Podophyllotoxin: a novel potential natural anticancer agent

Document Type: Mini Review Article

Authors

1 Department of Horticultural Sciences, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective: The aim of the present review is to give an overview about the role, biosynthesis, and characteristics of Podophyllotoxin (PTOX) as a potential antitumor agent with particular emphasis on key biosynthesis processes, function of related enzymes and characterization of genes encoding the enzymes.
Materials and Methods: Google scholar, PubMed and Scopus were searched for literatures which have studied identification, characterization, fermentation and therapeutic effects of PTOX and published in English language until end of 2016.
Results: PTOX is an important plant-derived natural product, has derivatives such as etoposide and teniposide, which have been used as therapies for cancers and venereal wart. PTOX structure is closely related to the aryltetralin lactone lignans that have antineoplastic and antiviral activities. Podophyllum emodi Wall. (syn. P. hexandrum) and Podophyllum peltatum L. (Berberidaceae) are the major sources of PTOX. It has been shown that ferulic acid and methylenedioxy substituted cinnamic acid are the enzymes involved in PTOX synthesis. PTOX prevents cell growth via polymerization of tubulin, leading to cell cycle arrest and suppression of the formation of the mitotic-spindles microtubules.
 

Conclusion: Several investigations have been performed in biosynthesis of PTOX such as cultivation of these plants, though they were unsuccessful. Thus, it is important to find alternative sources to satisfy the pharmaceutical demand for PTOX. Moreover, further preclinical studies are warranted to explore the molecular mechanisms of these agents in treatment of cancer and their possible potential to overcome chemoresistance of tumor cells.

 

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Main Subjects


Abad AS, López-Pérez JL, Del Olmo E, Garcia-Fernandez LF, Francesch AS, Trigili C, Barasoain I, Andreu JM, Díaz JF, San Feliciano A. 2012. Synthesis and antimitotic and tubulin interaction profiles of novel pinacol derivatives of podophyllotoxins. J Med Chem, 55: 6724-6737.

Aly AH, Debbab A, Kjer J, Proksch P. 2010. Fungal endophytes from higher plants: a prolific source of phytochemicals and other bioactive natural products. Fungal Divers, 41: 1-16.

Ardalani H, Hassanpour Moghadam M, Rahimi R, Soltani J, Mozayanimonfared A, Moradi M, Azizi A. 2016. Sumac as a novel adjunctive treatment in hypertension: A randomized, double-blind, placebo-controlled clinical trial. RSC Adv, 6: 11507-11512.

Arican O, Guneri F, Bilgic K, Karaoglu A. 2004. Topical Imiquimod 5% Cream in External Anogenital Warts: A Randomized, Double‐Blind, Placebo‐Controlled Study. J Dermatol, 31: 627-631.

Baldi A, Jain A, Gupta N, Srivastava A, Bisaria V. 2008. Co-culture of arbuscular mycorrhiza-like fungi (Piriformospora indica and Sebacina vermifera) with plant cells of Linum album for enhanced production of podophyllotoxins: a first report. Biotechnol Lett, 30: 1671-1677.

Berim A, Ebel R, Schneider B, Petersen M. 2008. UDP-glucose:(6-methoxy) podophyllotoxin 7-O-glucosyltransferase from suspension cultures of Linum nodiflorum. Phytochemistry, 69: 374-381.

Beutner K, Friedman-Kien A, Artman N, Conant M, Illeman M, Thisted R, King D. 1989. Patient-applied podofilox for treatment of genital warts. Lancet, 333: 831-834.

Beutner KR, Spruance SL, Hougham AJ, Fox TL, Owens ML, Douglas JM. 1998. Treatment of genital warts with an immune-response modifier (imiquimod). J Am Acad Dermatol, 38: 230-239.

Broomhead AJ, Dewick PM. 1990a. Aryltetralin lignans from Linum flavum and Linum capitatum. Phytochemistry, 29: 3839-3844.

Broomhead AJ, Dewick PM. 1990b. Tumour-inhibitory aryltetralin lignans in Podophyllum versipelle, Diphylleia cymosa and Diphylleia grayi. Phytochemistry, 29: 3831-3837.

Cantrell CL, Zheljazkov VD, Carvalho CR, Astatkie T, Jeliazkova EA, Rosa LH. 2014. Dual extraction of essential oil and podophyllotoxin from creeping juniper (Juniperus horizontalis). Plos One, 9: e106057.

Cantrell CL, Zheljazkov VD, Osbrink WL, Castro A, Maddox V, Craker LE, Astatkie T. 2013. Podophyllotoxin and essential oil profile of Juniperus and related species. Ind Crop Prod, 43: 668-676.

Chashmi NA, Sharifi M, Yousefzadi M, Behmanesh M, Rezadoost H, Cardillo A, Palazon J. 2013. Analysis of 6-methoxy podophyllotoxin and podophyllotoxin in hairy root cultures of Linum album Kotschy ex Boiss. Med Chem Res, 22: 745-752.

Chattopadhyay S, Srivastava AK, Bhojwani SS, Bisaria VS. 2002. Production of podophyllotoxin by plant cell cultures of Podophyllum hexandrum in bioreactor. J Biosci Bioeng, 93: 215-220.

Chen JY, Tang YA, Li WS, Chiou YC, Shieh JM, Wang YC. 2013. A synthetic podophyllotoxin derivative exerts anti-cancer effects by inducing mitotic arrest and pro-apoptotic ER stress in lung cancer preclinical models. Plos One, 8: e62082.

Choi JY, Cho HJ, Hwang SG, Kim WJ, Kim JI, Um HD, Park JK. 2015. Podophyllotoxin acetate enhances γ-ionizing radiation-induced apoptotic cell death by stimulating the ROS/p38/caspase pathway. Biomed Pharmacother, 70: 111-118.

Cushman KE, Maqbool M, Gerard PD, Bedir E, Lata H, Moraes RM. 2003. Variation of podophyllotoxin in leaves of Eastern Red Cedar (Juniperus virginiana). Planta Med, 69: 477-478.

Dar RA, Saba I, Shahnawaz M, Sangale MK, Ade AB, Rather SA, Qazi PH. 2013. Isolation, purification and characterization of carboxymethyl cellulase (CMCase) from endophytic Fusarium oxysporum producing podophyllotoxin. Adv Enz Res, 1: 91.

Deng JF, Huang CC, Lee YJ. 1998. Toxicokinetic parameters in the management of poisoning: An example of podophylotoxin intoxication. J Toxicol Sci, 23: 205-208.

Dhar U, Manjkhola S, Joshi M, Bhatt A, Bisht A, Joshi M. 2002. Current status and future strategy for development of medicinal plants sector in Uttaranchal, India. Cur Sci, 83: 956-964.

Edwards L, Ferenczy A, Eron L, Baker D, Owens ML, Fox TL, Hougham AJ, Schmitt KA. 1998. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol, 134: 25-30.

Eyberger AL, Dondapati R, Porter JR. 2006. Endophyte fungal isolates from Podophyllum peltatum produce podophyllotoxin. J Nat Prod, 69: 1121-1124.

Geo von krogh M. 1982. Podophyllotoxin in serum: absorption subsequent to three-day repeated applications of a 0.5% ethanolic preparation on condylomata acuminata. Sex Transm Dis, 9: 26-33.

Giri A, Narasu ML. 2000. Production of podophyllotoxin from Podophyllum hexandrum: a potential natural product for clinically useful anticancer drugs. Cytotechnology, 34: 17-26.

Gordaliza M, Garcıa P, Del Corral JM, Castro M, Gomez-Zurita M. 2004. Podophyllotoxin: distribution, sources, applications and new cytotoxic derivatives. Toxicon, 44: 441-459.

Guerram M, Jiang ZZ, Zhang LY. 2012. Podophyllotoxin, a medicinal agent of plant origin: past, present and future. Chin J Nat Med, 10: 161-169.

Huang JX, Zhang J, Zhang XR, Zhang K, Zhang X, He XR. 2014. Mucor fragilis as a novel source of the key pharmaceutical agents podophyllotoxin and kaempferol. Pharm Biol, 52: 1237-1243.

Jandaghi P, Noroozi M, Ardalani H, Alipour M. 2016. Lemon balm: A promising herbal therapy for patients with borderline hyperlipidemia—A randomized double-blind placebo-controlled clinical trial. Complement Ther Med, 26: 136-140.

Jeong GS, Kwon OK, Park BY, Oh SR, Ahn KS, Chang MJ, Oh WK, Kim JC, Min BS, Kim YC. 2007. Lignans and coumarins from the roots of Anthriscus sylvestris and their increase of caspase-3 activity in HL-60 cells. Biol Pharm Bull, 30: 1340-1343.

Kesting JR, Staerk D, Tejesvi MV, Kini KR, Prakash HS, Jaroszewski JW. 2009. HPLC‐SPE‐NMR Identification of a Novel Metabolite Containing the Benzo [c] oxepin Skeleton from the Endophytic Fungus Pestalotiopsis virgatula Culture. Planta Med, 75: 1104-1106.

Khaled M, Jiang ZZ, Zhang LY. 2013. Deoxypodophyllotoxin: A promising therapeutic agent from herbal medicine. J Ethnopharmacol, 149: 24-34.

Kirby P, Dunne A, King DH, Corey L. 1990. Double-blind randomized clinical trial of self-administered podofilox solution versus vehicle in the treatment of genital warts. Am J Med, 88: 465-469.

Komericki P, Akkilic-Materna M, Strimitzer T, Aberer W. 2011. Efficacy and safety of imiquimod versus podophyllotoxin in the treatment of anogenital warts. Sex Trans Dis, 38: 216-218.

Konuklugil B. 1996a. Aryltetralin lignans from genus Linum. Fitoterapia, 67: 379-381.

Konuklugil B. 1996b. Investigation of podophyllotoxin in some plants in Lamiaceae using HPLC. J Fac Pharm Ankara, 25: 23-27.

Koulman A, Kubbinga ME, Batterman S, Woerdenbag HJ, Pras N, Woolley JG, Quax WJ. 2003. A phytochemical study of lignans in whole plants and cell suspension cultures of Anthriscus sylvestris. Planta Med, 69: 733-738.

Kour A, Shawl AS, Rehman S, Sultan P, Qazi PH, Suden P, Khajuria RK, Verma V. 2008. Isolation and identification of an endophytic strain of Fusarium oxysporum producing podophyllotoxin from Juniperus recurva. World J Microb Biot, 24: 1115-1121.

Kuhnt M, Rimpler H, Heinrich M. 1994. Lignans and other compounds from the Mixe Indian medicinal plant Hyptis verticillata. Phytochemistry, 36: 485-489.

Kumar A, Patil D, Rajamohanan PR, Ahmad A. 2013. Isolation, purification and characterization of vinblastine and vincristine from endophytic fungus Fusarium oxysporum isolated from Catharanthus roseus. Plos One, 8: e71805.

Kumar P, Pal T, Sharma N, Kumar V, Sood H, Chauhan RS. 2015. Expression analysis of biosynthetic pathway genes vis-à-vis podophyllotoxin content in Podophyllum hexandrum Royle. Protoplasma, 252: 1253-1262.

Kupchan SM, Hemingway JC, Knox JR. 1965. Tumor inhibitors VII. Podophyllotoxin, the active principle of Juniperus virginiana. J Pharm Sci, 54: 659-660.

Kusari S, Lamshöft M, Spiteller M. 2009. Aspergillus fumigatus Fresenius, an endophytic fungus from Juniperus communis L. Horstmann as a novel source of the anticancer pro‐drug deoxypodophyllotoxin. J Appl Microbiol, 107: 1019-1030.

Kusari S, Zühlke S, Spiteller M. 2011. Chemometric Evaluation of the Anti‐cancer Pro‐drug Podophyllotoxin and Potential Therapeutic Analogues in Juniperus and Podophyllum Species. Phytochem Analysis, 22: 128-143.

Lacey C, Goodall R, Tennvall GR, Maw R, Kinghorn G, Fisk P, Barton S, Byren I, Group, P.P.G.W.C.T. 2003. Randomised controlled trial and economic evaluation of podophyllotoxin solution, podophyllotoxin cream, and podophyllin in the treatment of genital warts. Sex Trans Infect, 79: 270-275.

Liang Z, Zhang J, Zhang X, Li J, Zhang X, Zhao C. 2015. Endophytic fungus from Sinopodophyllum emodi (Wall.) Ying that produces Podophyllotoxin. J Chromatogr Sci, bmv124.

Lim S, Grassi J, Akhmedjanova V, Debiton E, Balansard G, Beliveau R, Barthomeuf C. 2007. Reversal of P-glycoprotein-mediated drug efflux by eudesmin from Haplophyllum perforatum and cytotoxicity pattern versus diphyllin, podophyllotoxin and etoposide. Planta Med, 73: 1563.

Liu JF, Sang CY, Xu XH, Zhang LL, Yang X, Hui L, Zhang JB, Chen SW, 2013. Synthesis and cytotoxic activity on human cancer cells of carbamate derivatives of 4β-(1, 2, 3-triazol-1-yl) podophyllotoxin. Eur J Med Chem, 64: 621-628.

Liu YQ, Tian J, Qian K, Zhao XB, Morris‐Natschke SL, Yang L, Nan X, Tian X, Lee KH. 2015. Recent Progress on C‐4‐Modified Podophyllotoxin Analogs as Potent Antitumor Agents. Med Res Rev, 35: 1-62.

Loike JD. 1982. VP16-213 and podophyllotoxin. Cancer Chemoth Pharm, 7: 103-111.

Luo J, Hu Y, Kong W, Yang M. 2014. Evaluation and structure-activity relationship analysis of a new series of arylnaphthalene lignans as potential anti-tumor agents. Plos one, 9: e93516.

Miyata M, Itoh K, Tachibana S. 1998. Extractives of Juniperus chinensis L. I: Isolation of podophyllotoxin and yatein from the leaves of J. chinensis. J Wood Sci, 44: 397-400.

Muranaka T, Miyata M, Ito K, Tachibana S. 1998. Production of podophyllotoxin in Juniperus chinensis callus cultures treated with oligosaccharides and a biogenetic precursor in honour of Professor GH Neil Towers 75th Birthday. Phytochemistry, 49: 491-496.

Nadeem M, Ram M, Alam P, Ahmad MM, Mohammad A, Al-Qurainy F, Khan S, Abdin MZ. 2012. Fusarium solani, P1, a new endophytic podophyllotoxin-producing fungus from roots of Podophyllum hexandrum. Afr J Microbiol Res, 6: 2493-2499.

Passarella D, Peretto B, Yepes RB, Cappelletti G, Cartelli D, Ronchi C, Snaith J, Fontana G, Danieli B, Borlak J. 2010. Synthesis and biological evaluation of novel thiocolchicine–podophyllotoxin conjugates. Eur J Med Chem, 45: 219-226.

Petersen M, Alfermann WA. 2001. The production of cytotoxic lignans by plant cell cultures. Appl Microbiol Biot, 55: 135-142.

Puri SC, Nazir A, Chawla R, Arora R, Riyaz-ul-Hasan S, Amna T, Ahmed B, Verma V, Singh S, Sagar R. 2006. The endophytic fungus Trametes hirsuta as a novel alternative source of podophyllotoxin and related aryl tetralin lignans. J Biotechnol, 122: 494-510.

Ramos AC, Peláez R, López JL, Caballero E, Medarde M, San Feliciano A. 2001. Heterolignanolides. Furo-and thieno-analogues of podophyllotoxin and thuriferic acid. Tetrahedron, 57: 3963-3977.

Samadi A, Jafari M, Nejhad NM, Hossenian F. 2014. Podophyllotoxin and 6-methoxy podophyllotoxin Production in Hairy Root Cultures of Liunm mucronatum ssp. mucronatum. Pharmacogn Mag, 10: 154.

San Feliciano A, Del Corral JMM, Gordaliza M, Castro MA. 1989a. Acetylated lignans from Juniperus sabina. Phytochemistry, 28: 659-660.

San Feliciano A, Medarde M, Lopez JL, Puebla P, Del Corral JMM, Barrer AF, 1989b. Lignans from Juniperus thurifera. Phytochemistry, 28: 2863-2866.

Sasheva P, Ionkova I. 2015. Podophyllotoxin production by cell culturrs of Linum thracicum ssp thracicum degen elicited eith methyl jasmonate and salicylic acid. Cr Acad Bul Sci, 883-888.

Schulz B, Boyle C, Draeger S, Römmert AK, Krohn K. 2002. Endophytic fungi: a source of novel biologically active secondary metabolites. Mycol Res, 106: 996-1004.

Seidel V, Windhövel J, Eaton G, Alfermann WA, Arroo RR, Medarde M, Petersen M, Woolley JG. 2002. Biosynthesis of podophyllotoxin in Linum album cell cultures. Planta, 215: 1031-1039.

Shin SY, Yong Y, Kim CG, Lee YH, Lim Y. 2010. Deoxypodophyllotoxin induces G 2/M cell cycle arrest and apoptosis in HeLa cells. Cancer Lett, 287: 231-239.

Soltani J, Moghaddam M S H. 2015. Fungal Endophyte Diversity and Bioactivity in the Mediterranean Cypress Cupressus sempervirens. Curr Microbiol, 70: 580-586.

Suzuki S, Sakakibara N, Umezawa T, Shimada M. 2002. Survey and enzymatic formation of lignans of Anthriscus sylvestris. J Wood Sci, 48: 536-541.

Syed T, Lundin S, Ahmad M. 1994. Topical 0.3% and 0.5% podophyllotoxin cream for self-treatment of molluscum contagiosum in males. Dermatology, 189: 65-68.

Utsugi T, Shibata J, Sugimoto Y, Aoyagi K, Wierzba K, Kobunai T, Terada T, Oh-hara T, Tsuruo T, Yamada Y. 1996. Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. Cancer Res, 56: 2809-2814.

Von Krogh G, Hellberg D. 1991. Self-treatment using a 0.5% podophyllotoxin cream of external genital condylomata acuminata in women. A placebo-controlled, double-blind study. Sex Trans Dis, 19: 170-174.

Von Krogh G, Szpak E, Andersson M, Bergelin I. 1994. Self-treatment using 0.25%-0.50% podophyllotoxin-ethanol solutions against penile condylomata acuminata: a placebo-controlled comparative study. Genitourin Med, 70: 105-109.

Wang J, Li G, Lu H, Zheng Z, Huang Y, Su W. 2000. Taxol from Tubercularia sp. strain TF5, an endophytic fungus of Taxus mairei. FEMS Microbiol Lett, 193: 249-253.

Wanner J, Jirovetz L, Schmidt E. 2015. Callitris intratropica RT Baker & HG Smith as a Novel Rich Source of Deoxypodophyllotoxin. Curr Bioact Compd, 11: 73-77.

Wilson J. 2002. Treatment of genital warts—what's the evidence? Int J Std Aids, 13: 216-222.

Wink M. 2012. Medicinal plants: a source of anti-parasitic secondary metabolites. Molecules, 17: 12771-12791.

Wrasidlo W, Gaedicke G, Guy RK, Renaud J, Pitsinos E, Nicolaou KC, Reisfeld RA, Lode HN. 2002. A novel 2 ‘-(N-methylpyridinium acetate) prodrug of paclitaxel induces superior antitumor responses in preclinical cancer models. Bioconjugate Chem, 13: 1093-1099.

Xu H, Lv M, Tian X. 2009. A review on hemisynthesis, biosynthesis, biological activities, mode of action, and structure-activity relationship of podophyllotoxins: 2003-2007. Curr Med Chem, 16: 327-349.

Yousefzadi M, Sharifi M, Chashmi NA, Behmanesh M, Ghasempour A. 2010. Optimization of podophyllotoxin extraction method from Linum album cell cultures. Pharma Biol, 48: 1421-1425.

Yu PZ, Wang LP, Chen ZN. 1991. A new podophyllotoxin-type lignan from Dysosma versipellis var. tomentosa. J Nat Prod, 54: 1422-1424.

Zhang J, Chen J, Liang Z, Zhao C. 2014. New lignans and their biological activities. Chem Biodivers, 11: 1-54.