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ISSN (Print): 2210-3155
ISSN (Online): 2210-3163

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Review Article

Aryltetralin-type Lignan of Podophyllum: A Comprehensive Review

Author(s): Dharmendra Kumar*, Mogana Rajagopal, Gabriel Akyirem Akowuah, Yong-Xin Lee, Chua Wei Chong , Pei Wen Gan and Jeou Chyi Liew

Volume 12, Issue 5, 2022

Published on: 10 February, 2021

Article ID: e100221191294 Pages: 10

DOI: 10.2174/2210315511666210210160903

Price: $65

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Abstract

Podophyllotoxin is a nonalkaloid toxin aryltetralin lactone lignan, occurring naturally and extracted from the rhizomes and roots of Podophyllum species. Podophyllotoxin and its derivatives have been shown to possess a broad spectrum of pharmacological activities, mainly antineoplastic and antiviral properties. Podophyllotoxin serves as a potential anticancer agent and also the precursor for the chemical synthesis of some clinically important anticancer agents. The chemical modification and pharmacological investigation of podophyllotoxin derivatives have become a concern nowadays. Research interest has been stimulated towards the innovation of podophyllotoxin derivatives as the semi-synthetic anticancer agents, especially etoposide and teniposide. Podophyllotoxin and its derivatives are available in several formulations and also found to be effective in combination therapy. This review article aims to provide an overview of the role of podophyllotoxin, its mechanism of action, pharmacological activities, pharmacokinetics, available formulations, and its effects in combination therapy. This article also reviews the biosynthesis, structure and modifications of podophyllotoxin and its derivatives as an anticancer agent.

Keywords: Podophyllotoxin, anticancer agents, etoposide, teniposide, lignan, structure-activity relationship.

Graphical Abstract

[1]
Cancer. 2020. Available from: https://www.who.int/health-topics/cancer#tab=tab_1
[2]
Jackson, D.E.; Dewick, P.M. Aryltetralin lignans from Podophyllum hexandrum and Podophyllum peltatum. Phytochemistry, 1984, 23, 1147-1152.
[http://dx.doi.org/10.1016/S0031-9422(00)82628-X]
[3]
Zhang, X.; Rakesh, K.P.; Shantharam, C.S.; Manukumar, H.M.; Asiri, A.M.; Marwani, H.M.; Qin, H.-L. Podophyllotoxin derivatives as an excellent anticancer aspirant for future chemotherapy: A key current imminent needs. Bioorg. Med. Chem., 2018, 26(2), 340-355.
[http://dx.doi.org/10.1016/j.bmc.2017.11.026] [PMID: 29269253]
[4]
Cheng, W.H.; Shang, H.; Niu, C.; Zhang, Z.H.; Zhang, L.M.; Chen, H.; Zou, Z.M. Synthesis and evaluation of new podophyllotoxin derivatives with in vitro anticancer activity. Molecules, 2015, 20(7), 12266-12279.
[http://dx.doi.org/10.3390/molecules200712266] [PMID: 26154885]
[5]
Mayeaux, E.J., Jr; Harper, M.B.; Barksdale, W.; Pope, J.B. Noncervical human papillomavirus genital infections. Am. Fam. Physician, 1995, 52(4), 1137-1146.
[PMID: 7668205]
[6]
Ardalani, H.; Avan, A.; Ghayour-Mobarhan, M. Podophyllotoxin: A novel potential natural anticancer agent. Avicenna J. Phytomed., 2017, 7(4), 285-294.
[PMID: 28884079]
[7]
Podophyllotoxin: Indication, Dosage, Side Effect, Precaution | MIMS.com Malaysia. 2020. Available from: https://www.mims.com/malaysia/drug/info/podophyllotoxin?mtype=generic
[8]
Podofilox Monograph for Professionals. 2020. Available from: https://www.drugs.com/monograph/podofilox.html
[9]
Molluscum Contagiosum: Causes, Symptoms, Treatment, and Pictures. Healthline, 2020. Available from: https://www.healthline.com/health/molluscum-contagiosum
[10]
You, Y. Podophyllotoxin derivatives: Current synthetic approaches for new anticancer agents. Curr. Pharm. Des., 2005, 11(13), 1695-1717.
[http://dx.doi.org/10.2174/1381612053764724] [PMID: 15892669]
[11]
Thompson, D.S.; Greco, A.; Miller, A.A.; Srinivas, N.R.; Igwenezue, K.B.; Hainsworth, J.D.; Schacter, L.P.; Kaul, S.; Barbhaiya, R.H.; Garrow, C. A phase I study of etoposide phosphate administered as a daily 30-minute infusion for 5 days. Clin. Pharmacol. Ther., 1995, 57(5), 499-507.
[http://dx.doi.org/10.1016/0009-9236(95)90034-9] [PMID: 7768072]
[12]
Montecucco, A.; Zanetta, F.; Biamonti, G. Molecular mechanisms of etoposide. EXCLI J., 2015, 14, 95-108.
[http://dx.doi.org/10.17179/excli2015-561] [PMID: 26600742]
[13]
Giri, A.; Lakshmi Narasu, M. Production of podophyllotoxin from Podophyllum hexandrum: A potential natural product for clinically useful anticancer drugs. Cytotechnology, 2000, 34(1-2), 17-26.
[http://dx.doi.org/10.1023/A:1008138230896] [PMID: 19003377]
[14]
Brenner, L. What are the main function of microtubules in the cell? Sciencing, 2019. Available from: https://sciencing.com/main-function-microtubules-cell-8552402.html
[15]
Lodish, H. The Role of Topoisomerases in DNA Replication. Molecular Cell Biology, 4th ed; U.S. National Library of Medicine, 2000.
[16]
Hartmann, J.T.; Lipp, H.P. Camptothecin and podophyllotoxin derivatives: Inhibitors of topoisomerase I and II - mechanisms of action, pharmacokinetics and toxicity profile. Drug Saf., 2006, 29(3), 209-230.
[http://dx.doi.org/10.2165/00002018-200629030-00005] [PMID: 16524321]
[17]
Ying-Qian, L. Podophyllotoxin: Current perspectives. Curr. Bioact. Compd., 2007, 3(1), 37-66.
[http://dx.doi.org/10.2174/157340707780126499]
[18]
Peter, I.C.; Maurice, L.S. The clinical pharmacology of etoposide and teniposide. Clin. Pharmacokinet., 1987, 2012(12), 223-252.
[http://dx.doi.org/10.2165/00003088-198712040-00001]
[19]
Saetern, A.M.; Brandl, M.; Bakkelund, W.H.; Sveinbjørnsson, B. Cytotoxic effect of different camptothecin formulations on human colon carcinoma in vitro. Anticancer Drugs, 2004, 15(9), 899-906.
[http://dx.doi.org/10.1097/00001813-200410000-00011] [PMID: 15457131]
[20]
What is the role of podophyllin in the treatment of human papillomavirus (HPV) infection?. Medscape.com, 2020.
[21]
Henwood, J.M.; Brogden, R.N. Etoposide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in combination chemotherapy of cancer. Drugs, 1990, 39(3), 438-490.
[http://dx.doi.org/10.2165/00003495-199039030-00008] [PMID: 2184009]
[22]
Hande, K.R. Etoposide: four decades of development of a topoisomerase II inhibitor. Eur. J. Cancer, 1998, 34(10), 1514-1521.
[http://dx.doi.org/10.1016/S0959-8049(98)00228-7] [PMID: 9893622]
[23]
Hande, K.R. Topoisomerase II inhibitors.Cancer chemotherapy and biological response modifiers; Giaccone, G.; Schil- sky, RL.; Sondel, P., Eds.; Amsterdam: Elsevier, 2003, pp. 103-25.
[http://dx.doi.org/10.1016/S0921-4410(03)21005-X]
[24]
Relling, M.V.; Nemec, J.; Schuetz, E.G.; Schuetz, J.D.; Gonzalez, F.J.; Korzekwa, K.R. O-demethylation of epipodophyllotoxins is catalyzed by human cytochrome P450 3A4. Mol. Pharmacol., 1994, 45(2), 352-358.
[PMID: 8114683]
[25]
Rodman, J.H.; Abromowitch, M.; Sinkule, J.A.; Hayes, F.A.; Rivera, G.K.; Evans, W.E. Clinical pharmacodynamics of continuous infusion teniposide: systemic exposure as a determinant of response in a phase I trial. J. Clin. Oncol., 1987, 5(7), 1007-1014.
[http://dx.doi.org/10.1200/JCO.1987.5.7.1007] [PMID: 3598607]
[26]
Lum, B.L.; Kaubisch, S.; Yahanda, A.M.; Adler, K.M.; Jew, L.; Ehsan, M.N.; Brophy, N.A.; Halsey, J.; Gosland, M.P.; Sikic, B.I. Alteration of etoposide pharmacokinetics and pharmacodynamics by cyclosporine in a phase I trial to modulate multidrug resistance. J. Clin. Oncol., 1992, 10(10), 1635-1642.
[http://dx.doi.org/10.1200/JCO.1992.10.10.1635] [PMID: 1403041]
[27]
Baker, D.K.; Relling, M.V.; Pui, C.H.; Christensen, M.L.; Evans, W.E.; Rodman, J.H. Increased teniposide clearance with concomitant anticonvulsant therapy. J. Clin. Oncol., 1992, 10(2), 311-315.
[http://dx.doi.org/10.1200/JCO.1992.10.2.311] [PMID: 1732431]
[28]
Splinter, T.A.; Holthuis, J.J.; Kok, T.C.; Post, M.H. Absolute bioavailability and pharmacokinetics of oral teniposide. Semin. Oncol., 1992, 19(2)(Suppl. 6), 28-34.
[PMID: 1411636]
[29]
Chattopadhyay, S.; Mehra, R.S.; Srivastava, A.K.; Bhojwani, S.S.; Bisaria, V.S. Effect of major nutrients on podophyllotoxin production in Podophyllum hexandrum suspension cultures. Appl. Microbiol. Biotechnol., 2003, 60(5), 541-546.
[http://dx.doi.org/10.1007/s00253-002-1149-7] [PMID: 12536253]
[30]
Golušin, Z.; Jovanović, M.; Matić, M.; Roš, T.; Vujanović, L.; Nikolić, O. Clinical efficacy of combination therapy with podophyllotoxin and liquid nitrogen cryotherapy in the treatment of genital warts in men. Acta Dermatovenerol. Croat., 2019, 27(4), 250-259.
[PMID: 31969238]
[31]
Kalita, B.; Ranjan, R.; Gupta, M.L. Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling. Apoptosis, 2019, 24(3-4), 326-340.
[http://dx.doi.org/10.1007/s10495-019-01519-x] [PMID: 30725351]
[32]
Khaled, M.; Jiang, Z.Z.; Zhang, L.Y. Deoxypodophyllotoxin: A promising therapeutic agent from herbal medicine. J. Ethnopharmacol., 2013, 149(1), 24-34.
[http://dx.doi.org/10.1016/j.jep.2013.06.021] [PMID: 23792585]
[33]
Lv, M.; Xu, H. Recent advances in semisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: An update (2008-2010). Mini Rev. Med. Chem., 2011, 11(10), 901-909.
[http://dx.doi.org/10.2174/138955711796575461] [PMID: 21781026]
[34]
Beers, S.A.; Imakura, Y.; Dai, H.J.; Li, D.H.; Cheng, Y.C.; Lee, K.H. Antitumor agents, 99. Synthetic ring C aromatized podophyllotoxin analogues as potential inhibitors of human DNA topoisomerase II. J. Nat. Prod., 1988, 51(5), 901-905.
[http://dx.doi.org/10.1021/np50059a014] [PMID: 2849640]
[35]
Parker, A.L.; Kavallaris, M.; McCarroll, J.A. Microtubules and their role in cellular stress in cancer. Front. Oncol., 2014, 4, 153.
[http://dx.doi.org/10.3389/fonc.2014.00153] [PMID: 24995158]
[36]
Cragg, G.; Kingston, D.; Newman, D. Anticancer Agents From Natural Products; CRC Press: Boca Raton, 2012, pp. 72-80.
[37]
MacRae, W.D.; Hudson, J.B.; Towers, G.H. The antiviral action of lignans. Planta Med., 1989, 55(6), 531-535.
[http://dx.doi.org/10.1055/s-2006-962087] [PMID: 2559420]
[38]
Bertounesque, E.; Imbert, T.; Monneret, C. Synthesis of podophyllotoxin A-ring pyridazine analogue. Tetrahedron, 1996, 52(45), 14235-14246.
[http://dx.doi.org/10.1016/0040-4020(96)00862-9]
[39]
Sudo, K.; Konno, K.; Shigeta, S.; Yokota, T. Inhibitory effects of podophyllotoxin derivatives on herpes simplex virus replication. Antivir. Chem. Chemother., 1998, 9(3), 263-267.
[http://dx.doi.org/10.1177/095632029800900307] [PMID: 9875405]
[40]
Castro, A.; del Corral, J.M.; Gordaliza, M.; Grande, C.; Gomez-Zurita, A.; Garcia-Gravalos, D. Synthesis of podophyllotoxin congeners as potential DNA topoisomerase II inhibitors. Eur. J. Med. Chem., 2003, 38, 65-74.
[http://dx.doi.org/10.1016/S0223-5234(02)00007-7] [PMID: 12593917]
[41]
Lee, C.C.; Huang, T.S. A novel topoisomerase II poison GL331 preferentially induces DNA cleavage at (C/G)T sites and can cause telomere DNA damage. Pharm. Res., 2001, 18(6), 846-851.
[http://dx.doi.org/10.1023/A:1011048831698] [PMID: 11474790]
[42]
Zhang, Y.L.; Shen, Y.C.; Wang, Z.Q.; Chen, H.X.; Guo, X.; Cheng, Y.C.; Lee, K.H. Antitumor agents, 130, Novel 4 β-arylamino derivatives of 3′,4′-didemethoxy-3′,4′-dioxo-4-deoxypodophyllotoxin as potent inhibitors of human DNA topoisomerase II. J. Nat. Prod., 1992, 55(8), 1100-1111.
[http://dx.doi.org/10.1021/np50086a011] [PMID: 1331331]

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