Abstract
Background: Polyalthia cerasoides is well known for its therapeutic effects and is extensively used by the tribal people of South India and Africa to treat infertility, toothache, inflammation, rheumatism, fever, and to combat stress.
Objective: In the present research, the anti-proliferative potential of two bioactive compounds isolated from the stem bark of P. cerasoides (Roxb.) Bedd. of the Annonaceae family was investigated.
Methods: The dried stem bark was powdered and subjected to extraction using methanol and further partitioned using petroleum ether. Yellow viscous oil was isolated from the petroleum ether fraction using column and preparative thin-layer chromatography. The chromatographic fractions were characterized using GC-MS. The anti-proliferative effect of the isolated compounds was assessed against HepG2 Cells using MTT- Cytotoxicity test. Furthermore, comparative in-silico docking studies were performed to predict the binding pattern of isolated molecules individually, as well as simultaneously with α, β-tubulin, a critical protein involved in the molecular mechanism of microtubule formation.
Results: GC-MS analysis of yellow viscous oil from petroleum fraction confirmed the presence of two labdane diterpenes that were identified as 12E-3,4-Seco-labda-4(18),8(17),12,14-tetraen-3-oic acid, and methyl harvadate C by mass fragmentation analysis. The MTT-cytotoxicity assay showed the dose-dependent cytotoxic effect on HepG2 Cells. The comparative docking studies of the isolated compounds exhibited strong interactions with the α, β-tubulin protein.
Conclusion: The prominent anti-proliferative effect exhibited by the isolated compounds, along with effective binding to α, β-tubulin protein, encourages their future utilization as prominent anti-cancer molecules.
Keywords: Labdane diterpenoids, anti-proliferative, Polyalthia cerasoides, in-silico docking, MLSD, cytotoxicity.
Graphical Abstract
[1]
Jain R, Kosta S, Tiwari A. Ayurveda and cancer. Pharmacognosy Res 2010; 2(6): 393-4.
[http://dx.doi.org/10.4103/0974-8490.75463] [PMID: 21713145]
[http://dx.doi.org/10.4103/0974-8490.75463] [PMID: 21713145]
[2]
World Health Organization. Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. Int Agency Res Cancer 2018; 50(1): 106-7.
[3]
Liu H, Lv L, Yang K. Chemotherapy targeting cancer stem cells. Am J Cancer Res 2015; 5(3): 880-93.
[PMID: 26045975]
[PMID: 26045975]
[4]
Mudhafar M, Zainol I, Desa S, Nor C, Jaafar A. Mini-review of phytochemistry for polyalithia longifolia. Eur J of Analy Chem 2019; 14.
[5]
Demain AL, Vaishnav P. Natural products for cancer chemotherapy. Microb Biotechnol 2011; 4(6): 687-99.
[http://dx.doi.org/10.1111/j.1751-7915.2010.00221.x] [PMID: 21375717]
[http://dx.doi.org/10.1111/j.1751-7915.2010.00221.x] [PMID: 21375717]
[6]
Pellegrini F, Budman DR. Review: tubulin function, action of antitubulin drugs, and new drug development. Cancer Invest 2005; 23(3): 264-73.
[http://dx.doi.org/10.1081/CNV-200055970] [PMID: 15948296]
[http://dx.doi.org/10.1081/CNV-200055970] [PMID: 15948296]
[7]
Yadava U, Gupta H, Roychoudhury M. Stabilization of microtubules by taxane diterpenoids: insight from docking and MD simulations. J Biol Phys 2015; 41(2): 117-33.
[http://dx.doi.org/10.1007/s10867-014-9369-5] [PMID: 25542396]
[http://dx.doi.org/10.1007/s10867-014-9369-5] [PMID: 25542396]
[8]
Katsetos CD, Herman MM, Mörk SJ. Class III beta-tubulin in human development and cancer. Cell Motil Cytoskeleton 2003; 55(2): 77-96.
[http://dx.doi.org/10.1002/cm.10116] [PMID: 12740870]
[http://dx.doi.org/10.1002/cm.10116] [PMID: 12740870]
[9]
Katsetos CD, Dráber P. Tubulins as therapeutic targets in cancer: from bench to bedside. Curr Pharm Des 2012; 18(19): 2778-92.
[http://dx.doi.org/10.2174/138161212800626193] [PMID: 22390762]
[http://dx.doi.org/10.2174/138161212800626193] [PMID: 22390762]
[10]
Polur H, Joshi T, Workman CT, Lavekar G, Kouskoumvekaki I. Back to the roots: Prediction of biologically active natural products from ayurveda traditional medicine. Mol Inform 2011; 30(2-3): 181-7.
[http://dx.doi.org/10.1002/minf.201000163] [PMID: 27466772]
[http://dx.doi.org/10.1002/minf.201000163] [PMID: 27466772]
[12]
Ravikumar YS, Mahadevan KM, Kumaraswamy MN, et al. Antioxidant, cytotoxic and genotoxic evaluation of alcoholic extract of Polyalthia cerasoides (Roxb.) Bedd. Environ Toxicol Pharmacol 2008; 26(2): 142-6.
[http://dx.doi.org/10.1016/j.etap.2008.03.001] [PMID: 21783902]
[http://dx.doi.org/10.1016/j.etap.2008.03.001] [PMID: 21783902]
[13]
Ravikumar YS, Mahadevan KM, Manjunatha H, Satyanarayana ND. Antiproliferative, apoptotic and antimutagenic activity of isolated compounds from Polyalthia cerasoides seeds. Phytomedicine 2010; 17(7): 513-8.
[http://dx.doi.org/10.1016/j.phymed.2009.09.005] [PMID: 19879119]
[http://dx.doi.org/10.1016/j.phymed.2009.09.005] [PMID: 19879119]
[14]
Chen C-Y, Chang F-R, Shih YC, et al. Cytotoxic constituents of Polyalthia longifolia var. pendula. J Nat Prod 2000; 63(11): 1475-8.
[http://dx.doi.org/10.1021/np000176e] [PMID: 11087586]
[http://dx.doi.org/10.1021/np000176e] [PMID: 11087586]
[15]
Tegos G, Stermitz FR, Lomovskaya O, Lewis K. Multidrug pump inhibitors uncover remarkable activity of plant antimicrobials. Antimicrob Agents Chemother 2002; 46(10): 3133-41.
[http://dx.doi.org/10.1128/AAC.46.10.3133-3141.2002] [PMID: 12234835]
[http://dx.doi.org/10.1128/AAC.46.10.3133-3141.2002] [PMID: 12234835]
[16]
Kanokmedhakul S, Kanokmedhakul K, Yodbuddee D, Phonkerd N. New antimalarial bis-dehydroaporphine alkaloids from Polyalthia debilis. J Nat Prod 2003; 66(5): 616-9.
[http://dx.doi.org/10.1021/np020498d] [PMID: 12762793]
[http://dx.doi.org/10.1021/np020498d] [PMID: 12762793]
[17]
de Boer HJ, Kool A, Broberg A, Mziray WR, Hedberg I, Levenfors JJ. Anti-fungal and anti-bacterial activity of some herbal remedies from Tanzania. J Ethnopharmacol 2005; 96(3): 461-9.
[http://dx.doi.org/10.1016/j.jep.2004.09.035] [PMID: 15619565]
[http://dx.doi.org/10.1016/j.jep.2004.09.035] [PMID: 15619565]
[18]
Marthanda Murthy M, Subramanyam M, Hima Bindu M, Annapurna J. Antimicrobial activity of clerodane diterpenoids from Polyalthia longifolia seeds. Fitoterapia 2005; 76(3-4): 336-9.
[http://dx.doi.org/10.1016/j.fitote.2005.02.005] [PMID: 15890465]
[http://dx.doi.org/10.1016/j.fitote.2005.02.005] [PMID: 15890465]
[19]
Qayed WS, Aboraia AS, Abdel-Rahman HM, Youssef AF. Annonaceous acetogenins as a new anticancer agent. Der Pharma Chem 2015; 7(6): 24-35.
[20]
Padma JP, Chansauria PN, Khosa RL, Ray AK. Effect of Annooa muricata and polyalthia cerasoides on brain neurotransimitters and enzyme monoamine oxidase following cold immobilization stress. J Nat Rem 2001; 1(2): 144-6.
[21]
Cousins D, Huffman M. Medicinal properties in the diet of gorillas: an ethno-pharmacological evaluation. Afr Study Monogr 2002; 23(June): 65-89.http://repository.kulib.kyotou.ac.jp/dspace/handle/2433/68214
[22]
Goudarshivananavar BC, Vigneshwaran V, Somegowda M, Dharmappa KK, Pramod SN. Therapeutic potential of Polyalthia cerasoides stem bark extracts against oxidative stress and nociception. Anc Sci Life 2015; 35(2): 70-8.
[http://dx.doi.org/10.4103/0257-7941.171667] [PMID: 26865738]
[http://dx.doi.org/10.4103/0257-7941.171667] [PMID: 26865738]
[23]
Parker AL, Kavallaris M, McCarroll JA. Microtubules and their role in cellular stress in cancer. JUN. Front Oncol 2014; 4.
[24]
Prota AE, Bargsten K, Diaz JF, et al. A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs. Proc Natl Acad Sci USA 2014; 111(38): 13817-21.
[http://dx.doi.org/10.1073/pnas.1408124111] [PMID: 25114240]
[http://dx.doi.org/10.1073/pnas.1408124111] [PMID: 25114240]
[25]
Loske C, Neumann A, Cunningham AM, et al. Cytotoxicity of advanced glycation endproducts is mediated by oxidative stress. J Neural Transm (Vienna) 1998; 105(8-9): 1005-15.
[http://dx.doi.org/10.1007/s007020050108] [PMID: 9869332]
[http://dx.doi.org/10.1007/s007020050108] [PMID: 9869332]
[26]
Rao Rao Shimoga Janakirama A, Mathad Shivayogi S, Kolkar Satyanarayana J, Chapeyil Kumaran R. Characterization of isolated compounds from Morus spp. and their biological activity as anticancer molecules. Bioimpacts 2021; 11(3): 187-97.
[http://dx.doi.org/10.34172/bi.2021.09] [PMID: 34336607]
[http://dx.doi.org/10.34172/bi.2021.09] [PMID: 34336607]
[27]
Sj AR, Ck R. S R, M P. Dehydroabietylamine, A Diterpene from carthamus tinctorious L. Showing antibacterial and anthelmintic effects with computational evidence. Curr Computeraided Drug Des 2020; 16(3): 231-7.
[http://dx.doi.org/10.2174/1573409915666190301142811] [PMID: 30827256]
[http://dx.doi.org/10.2174/1573409915666190301142811] [PMID: 30827256]
[28]
Löwe J, Li H, Downing KH, Nogales E. Refined structure of alpha beta-tubulin at 3.5 A resolution. J Mol Biol 2001; 313(5): 1045-57.
[http://dx.doi.org/10.1006/jmbi.2001.5077] [PMID: 11700061]
[http://dx.doi.org/10.1006/jmbi.2001.5077] [PMID: 11700061]
[29]
Xu D, Zhang Y. Improving the physical realism and structural accuracy of protein models by a two-step atomic-level energy minimization. Biophys J 2011; 101(10): 2525-34.
[http://dx.doi.org/10.1016/j.bpj.2011.10.024] [PMID: 22098752]
[http://dx.doi.org/10.1016/j.bpj.2011.10.024] [PMID: 22098752]
[30]
Kollman P. Free-energy calculations - Applications to chemical and biochemical phenomena. Chem Rev 1993; 93(7): 2395-417.
[http://dx.doi.org/10.1021/cr00023a004]
[http://dx.doi.org/10.1021/cr00023a004]
[31]
Sanner MF. Python: a programming language for software integration and development. J Mol Graph Model 1999; 17(1): 57-61.
[PMID: 10660911]
[PMID: 10660911]
[32]
Aditya Rao SJ, Jeevitha B, Smitha R, Ramesh CK, Paramesha M, Jamuna KS. Wound healing activity from the leaf extracts of morus laevigata and in silico binding studies from its isolates with Gsk 3- β. Int J Res Dev Pharm Life Sci 2015; 4(4): 1686-96.www.ijrdpl.com
[33]
Paramesha M, Ramesh CK, Krishna V, Kumar Swamy HM, Aditya Rao SJ, Hoskerri J. Effect of dehydroabietylamine in angiogenesis and GSK3-$β$ inhibition during wound healing activity in rats. Med Chem Res 2015; 24(1): 295-303.
[http://dx.doi.org/10.1007/s00044-014-1110-1]
[http://dx.doi.org/10.1007/s00044-014-1110-1]
[34]
Li H, Li C. Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein. J Comput Chem 2010; 31(10): 2014-22.
[http://dx.doi.org/10.1002/jcc.21486] [PMID: 20166125]
[http://dx.doi.org/10.1002/jcc.21486] [PMID: 20166125]
[35]
Paramesha M, Manivannan S, Rao SJA, Srikanth KS, Neelwarne B, Shetty NP. Augmentation of pyrethrins content in callus of
Chrysanthemum cinerariaefolium and establishing its insecticidal
activity by molecular docking of NavMS Sodium Channel Pore
receptor. 3 Biotech 2018; 8(8): 367.
[37]
Raghavendra S, Aditya Rao SJ, Kumar V, Ramesh CK. Multiple ligand simultaneous docking (MLSD): A novel approach to study the effect of inhibitors on substrate binding to PPO. Comput Biol Chem 2015; 59(Pt A): 81-6.
[http://dx.doi.org/10.1016/j.compbiolchem.2015.09.008] [PMID: 26414950]
[http://dx.doi.org/10.1016/j.compbiolchem.2015.09.008] [PMID: 26414950]
[38]
Jolad SD, Timmermann BN, Hoffmann JJ, Bates RB, Siahaan TJ. Havardic acids A-F and havardiol, labdane diterpenoids from Grindelia havardii. Phytochemistry 1987; 26(2): 483-9.
[http://dx.doi.org/10.1016/S0031-9422(00)81438-7]
[http://dx.doi.org/10.1016/S0031-9422(00)81438-7]
[39]
Pertino MW, Theoduloz C, Bastías M, Schmeda-Hirschmann G. Dimeric labdane diterpenes: synthesis and antiproliferative effects. Molecules 2013; 18(5): 5936-53.
[http://dx.doi.org/10.3390/molecules18055936] [PMID: 23698047]
[http://dx.doi.org/10.3390/molecules18055936] [PMID: 23698047]
[40]
Chen SP, Dong M, Kita K, et al. Anti-proliferative and apoptosis-inducible activity of labdane and abietane diterpenoids from the pulp of Torreya nucifera in HeLa cells. Mol Med Rep 2010; 3(4): 673-8.
[PMID: 21472297]
[PMID: 21472297]
[41]
Nambiar SS, Paramesha M, Shetty NP. Comparative analysis of phytochemical profile, antioxidant activities and foam prevention abilities of whole fruit, pulp and seeds of Emblica officinalis. J Food Sci Technol 2015; 52(11): 7254-62.
[http://dx.doi.org/10.1007/s13197-015-1844-x]
[http://dx.doi.org/10.1007/s13197-015-1844-x]
[42]
Sukanya SH, Venkatesh T, Aditya Rao SJ, Nibin M. Efficient L-Proline catalyzed synthesis of some new thiazolopyrimidine derivatives and evaluation of their pharmacological activities. J Mol Struct 2022; 1247131324.
[http://dx.doi.org/10.1016/j.molstruc.2021.131324]
[http://dx.doi.org/10.1016/j.molstruc.2021.131324]
[43]
Hegazy ME, Ohta S, Abdel-Latif FF, et al. Cyclooxygenase (COX)-1 and -2 inhibitory labdane diterpenes from Crassocephalum mannii. J Nat Prod 2008; 71(6): 1070-3.
[http://dx.doi.org/10.1021/np800017x] [PMID: 18473477]
[http://dx.doi.org/10.1021/np800017x] [PMID: 18473477]
[44]
Franco MS, Cordero CP, Morantes SJ, Aristizabal F, Osorio C. Cytotoxic labdane diterpenoids isolated from the hexane fraction of the croton stipuliformis stem bark. Vitae 2011; 18(2): 173-82.
[45]
Dal Piaz F, Cotugno R, Lepore L, et al. Chemical proteomics reveals HSP70 1A as a target for the anticancer diterpene oridonin in Jurkat cells. J Proteomics 2013; 82: 14-26.
[http://dx.doi.org/10.1016/j.jprot.2013.01.030] [PMID: 23416714]
[http://dx.doi.org/10.1016/j.jprot.2013.01.030] [PMID: 23416714]
[46]
Endringer DC, Taveira FSN, Kondratyuk TP, Pezzuto JM, Bragaa FC. Cancer chemoprevention activity of labdane diterpenes from rhizomes of Hedychium coronarium. Rev Bras Farmacogn 2014; 24(4): 408-12.
[http://dx.doi.org/10.1016/j.bjp.2014.08.002]
[http://dx.doi.org/10.1016/j.bjp.2014.08.002]
[47]
Petiwala SM, Johnson JJ. Diterpenes from rosemary (Rosmarinus officinalis): Defining their potential for anti-cancer activity. Cancer Lett 2015; 367(2): 93-102.
[http://dx.doi.org/10.1016/j.canlet.2015.07.005] [PMID: 26170168]
[http://dx.doi.org/10.1016/j.canlet.2015.07.005] [PMID: 26170168]
[48]
Shibazaki M, Maesawa C, Akasaka K, et al. Transcriptional and post-transcriptional regulation of βIII-tubulin protein expression in relation with cell cycle-dependent regulation of tumor cells. Int J Oncol 2012; 40(3): 695-702.
[PMID: 22159867]
[PMID: 22159867]
[49]
Karki R, Ferlini C. Class III beta-tubulin, drug resistance and therapeutic approaches in cancers. Atlas Genet Cytogenet Oncol Haematol 2014; 11.
[http://dx.doi.org/10.4267/2042/54174]
[http://dx.doi.org/10.4267/2042/54174]
[50]
Subramanyan S, Deepika S, Ajith A, et al. Antiproliferative labdane diterpenes from the rhizomes of Hedychium flavescens Carey ex Roscoe. Chem Biol Drug Des 2021; 98(4): 501-6.
[http://dx.doi.org/10.1111/cbdd.13906] [PMID: 34143941]
[http://dx.doi.org/10.1111/cbdd.13906] [PMID: 34143941]
[51]
Castillo QA, Triana J, Eiroa JL, et al. ent-Labdane diterpenoids from the aerial parts of eupatorium obtusissmum. J Nat Prod 2016; 79(4): 907-13.
[http://dx.doi.org/10.1021/acs.jnatprod.5b00954] [PMID: 27023255]
[http://dx.doi.org/10.1021/acs.jnatprod.5b00954] [PMID: 27023255]
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