9Drug TargeT InsIghTs 2015:9 Medicinal Plants: A Potential Source of Compounds for Targeting Cell Division Ihsan n. Zulkipli, sheba r. David, rajan rajabalaya and adi Idris PAP Rashidah Sa’adatul Bolkiah Institute of Health Sciences, Universiti Brunei Darussalam, Gadong, Brunei Darussalam. A BSTR ACT: Modern medicinal plant drug discovery has provided pharmacologically active compounds targeted against a multitude of conditions and diseases, such as infection, inflammation, and cancer. To date, natural products from medicinal plants remain a solid niche as a source from which cancer therapies can be derived. Among other properties, one favorable characteristic of an anticancer drug is its ability to block the uncontrollable process of cell division, as cancer cells are notorious for their abnormal cell division. There are numerous other documented works on the potential anticancer activity of drugs derived from medicinal plants, and their effects on cell division are an attractive and growing therapeutic target. Despite this, there remains a vast number of unidentified natural products that are potentially promising sources for medical applications. This mini review aims to revise the current knowledge of the effects of natural plant products on cell division. K E Y WOR DS: cell division, cancer, medicinal plants, microtubule, natural products CITATION: Zulkipli et al. Medicinal Plants: a Potential source of Compounds for Targeting Cell Division. Drug Target Insights 2015:9 9–19 doi:10.4137/DTI.s24946. RECEIVED: February 13, 2015. RESUBMITTED: april 7, 2015. ACCEPTED FOR PUBLICATION: april 20, 2015. ACADEMIC EDITOR: anuj Chauhan, editor in Chief TYPE: short review FUNDING: We would like to thank the universiti Brunei Darussalam (uBD) research Grant (UBCD/PNC2/2/RG/1(322)) for funding this research. The authors confirm that the funder had no influence over the study design, content of the article, or selection of this journal. COMPETING INTERESTS: Authors disclose no potential conflicts of interest. COPYRIGHT: © the authors, publisher and licensee Libertas academica Limited. This is an open-access article distributed under the terms of the Creative Commons CC-BY-nC 3.0 License. CORRESPONDENCE: yusri.idris@ubd.edu.bn Paper subject to independent expert blind peer review by minimum of two reviewers. all editorial decisions made by independent academic editor. upon submission manuscript was subject to anti-plagiarism scanning. Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication ethics (COPe). Published by Libertas academica. Learn more about this journal. Introduction Human beings have long used plants as a medicinal source. Their use has grown more sophisticated with modern chem- ists using compounds isolated from plants as a basis for gen- erating novel compounds with additional benefits, such as its lower toxicity and potential for combating drug-resistant diseases. Between 1981 and 2010, naturally derived products and their mimics composed an estimated 70% of new chemi- cal compounds reported.1 Naturally derived compounds with anticancer activity have also been used as the basis for original synthetic analogs, forming their own novel class of chemical compounds.2 Mammalian microtubules appear to be a common tar- get for naturally occurring toxic molecules produced by a large number of flora, presumably with the original intent of self-defense. Microtubules are a component of the cyto- skeleton, found throughout the cell cytoplasm, which is important in the process of mitosis (ie, cell division). Most microtubule-targeting compounds have been discovered in large-scale screens of natural products3,4 (Table 1). Approxi- mately 75% of the available anticancer drugs between 1940 and 2010 were naturally derived products or their mimics. Additionally, of the seven anticancer drugs approved in 2010, almost half of them exert their effects by binding onto microtubules.1 One of the biggest success stories of microtubule-targeted compounds from a naturally derived source is Paclitaxel (commercially known as Taxol), a member of the Taxane family. Paclitaxel is extracted from the bark of the Pacific yew tree (Taxus brevifolia) and acts as an antimitotic drug, by bind- ing to microtubules, thus stabilizing them and arresting cells in mitosis.5–9 Taxol and its derivatives have successfully been used clinically to treat ovarian cancer, breast cancer, and non- small cell lung cancer for almost 40 years, making Taxol the best-selling anticancer drug currently manufactured. Its suc- cess has sparked the search for similar microtubule-stabilizing compounds. Another class of microtubule-targeted compounds from a naturally derived source is the vinca alkaloids, vincristine and vinblastine, which were initially isolated from the Madagas- car periwinkle plant (Catharanthus roseus).10 The vinca alkaloids are microtubule destabilizers and have proven to be particu- larly effective against hematological malignancies,11 and their success has generated several semisynthetic derivatives. Semi- synthetic and synthetic derivatives may offer advantages over a fully natural source, as the bioactive natural compound may be present only in trace amounts. Natural compounds may instead act as lead compounds, where analogs with higher potencies and lower toxicities may be developed12,13 (Table 2). Natural products are ideal as lead compounds as their chemical struc- tures are complex and diverse (Table 3). The biggest study looking into the isolation of compounds with clinical bioac- tivity, specifically anticancer activity, from natural sources was done by the National Cancer Institute (NCI) of the National Journal name: Drug Target Insights Journal type: Short Review Year: 2015 Volume: 9 Running head verso: Zulkipli et al Running head recto: Medicinal plants: a potential source of compounds for targeting cell division http://www.la-press.com/drug-target-insights-journal-j23 http://www.la-press.com http://dx.doi.org/10.4137/DTI.S24946 http://creativecommons.org/licenses/by-nc/3.0/ http://creativecommons.org/licenses/by-nc/3.0/ mailto:yusri.idris@ubd.edu.bn http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 Zulkipli et al 10 Drug TargeT InsIghTs 2015:9 Ta b le 1 . s el ec te d co m po un ds o rig in al ly is ol at ed fr om n at ur al s ou rc es th at a ct o n m ic ro tu bu le s. B IO LO G IC A LL Y A C T IV E C O M P O U N D (S ) A N D T H E IR S T R U C T U R E S C IE N T IF IC N A M E (S ) O F N A T U R A L S O U R C E M E C H A N IS M O F A C T IO N O N M IC R O TU B U LE S S TA T U S A S A N T I- C A N C E R D R U G T E S T E D C A N C E R T Y P E S R E FE R E N C E S P ac lit ax el Ta xu s br ev ifo lia s ta bi liz es m ic ro tu bu le s In c lin ic al u se O va ria n ca nc er , b re as t c an ce r, no n- sm al l c el l l un g ca nc er , a dv an ce d K ap os i sa rc om a 47 ,4 8 V in bl as tin e V in cr is tin e C at ha ra nt hu s ro se us D es ta bi liz es m ic ro tu bu le s In c lin ic al u se a cu te ly m ph ob la st ic le uk ae m ia , b re as t ca nc er , c ho rio ca rc in om a, h od gk in ly m ph om a, K ap os i s ar co m a, M yc os is fu ng oi de s, h od gk in a nd n on -h od gk in ly m ph om a, te st ic ul ar c an ce r, ne ur o- bl as to m a, r ha dd om yc os ar co m a, W ilm s tu m ou r, bl ad de r ca nc er , t es tic ul ar c an - ce r, br ea st c an ce r, ch or io ca rc in om a, lu ng c an ce r, m ul tip le m ye lo m a, s of t t is - su e sa rc om a, b ra in tu m ou rs . L eu ka em ia , he ad a nd n ec k ca nc er s 10 ,1 1, 49 ,5 0 C ol ch ic in e C ol ch ic um a ut um na le D es ta bi liz es m ic ro tu bu le s Fa ile d an ti- ca nc er tr ia ls du e to to xi ci ty ; i n cl in ic al us e fo r go ut th er ap y h ep at oc el lu la r ca rc in om a, m ul tip le m ye lo m a, h od gk in ’s ly m ph om a, c hr on ic ly m ph at ic le uk ae m ia , b re as t c an ce r, lu ng ca nc er , c hr on ic ly m ph oc yt ic le uk ae m ia 51 – 53 P od op hy llo to xi n P od op hy llu m s pp . D es ta bi liz es m ic ro tu bu le s In u se fo r th e to pi ca l t re at - m en t o f e xt er na l g en ita l w ar ts n on e 43 ,5 4, 55 C om br et as ta tin s C om br et um c af fr um D es ta bi liz es m ic ro tu bu le s P ha se I, II c lin ic al tr ia ls ; s em i- sy nt he tic d er iv at iv e in P ha se II I c lin ic al tr ia ls a cu te m ye lo id le uk ae m ia , m ye lo dy sp la s- tic s yn dr om e, th yr oi d ca nc er , n on -s m al l ce ll lu ng c an ce r, va rio us s ol id tu m ou rs 56 n os ca pi ne P ap av er ac ea e sp p. s up pr es se s m ic ro tu bu le dy na m ic s P ha se II c lin ic al tr ia ls M ul tip le m ye lo m a 57 N o te : D at a in th is ta bl e w er e ob ta in ed fr om a c om bi na tio n of n C I D ru g D ic tio na ry ( ht tp :// w w w .c an ce r.g ov /d ru gd ic tio na ry ), p ub lis he d lit er at ur e, a nd c om pa ny w eb s ite s. http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 11Drug TargeT InsIghTs 2015:9 Medicinal plants: a potential source of compounds for targeting cell division Table 2. selected synthetic and semisynthetic compounds originally isolated from natural sources that act on microtubules. COMPOUND AND STRUCTURE ORIGINAL COMPOUND MECHANISM OF ACTION ON MICROTUBULES STATUS AS ANTI- CANCER DRUG TESTED CANCER TYPES REFERENCES Vindesine Vinca alkaloids Destabilizes microtubules In clinical use Various lung cancers, various haematological malignancies, mel- anoma, renal cancer, colorectal can- cer and breast cancer. Currently in clinical trials for other cancer types 58 Vinorelbine Vinca alkaloids Destabilizes microtubules In clinical use non-small cell lung cancer, meta- static breast cancer, renal cancer 42,59,60 Vinflunine Vinca alkaloids Destabilizes microtubules In clinical use Bladder cancer, urethral cancer, ureteral cancer, cancer of the renal pelvis 42 Docetaxel Paclitaxel stabilizes microtubules In clinical use Breast cancer, gastric cancer, non- small cell lung cancer, prostrate can- cer, squamous cell carcinoma of the head and neck, stomach cancer 61 Cabazitaxel Paclitaxel stabilizes microtubules In clinical use Metastatic prostrate cancer 62,63 Larotaxel Paclitaxel stabilizes microtubules Phase III clinical trials Breast cancer, pancreatic cancer, urothelial tract cancer, bladder can- cer, various solid tumours 63 Tesetaxel Paclitaxel stabilizes microtubules Phase II clinical trials gastric cancer, melanoma, bladder cancer, breast cancer, prostate can- cer, various solid tumours 63 Ombrabulin Combrestatin Destabilizes microtubules Discontinued, due to insufficient clinical benefit soft tissue sarcoma, non-small cell lung cancer, ovarian cancer, various solid tumours 55,64 Fosbretabulin Combrestatin Destabilizes microtubules Phase I and phase II clinical trials Ovarian cancer, gastrointestinal neu- roendocrine tumours, ovarian epi- thelial, fallopian tube, and primary peritoneal cancers, gliomas, thyroid cancer 65 Crolibulin Combrestatin Destabilizes microtubules Phase I and phase II clinical trials Thyroid cancer 66 Verubulin Combrestatin Destabilizes microtubules Phase I and phase II clinical trials glioblastoma 66–68 Note: Data in this table were obtained from a combination of nCI Drug Dictionary (http://www.cancer.gov/drugdictionary), published literature, and company web sites. Institute of Health in USA from 1960 to 1980.14 However, it is estimated that .90% of plant species worldwide remain understudied. Discovery of drug molecules has been limited because of genomic instability and drug resistance characteris- tics in certain cancer cells.15 Therefore, modern drug discovery has shifted to personalized treatment of patients, where drugs are selected for specific molecular targets, taking advantage of the vulnerabilities of cancer in a particular patient, leading to increased interest in studying traditional herbs as an alterna- tive source of anticancer drugs because of its multitargeted characteristic.16 The Role of the Microtubule in Cell Division Microtubules are a class of the cytoskeletal proteins pres- ent in all eukaryotic cells. They form long, filamentous, poly- meric structures within the cell, composed of α- and β-tubulin heterodimers, of which there are several isotypes.17 The dif- ferent isotypes of tubulin in human beings are summarized in Table 4. Microtubules play many roles in eukaryotic cells, including development and maintenance of cell shape,18 intracellular transport,19 cell motility,20,21 cell signaling,22 and cell division.23 Cell division, or mitosis, is a crucial event in the cell cycle that results in the division of a single cell into two identical daughter cells with the equal distribution of genetic materi- als (Fig. 1). During mitosis, the cytoskeleton forms a super- structure called the mitotic spindle, which facilitates many of the cell division processes. Mitosis involves a series of stages. The initial prophase and prometaphase stages are where there is condensation of chromosomes, which then attaches to the mitotic spindle. The chromosomes then align at the equa- tor of the mitotic spindle (metaphase) before the sister chro- mosomes segregate into daughter cells (anaphase). The final stage is where the chromosomes decondense and the cells divide fully into two daughter cells (telophase). All the stages of mitosis must be regulated for the proper development and function of a multicellular organism. Central to the function of microtubules is the regulation of microtubule dynamics. Microtubule filaments are able to polymerize and depolymerize stochastically within a cell, in what is termed http://www.la-press.com/drug-target-insights-journal-j23 http://www.la-press.com Zulkipli et al 12 Drug TargeT InsIghTs 2015:9 Ta b le 3 . C he m ic al s tr uc tu re s of n at ur al m ic ro tu bu le -t ar ge tin g co m po un ds a nd th ei r sy nt he tic a nd s em is yn th et ic d er iv at iv es . V in b la st in e V in cr is ti ne V in d es in e V in fl u n in e V in o re lb in e http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 13Drug TargeT InsIghTs 2015:9 Medicinal plants: a potential source of compounds for targeting cell division P ac lit ax el D o ce ta xe l C ab az it ax el L ar o ta xe l Te se ta xe l C om br es ta tin O m br ab ul in Fi sb re ta b u lin (c on tin ue d) http://www.la-press.com/drug-target-insights-journal-j23 http://www.la-press.com Zulkipli et al 14 Drug TargeT InsIghTs 2015:9 C ro lib u lin V er u b u lin C ol ch ic in e P o d o p hy llo to xi n N o sc ap in e Ta b le 3 . ( C on tin ue d ) http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 15Drug TargeT InsIghTs 2015:9 Medicinal plants: a potential source of compounds for targeting cell division Table 4. subtypes and isoforms of microtubules. TUBULIN SUBTYPE ISOTYPE GENE LENGTH (AMINO ACIDS) TISSUE DISTRIBUTION PUTATIVE FUNCTION (IF ANY) ALTERED EXPRES- SION IN CANCERS? α 1a TuBa1a 451 ubiquitous No isoform-specific function identified no 1B TuBa1B 451 ubiquitous no 1C TuBa1C 449 ubiquitous no 3C TuBa3C 450 enriched expression in testis, fallopian tube, soft tissues, central nervous system and other selected tissues Variable expression 3D TuBa3D 450 enriched expression in testis, fallopian tube, soft tissues, central nervous system and other selected tissues Decreased 3e TuBa3e 448 enriched expression in testis, fallopian tube, soft tissues, central nervous system and other selected tissues Decreased 4a TuBa4a 446 ubiquitous no 8 TuBa8 449 ubiquitous, but enriched in heart muscle, skeletal muscle and testis Decreased β 1 TuBB1 451 enriched in haematopoietic cells May play a role in micro- tubule stability, as well as interaction with actin Increased on expo- sure to microtubule- targeting drugs 2a TuBB2a 445 ubiquitous, enriched in brain May play a role in neuronal differentation Increased in microtubule-target- ing drug-resistant cancers 2B TuBB2B 445 ubiquitous, enriched in brain May play a role in neuronal differentation no 3 TuBB3 450 Mostly expressed in central and peripheral nervous system May play a role in neuronal differentiation. May help cells cope with oxidative stress Overexpressed in aggressive tumours 4a TuBB4a 444 highly expressed in brain, moderate levels in testis, very low levels in other tissues Occurs in axonemes, may be required for determina- tion of axonemal microtu- bule structure Increased on expo- sure to microtubule- targeting drugs 4B TuBB4B 445 ubiquitous Occurs in axonemes, may be required for determina- tion of axonemal microtu- bule structure no 5 TuBB 444 ubiquitously expressed with highest levels in spleen, thymus and immature brain unknown unknown 6 TuBB6 446 ubiquitous, with highest expression in the breast and lung unknown Largely decreased 8 TuBB8 444 ubiquitous, enriched in clili- ated cells and lymphoid tissue unknown unknown γ 1 TuBg1 451 ubiquitous Important for nucleation and polarity of microtubules, mostly found in microtubule- organising centres unknown 2 TuBg2 451 ubiquitous Important for nucleation and polarity of microtubules, mostly found in microtubule- organising centres unknown δ – TuBD1 453 ubiquitous sperm differentiation Decreased ε – TuBe1 475 Majority of tissues Centrosome cycle Decreased Notes: Data in this table were obtained from uniprot (http://www.uniprot.org) and Proteinatlas (http://www.proteinatlas.org). http://www.la-press.com/drug-target-insights-journal-j23 http://www.la-press.com Zulkipli et al 16 Drug TargeT InsIghTs 2015:9 Figure 1. The process of cell division in mammalian cells. This figure illustrates the different microtubule structures present during different stages of the cell cycle. In the interphase stage of the cell cycle, microtubules (green) emanate out from the microtubule-organizing center, the centrosome (dark blue circle), forming an array that extends toward the cell periphery. During the mitotic stage of the cell cycle, the centrosomes are duplicated and separated to form spindle poles, while the microtubule cytoskeleton is reorganized to form a superstructure called the mitotic spindle. The mitotic spindle is responsible for mitotic events such as chromosome congression and chromosome segregation. Two stages of the mitotic stage of the cell cycle are illustrated—metaphase and anaphase. at metaphase, the mitotic spindle holds sister chromatids (blue) together at the cell equator. at anaphase, the cell elongates the spindle poles move further apart and the sister chromatids move toward the opposite poles. Black arrows indicate the path normally followed by a cell in a cell cycle. When the cell cycle is disrupted at mitosis by tubulin-binding agents, the cell is unable to complete mitosis and follows an alternative pathway (red arrows) where it undergoes mitotic arrest and eventually cell death. all stages of mitosis must be regulated for proper development and function of a multicellular organism. Unregulated mitosis may lead to an overgrowth of cells, as in cancer. The ability to carry out an infinite number of cell divisions is one of the hallmarks of cancer. Blockage of any stage of mitosis may not allow the cells to complete mitosis, resulting in cell cycle arrest and ultimately, cell death. as microtubule dynamicity.24 Microtubule dynamics are tightly regulated within cells, through the binding of various regulatory proteins, expression of different tubulin isotypes, and posttranslational modifications of tubulin subunits.25,26 Dynamic microtubules have a very short half-life of a few minutes, or even seconds, whereas stable microtubules have half-lives of minutes to hours.27 During mitosis, microtubules are the main compo- nents of the mitotic spindle, where microtubule dynam- ics are increased significantly.27,28 Dynamic microtubules are required for all stages of mitosis: from capturing and congressing chromosomes to the metaphase plate,29 pull- ing chromosomes toward opposite poles and initiating ana- phase,30 and finally cytokinesis to complete mitosis.31,32 Microtubule-binding compounds may either stabilize micro- tubules (promoting growth and not supporting shrinkage of the microtubule filament) or destabilize microtubules (pro- moting shrinkage and not supporting growth of the microtu- bule filament). Any alterations in microtubule dynamics will affect the different events in mitosis. For example, if micro- tubule dynamics are suppressed, chromosomes may not be able to congress to the metaphase plate.33,34 The presence of a single uncongressed chromosome is enough to induce mitotic arrest.1 Accordingly, altered microtubule dynamics is among the major causes of mitotic arrest. A cell that is arrested in mitosis for a prolonged time may eventually undergo apopto- sis, or programed cell death.35 At present, most of the drugs used to treat cancer target microtubule dynamics in order to arrest cancerous cells in mitosis. Microtubules—A Potential Target for Cancer Therapy Unregulated cell division may lead to an overgrowth of cells, as in cancer. The ability to carry out an infinite number of cell divisions is one of the hallmarks of cancer.36 Blockage of any stage of mitosis may not allow the cells to complete mitosis, resulting in cell cycle arrest and ultimately, cell death. Micro- tubules represent the best and most successful target thus far http://www.la-press.com http://www.la-press.com/drug-target-insights-journal-j23 17Drug TargeT InsIghTs 2015:9 Medicinal plants: a potential source of compounds for targeting cell division identified in cancer treatment.37–39 Cancer cells are sensitive to microtubule poisons that arrest cells in mitosis because they undergo mitosis more frequently than normal cells. At high con- centrations, anticancer drugs that target microtubules may act in one of the two ways. Each approach has different effects, includ- ing affecting the polymerized microtubule mass, destabilization of microtubules (decreases microtubule mass), and stabilization of microtubules (increases microtubule mass), dependent on the site of binding on the microtubule lattice.40 The effects of each compound on microtubules are indicated in both Tables 1 and 2. Currently, there are two main classes of microtubule- binding anticancer drugs. These are the microtubule destabiliz- ers, such as the Vinca alkaloids,41–44 and microtubule stabilizers that prevent microtubule disassembly without affecting their polymerization, such as the taxanes.6 However, studies have shown that various microtubule-targeting drugs, irrespective of their effects on polymerized microtubule mass at high con- centrations, all suppress microtubule dynamics at lower concen- trations, ie, prevent the growth or shrinkage of microtubules without changing the microtubule polymer mass6,8,33,34,42–45 (Fig. 2). In this way, changes in microtubule dynamics can be used as an indicator of the efficacy of the anticancer activities of a naturally derived compound. Conversely, tumors can acquire resistance to microtubule- targeting drugs. Although a discussion on the resistance mechanisms to these drugs is beyond the scope of this review, the possible methods of resistance include multidrug resistance pumps, altered drug binding, altered microtubule assembly, altered tubulin synthesis, and alterations in microtubule- interacting proteins (refer to Fojo and Menefee46 for a more extensive review). As with all drugs, the toxic side effects of microtu- bule-targeting agents must be taken into account. Owing to the physiological functions of microtubules, treatment with microtubule-targeting agents often exhibits myelo- suppression and peripheral neuropathy. The specif icity of each compound must therefore be tested. The cancers identif ied to be susceptible to each drug are illustrated in Tables 1 and 2. Conclusion Mitosis is an important stage of the cell cycle, which is deregulated in cancer, leading to uncontrolled cancer growth. An important facilitator of mitosis is the microtubule cyto- skeleton. Hence, many anticancer drugs target the microtu- bule skeleton in order to arrest cancer cells in mitosis, which eventually leads to cell death. Most of these microtubule- targeting drugs act by suppressing microtubule dynamics, which is particularly important for the microtubule function in mitosis. Interestingly, many of the microtubule-binding anticancer drugs are derived from natural sources, including Taxol and the vinca alkaloids, two very successful classes of anticancer drugs. Therefore, there is great potential for the isolation of compounds with similar microtubule-targeting Figure 2. Microtubule dynamic instability. The figure illustrates the growth and shrinkage of a single microtubule, with each row representative of a single time point. Microtubules are composed of stable αβ-tubulin heterodimers that are arranged in a head-to-tail fashion, forming a polar structure. each heterodimer is illustrated as a single circle. Microtubules therefore consist of two distinct ends: the plus (+) end and the minus (-) end. In vivo, the—ends are anchored at the microtubule-organizing centers. The + ends are more dynamic than the—ends, with the microtubule end constantly switching between growth and shrinkage in what is termed dynamic instability. Microtubules are normally very dynamic (top), with tubulin subunits randomly added or lost from both ends. In vivo, microtubule elongation usually occurs in the plus end. When microtubule dynamics are suppressed (for example, through the action of tubulin-binding agents) (bottom), tubulin subunits are rarely added or lost from the microtubule ends. activities from medicinal plants. Future aims for the develop- ment of novel microtubule-binding agents are the develop- ment of compounds specific to cancer cells, thereby reducing potential toxic side effects, as well as the development of compounds that are able to overcome current drug-resistant cancers. Author Contributions Prepared the first draft of the manuscript: INZ. Contributed to the writing of the manuscript: SRD, RR, and AI. Jointly developed the structure and arguments for the paper: INZ, SRD, RR, and AI. Made critical revisions and approved the final version: AI. All the authors reviewed and approved the final manuscript. http://www.la-press.com/drug-target-insights-journal-j23 http://www.la-press.com Zulkipli et al 18 Drug TargeT InsIghTs 2015:9 R EFER ENCES 1. Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod. 2012;75(3):311–335. 2. Loong HH, Yeo W. Microtubule-targeting agents in oncology and therapeutic potential in hepatocellular carcinoma. Onco Targets Ther. 2014;7:575–585. 3. Balunas MJ, Kinghorn AD. Drug discovery from medicinal plants. Life Sci. 2005;78(5):431–441. 4. Gurib-Fakim A. Medicinal plants: traditions of yesterday and drugs of tomor- row. Mol Aspects Med. 2006;27(1):1–93. 5. Arnal I, Wade RH. 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