. leontopetaloides and T. involucrata could reduce the cost of producing starch and eliminate or minimize competition on stable food crops like cassava or potatoes or as a kind of pharmaceutical source.

Cytotoxic activity
In the years of 1988 and 1995, Chen et al found that taccalonolide A (1) displayed a cytotoxic activity against P-388 leukemia in cell culture [15,49], but taccalonolides G-K (7-11) showed only a weak cytotoxicity against P 388 leukemia cells in vitro [17].   [52].

Microtubule-stabilizing activity
Microtubules remain an important target for anticancer drug discovery. Paclitaxel, a plantderived microtubule stabilizer, is one of the most successful anticancer drugs currently used. Taccalonolides (oxygenated steroids) are a new class of structurally and mechanistically distinct microtubule-stabilizing agents isolated from plants of the genus Tacca. Taccalonolides stand alone among new microtubule stabilizers in that they appear to have a unique mechanism of action which does not involve direct binding to tubulin [63]. Risinger et al summarized the biological activities in vitro and in vivo and their potential advantages over clinically used microtubule stabilizers. They also discussed the challenges in formulation and supply that are to be solved before taccalonolides could become candidates for clinical development [10]. Herein we will review the microtubule stabilizers of taccalonolides for the latest three years.  14), displayed microtubule stabilizing activities, but profound differences in antiproliferative potencies were also noted (IC 50 32 nM to 13 μM) [21]. These studies demonstrate that diverse taccalonolides possess microtubule stabilizing properties and that significant structure-activity relationships exist. In efforts to define their structure-activity relationships, six taccalonolides AC-H2 (29 -34), demonstrated cellular microtubule-stabilizing activities and antiproliferative actions against cancer cells, with taccalonolide AJ (33) (an epoxidation product of taccalonolide B generated by semisynthesis) exhibiting the highest potency with an IC 50 value of 4.2 nM. The range of potencies of these compounds, from 4.2 nM to > 50 μM, for the first time provided an opportunity to identify specific structural moieties crucial for potent biological activities as well as those that impede optimal cellular effects. In mechanistic assays, taccalonolides AF (32) and AJ (33) could interact directly with tubulin/microtubules and were able to enhance tubulin polymerization to the same extent as paclitaxel but exhibited a distinct kinetic profile, suggesting a distinct binding mode or the possibility of a new binding site [12].
In an effort to find new microtubule stabilizing agents, Risinger et al identified taccalonolide AF (32) with an epoxide group bridging C (22)-C (23), the only difference between AF and the major plant component taccalonolide A, and found it shows microtubule stabilizing activity with IC 50 value of 23 nM in Hela cells. A wide range of antiproliferative potencies was obtained with the natural taccalonolides with IC 50 values ranging from 23 nM to > 50µM in HeLa cells. A one-step epoxidation reaction was used to synthesize AF (32) from A (1) and AJ (33) from B (2) and AJ is highly potent with an IC 50 value of 4.2 nM. They found the C (22)-C (23) epoxy group facilitates optimal potency for microtubule stabilizers [64,65].
Clonogenic assays showed that taccalonolide A and radiation act in an additive manner to cause cell death. These studies suggested that diverse antimitotic agents, including the taccalonolides, may have utility in chemoradiotherapy [66]. Risinger et al found the close linkage between the microtubule bundling and antiproliferative effects of taccalonolide A were of interest given the recent hypothesis that the effects of microtubule targeting agents on interphase microtubules might play a prominent role in their clinical anticancer efficacy [67]. The latter finding that the anticancer effects of microtubule targeting agents may be due in large part to their interphase effects. The kinetic profile of tubulin polymerization observed in the presence of potent taccalonolides was unlike that observed with other stabilizers, further suggesting that the taccalonolides interact with tubulin in a manner that was markedly distinct from other classes of microtubule targeting agents. The unique biochemical and cell biological properties of these potent taccalonolides, together with the excellent in vivo antitumor activity observed for this class of agents in drug resistant tumor models, reveal the potential of taccalonolides as a new class of anticancer drugs [68].

CONCLUSION
Phytochemical studies on the plants of this genus have led to the isolation of ca. 122 compounds including steroidals, diarylheptanoids, and terpenoids. Some chemical constituents displayed cytotoxic activity, microtubule-stabilizing activity and so on. However, there still arise questions concerning the structure-activity relationships and elucidation of the action mechanism. Tacca are important plants not only in the medicinal sense but also as a food source or as an energy material. Thus much more attention should be paid to Tacca species for further phytochemical, pharmacological and cultural studies.

ACKNOWLEDGEMENT
We thank Professor X.W. Sun for their help in improving grammatical expressions in the manuscript. The work was supported by a grant (no. 31260085) from the Natural Science Foundation of China and a grant (no. 2012Y175) for scientific research from the Educational Department of Yunnan, China.