Cytotoxic Agents in the Minor Alkaloid Groups of the Amaryllidaceae^{[ # ]}

 

 Permissions and Reprints

Abstract

Over 600 alkaloids have to date been identified in the plant family Amaryllidaceae. These have been arranged into as many as 15 different groups based on their characteristic structural features. The vast majority of studies on the biological properties of Amaryllidaceae alkaloids have probed their anticancer potential. While most efforts have focused on the major alkaloid groups, the volume and diversity afforded by the minor alkaloid groups have promoted their usefulness as targets for cancer cell line screening purposes. This survey is an in-depth review of such activities described for around 90 representatives from 10 minor alkaloid groups of the Amaryllidaceae. These have been evaluated against over 60 cell lines categorized into 18 different types of cancer. The montanine and cripowellin groups were identified as the most potent, with some in the latter demonstrating low nanomolar level antiproliferative activities. Despite their challenging molecular architectures, the minor alkaloid groups have allowed for facile adjustments to be made to their structures, thereby altering the size, geometry, and electronics of the targets available for structure-activity relationship studies. Nevertheless, it was seen with a regular frequency that the parent alkaloids were better cytotoxic agents than the corresponding semisynthetic derivatives. There has also been significant interest in how the minor alkaloid groups manifest their effects in cancer cells. Among the various targets and pathways in which they were seen to mediate, their ability to induce apoptosis in cancer cells is most appealing.

^# Dedicated to Professor Arnold Vlietinck on the occasion of his 80th birthday.

Publication History

Received: 12 December 2020

Accepted after revision: 16 February 2021

Article published online:
11 March 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

• References

• 1 World Health Organization. WHO Report on Cancer. Geneva: WHO Press; 2020: 1-160
  Google Scholar
• 2 Cragg GM, Pezzuto JM. Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med Princ Pract 2016; 25: 41-59
  CrossrefPubMedGoogle Scholar
• 3 Bastida J, Lavilla R, Viladomat F. Chemical and biological Aspects of Narcissus Alkaloids. In: Cordell GA. ed. The Alkaloids. Amsterdam: Elsevier; 2006: 87-179
  Google Scholar
• 4 Nair JJ, van Staden J. Pharmacological and toxicological insights to the South African Amaryllidaceae. Food Chem Toxicol 2013; 62: 262-275
  CrossrefPubMedGoogle Scholar
• 5 Kornienko A, Evidente A. Chemistry, biology and medicinal potential of narciclasine and its congeners. Chem Rev 2008; 108: 1982-2014
  CrossrefPubMedGoogle Scholar
• 6 Ceriotti G. Narciclasine: an antimitotic substance from Narcisssus bulbs. Nature 1967; 213: 595-596
  CrossrefPubMedGoogle Scholar
• 7 Pettit GR, Gaddamidi V, Cragg GM. Antineoplastic agents. 105. Zephyranthes grandiflora . J Nat Prod 1984; 47: 1018-1020
  CrossrefPubMedGoogle Scholar
• 8 Nair JJ, van Staden J, Bastida J. Cytotoxic Alkaloid Constituents of the Amaryllidaceae. In: Rahman A-U. ed. Studies in natural Products Chemistry. Oxford: Elsevier; 2016: 107-156
  Google Scholar
• 9 Jin Z, Yao G. Amaryllidaceae and Sceletium alkaloids. Nat Prod Rep 2019; 36: 1462-1488
  CrossrefPubMedGoogle Scholar
• 10 Kaya GI, Sarıkaya B, Onur MA, Somer NU, Viladomat F, Codina C, Bastida J, Lauinger IL, Kaiser M, Tasdemir D. Antiprotozoal alkaloids from Galanthus trojanus . Phytochem Lett 2011; 4: 301-305
  CrossrefPubMedGoogle Scholar
• 11 NʼTamon AD, Okpekon AT, Bony NF, Bernadat G, Gallard JF, Kouamé T, Séon-Méniel B, Leblanc K, Rharrabti S, Mouray E, Grellier P, Ake M, Amin NC, Champy P, Beniddir MA, Le Pogam P. Streamlined targeting of Amaryllidaceae alkaloids from the bulbs of Crinum scillifolium using spectrometric and taxonomically-informed scoring metabolite annotations. Phytochemistry 2020; 179: 112485/1-112485/8
  PubMedGoogle Scholar
• 12 Hulcova D, Breiterova K, Zemanova L, Siatka T, Safratova M, Vaneckova N, Hostalkova A, Wsol V, Cahlikova L. AKR1C3 inhibitory potency of naturally-occurring Amaryllidaceae alkaloids of different structural types. Nat Prod Commun 2017; 12: 245-246
  PubMedGoogle Scholar
• 13 Hulcova D, Breiterova K, Siatka T, Klimova K, Davani L, Safratova M, Hostalkova A, de Simone A, Andrisano V, Cahlikova L. Amaryllidaceae alkaloids as potential glycogen synthase kinase-3β inhibitors. Molecules 2018; 23: 719/1-719/9
  CrossrefPubMedGoogle Scholar
• 14 Shawky E. In-silico profiling of the biological activities of Amaryllidaceae alkaloids. J Pharm Pharmacol 2017; 69: 1592-1605
  CrossrefPubMedGoogle Scholar
• 15 Zupko I, Rethey B, Hohmann J, Molnar J, Ocsovski I, Falkay G. Antitumor activity of alkaloids derived from Amaryllidaceae species. In Vivo 2009; 23: 41-48
  Google Scholar
• 16 Ibrahim SRM, Mohamed GA, Shaala LA, Youssef DTA, El Sayed KA. New alkaloids from Pancratium maritimum . Planta Med 2013; 79: 1480-1484
  Article in Thieme ConnectPubMedGoogle Scholar
• 17 Luo Z, Wang F, Zhang J, Li X, Zhang M, Hao X, Xue Y, Li Y, Horgen FD, Yao G, Zhang Y. Cytotoxic alkaloids from the whole plants of Zephyranthes candida . J Nat Prod 2012; 75: 2113-2120
  CrossrefPubMedGoogle Scholar
• 18 Ang S, Liu XM, Huang XJ, Zhang DM, Zhang W, Wang L, Ye WC. Four new Amaryllidaceae alkaloids from Lycoris radiata and their cytotoxicity. Planta Med 2015; 81: 1712-1718
  Article in Thieme ConnectPubMedGoogle Scholar
• 19 Zhu YY, Li X, Yu HY, Xiong YF, Zhang P, Pi HF, Ruan HL. Alkaloids from the bulbs of Lycoris longituba and their neuroprotective and acetylcholinesterase inhibitory activities. Arch Pharm Res 2015; 38: 604-613
  CrossrefPubMedGoogle Scholar
• 20 Morikawa T, Ninomiya K, Kuramoto H, Kamei I, Yoshikawa M, Muraoka O. Phenylethanoid and phenylpropanoid glycosides with melanogenesis inhibitory activity from the flowers of Narcissus tazetta var. chinensis . J Nat Med 2016; 70: 89-101
  CrossrefPubMedGoogle Scholar
• 21 Cole ER, de Andrade JP, Filho JFA, Schmitt EFP, Alves-Araujo A, Bastida J, Endringer DC, de Souza Borges W, Lacerda V. Cytotoxic and genotoxic activities of alkaloids from the bulbs of Griffinia gardneriana and Habranthus itaobinus (Amaryllidaceae). Anticancer Agents Med Chem 2019; 19: 707-717
  CrossrefPubMedGoogle Scholar
• 22 Weniger B, Italiano L, Beck JP, Bastida J, Bergoñon S, Codina C, Lobstein A, Anton R. Cytotoxic activity of Amaryllidaceae alkaloids. Planta Med 1995; 61: 77-79
  Article in Thieme ConnectPubMedGoogle Scholar
• 23 Hao B, Shen SF, Zhao QJ. Cytotoxic and antimalarial alkaloids from the bulbs of Lycoris radiata . Molecules 2013; 18: 2458-2468
  CrossrefPubMedGoogle Scholar
• 24 Song JH, Zhang L, Song Y. Alkaloids from Lycoris aurea and their cytotoxicities against the head and neck squamous cell carcinoma. Fitoterapia 2014; 95: 121-126
  CrossrefPubMedGoogle Scholar
• 25 Ka S, Masi M, Merindol N, Di Lecce R, Plourde MB, Seck M, Gorecki M, Pescitelli G, Desgagne-Penix I, Evidente A. Gigantelline, gigantellinine and gigancrinine, cherylline- and crinine-type alkaloids isolated from Crinum jagus with anti-acetylcholinesterase activity. Phytochemistry 2020; 175: 112390/1-112390/9
  PubMedGoogle Scholar
• 26 Heinrich M. Galanthamine from Galanthus and other Amaryllidaceae – Chemistry and Biology based on traditional Use. In: Cordell GA. ed. The Alkaloids. Chennai: Academic Press; 2010: 157-165
  Google Scholar
• 27 Jimenez A, Santos A, Alonso G, Vazquez D. Inhibitors of protein synthesis in eukaryotic cells. Comparative effects of some Amaryllidaceae alkaloids. Biochim Biophys Acta 1976; 425: 342-348
  CrossrefPubMedGoogle Scholar
• 28 Furusawa E, Irie H, Combs D, Wildman WC. Therapeutic activity of pretazettine on Rauscher leukemia: comparison with the related Amaryllidaceae alkaloids. Chemotherapy 1980; 26: 36-45
  CrossrefPubMedGoogle Scholar
• 29 Nair JJ, Rárová L, Strnad M, Bastida J, van Staden J. Apoptosis-inducing effects of distichamine and narciprimine, rare alkaloids of the plant family Amaryllidaceae. Bioorg Med Chem Lett 2012; 22: 6195-6199
  CrossrefPubMedGoogle Scholar
• 30 Ezoulin MJM, Dong CZ, Liu Z, Li J, Chen HZ, Heymans F, Lelievre L, Ombetta JE, Massicot F. Study of PMS777, a new type of acetylcholinesterase inhibitor, in human HepG2 cells. Comparison with tacrine and galanthamine on oxidative stress and mitochondrial impairment. Toxicol In Vitro 2006; 20: 824-831
  CrossrefPubMedGoogle Scholar
• 31 Breiterova K, Koutova D, Marikova J, Havelek R, Kunes J, Majorosova M, Opletal L, Hostalkova A, Jenco J, Rezacova M, Cahlikova L. Amaryllidaceae alkaloids of different structural types from Narcissus L. cv. Professor Einstein and their cytotoxic activity. Plants 2020; 9: 137/1-137/12
  CrossrefPubMedGoogle Scholar
• 32 Osorio EJ, Berkov S, Brun R, Codina C, Viladomat F, Cabezas F, Bastida J. In vitro antiprotozoal activity of alkaloids from Phaedranassa dubia (Amaryllidaceae). Phytochem Lett 2010; 3: 161-163
  CrossrefPubMedGoogle Scholar
• 33 Doskocil I, Hostalkova A, Safratova M, Benesova N, Havlik J, Havelek R, Kunes J, Kralovec K, Chlebek J, Cahlikova L. Cytotoxic activities of Amaryllidaceae alkaloids against gastrointestinal cancer cells. Phytochem Lett 2015; 13: 394-398
  CrossrefPubMedGoogle Scholar
• 34 Havelek R, Muthna D, Tomsik P, Kralovec K, Seifrtova M, Cahlikova L, Hostalkova A, Safratova M, Perwein M, Cermakova E, Rezacova M. Anticancer potential of Amaryllidaceae alkaloids evaluated by screening with a panel of human cells, real-time cellular analysis and Ehrlich tumor-bearing mice. Chem Biol Interact 2017; 275: 121-132
  CrossrefPubMedGoogle Scholar
• 35 Carvalho KR, Silva AB, Torres MCM, Pinto FCL, Guimaraes LA, Rocha DD, Silveira ER, Costa-Lotufo LV, Braz-Filho R, Pessoa ODL. Cytotoxic alkaloids from Hippeastrum solandriflorum Lindl. J Braz Chem Soc 2015; 26: 1976-1980
  PubMedGoogle Scholar
• 36 Jitsuno M, Yokosuka A, Hashimoto K, Amano O, Sakagami H, Mimaki Y. Chemical constituents of Lycoris albiflora and their cytotoxic activities. Nat Prod Commun 2011; 6: 187-192
  PubMedGoogle Scholar
• 37 Jin A, Li X, Zhu YY, Yu HY, Pi HF, Zhang P, Ruan HL. Four new compounds from the bulbs of Lycoris aurea with neuroprotective effects against CoCl₂ and H₂O₂-induced SH-SY5Y cell injuries. Arch Pharm Res 2014; 37: 315-323
  CrossrefPubMedGoogle Scholar
• 38 Castillo WO, Aristizabal-Pachon AF, de Lima Montaldi AP, Sakamoto-Hojo ET, Takahashi CS. Galanthamine decreases genotoxicity and cell death induced by β-amyloid peptide in SH-SY5Y cell line. Neurotoxicology 2016; 57: 291-297
  CrossrefPubMedGoogle Scholar
• 39 Trujillo-Chacon LM, Alarcon-Enos JE, Cespedes-Acuna CL, Bustamante L, Baeza M, Lopez MG, Fernandez-Mendivil C, Cabezas F, Pastene-Navarrete ER. Neuroprotective activity of isoquinoline alkaloids from of Chilean Amaryllidaceae plants against oxidative stress-induced cytotoxicity on human neuroblastoma SH-SY5Y cells and mouse hippocampal slice culture. Food Chem Toxicol 2019; 132: 110665/1-110665/11
  CrossrefPubMedGoogle Scholar
• 40 Labrana J, Machocho AK, Kricsfalusy V, Brun R, Codina C, Viladomat F, Bastida J. Alkaloids from Narcissus angustifolius subsp. transcarpathicus (Amaryllidaceae). Phytochemistry 2002; 60: 847-852
  CrossrefPubMedGoogle Scholar
• 41 Cedron JC, Ravelo AG, Leon LG, Padron JM, Estevez-Braun A. Antiproliferative and structure activity relationships of Amaryllidaceae alkaloids. Molecules 2015; 20: 13854-13863
  CrossrefPubMedGoogle Scholar
• 42 Govindaraju K, Ingels A, Hasan MN, Sun D, Mathieu V, Masi M, Evidente A, Kornienko A. Synthetic analogues of the montanine-type alkaloids with activity against apoptosis-resistant cancer cells. Bioorg Med Chem Lett 2018; 28: 589-593
  CrossrefPubMedGoogle Scholar
• 43 Silva AFS, de Andrade JP, Machado KRB, Rocha AB, Apel MA, Sobral MEG, Henriques AT, Zuanazzi JAS. Screening for cytotoxic activity of extracts and isolated alkaloids from bulbs of Hippeastrum vittatum . Phytomedicine 2008; 15: 882-885
  CrossrefPubMedGoogle Scholar
• 44 Al Shammari L, Al Mamun A, Koutová D, Majorošová M, Hulcová D, Šafratová M, Breiterová K, Maříková J, Havelek R, Cahlíková L. Alkaloid profiling of Hippeastrum cultivars by GC-MS, isolation of Amaryllidaceae alkaloids and evaluation of their cytotoxicity. Rec Nat Prod 2020; 14: 154-159
  CrossrefPubMedGoogle Scholar
• 45 Wu WM, Zhu YY, Li HR, Yu HY, Zhang P, Pi HF, Ruan HL. Two new alkaloids from the bulbs of Lycoris sprengeri . J Asian Nat Prod Res 2014; 16: 192-199
  CrossrefPubMedGoogle Scholar
• 46 Masi M, van Slambrouck S, Gunawardana S, van Rensburg MJ, James PC, Mochel JG, Heliso PS, Albalawi AS, Cimmino A, van Otterlo WAL, Kornienko A, Green IR, Evidente A. Alkaloids isolated from Haemanthus humilis Jacq., an indigenous South African Amaryllidaceae: anticancer activity of coccinine and montanine. S Afr J Bot 2019; 126: 277-281
  CrossrefPubMedGoogle Scholar
• 47 Hulcova D, Marikova J, Korabecny J, Hostalkova A, Jun D, Kunes J, Chlebek J, Opletal L, de Simone A, Novakova L, Andrisano V, Ruzicka A, Cahlikova L. Amaryllidaceae alkaloids from Narcissus pseudonarcissus L. cv. Dutch Master as potential drugs in treatment of Alzheimerʼs disease. Phytochemistry 2019; 165: 112055/1-112055/9
  CrossrefPubMedGoogle Scholar
• 48 Ali AA, Hambloch H, Frahm AW. Alkaloids of Crinum augustum. Part 4. Relative configuration of the alkaloid augustamine. Phytochemistry 1983; 22: 283-287
  CrossrefPubMedGoogle Scholar
• 49 Machocho AK, Bastida J, Codina C, Viladomat F, Brun R, Chhabra SC. Augustamine-type alkaloids from Crinum kirkii . Phytochemistry 2004; 65: 3143-3149
  CrossrefPubMedGoogle Scholar
• 50 Hanh TTH, Anh DH, Huong PTT, Nguyen VT, Nguyen QT, Cuong TV, Nguyen TM, Nguyen TC, Nguyen XC, Nguyen HN, Minh CV. Crinane, augustamine, and β-carboline alkaloids from Crinum latifolium . Phytochem Lett 2018; 24: 27-30
  CrossrefPubMedGoogle Scholar
• 51 Tallini LR, Torras-Claveria L, de Souza Borges W, Kaiser M, Viladomat F, Zuanazzi JAS, Bastida J. N-oxide alkaloids from Crinum amabile (Amaryllidaceae). Molecules 2018; 23: 1277/1-1277/11
  CrossrefPubMedGoogle Scholar
• 52 Hafiz AMA, Ramadan MA, Jung ML, Beck JP, Anton R. Cytotoxic activity of Amaryllidaceae alkaloids from Crinum augustum and Crinum bulbispermum . Planta Med 1991; 57: 437-439
  Article in Thieme ConnectPubMedGoogle Scholar
• 53 Velten R, Erdelen C, Gehling M, Gohrt A, Gondol D, Lenz J, Lockhoff O, Wachendorff U, Wendisch D. Cripowellin A and B, a novel type of Amaryllidaceae alkaloid from Crinum powellii . Tet Lett 1998; 39: 1737-1740
  CrossrefPubMedGoogle Scholar
• 54 Presley CC, Krai P, Dalal S, Su Q, Cassera M, Goetz M, Kingston DGI. New potently bioactive alkaloids from Crinum erubescens . Bioorg Med Chem 2016; 24: 5418-5422
  CrossrefPubMedGoogle Scholar
• 55 Chen MX, Huo JM, Hu J, Xu ZP, Zhang X. Amaryllidaceae alkaloids from Crinum latifolium with cytotoxic, antimicrobial, antioxidant and anti-inflammatory activities. Fitoterapia 2018; 130: 48-53
  CrossrefPubMedGoogle Scholar
• 56 Tram NTM, Titorenkova TV, Bankova VS, Handjieva NV, Popov SS. Crinum L. (Amaryllidaceae); a review. Fitoterapia 2002; 73: 183-208
  CrossrefPubMedGoogle Scholar
• 57 Zhan G, Qu X, Liu J, Tong Q, Zhou J, Sun B, Yao G. Zephycandidine A, the first naturally occurring imidazo[1,2-f. phenanthridine alkaloid from Zephyranthes candida, exhibits significant anti-tumor and antiacetylcholinesterase activities. Sci Rep 2016; 6: 33990/1-33990/9
  CrossrefPubMedGoogle Scholar
• 58 Nair JJ, van Staden J. Cytotoxic tazettine alkaloids of the plant family Amaryllidaceae. S Afr J Bot 2021; 136: 147-156
  CrossrefPubMedGoogle Scholar
• 59 Nair JJ, van Staden J. The plant family Amaryllidaceae as a source of cytotoxic homolycorine alkaloid principles. S Afr J Bot 2021; 136: 157-174
  CrossrefPubMedGoogle Scholar
• 60 Schmeda-Hirschmann G, Astudillo L, Bastida J, Viladomat F, Codina C. DNA binding activity of Amaryllidaceae alkaloids. J Chil Chem Soc 2000; 45: 515-518
  PubMedGoogle Scholar
• 61 Hohmann J, Forgo P, Molnár J, Wolfard K, Molnár A, Thalhammer T, Mathé I, Sharples D. Antiproliferative Amaryllidaceae alkaloids isolated from the bulbs of Sprekelia formosissima and Hymenocallis x festalis . Planta Med 2002; 68: 454-457
  Article in Thieme ConnectPubMedGoogle Scholar
• 62 Ingrassia L, Lefranc F, Dewelle J, Pottier L, Mathieu V, Spiegl-Kreinecker S, Sauvage S, El Yazidi M, Dehoux M, Berger W, van Quaquebeke E, Kiss R. Structure-activity relationship analysis of novel derivatives of narciclasine (an Amaryllidaceae isocarbostyril derivative) as potential anticancer agents. J Med Chem 2009; 52: 1100-1114
  CrossrefPubMedGoogle Scholar
• 63 Lefranc F, Sauvage S, van Goietsenoven G, Mégalizzi V, Lamoral-Theys D, Debeir O, Spiegl-Kreinecker S, Berger W, Mathieu V, Decaestecker C, Kiss R. Narciclasine, a plant growth modulator, activates Rho and stress fibers in glioblastoma cells. Mol Cancer Ther 2009; 8: 1739-1750
  CrossrefPubMedGoogle Scholar
• 64 Antonicek HP, Velten R, Jeschke P. Cripowellins and synthetic derivatives thereof used as medicaments. European Patent WO2006136309A1, 2006
  Google Scholar
• 65 McNulty J, Nair JJ, Singh M, Crankshaw DJ, Holloway AC, Bastida J. Selective cytochrome P450 3A4 inhibitory activity of Amaryllidaceae alkaloids. Bioorg Med Chem Lett 2009; 19: 3233-3237
  CrossrefPubMedGoogle Scholar
• 66 Rendic S, Di Carlo FJ. Human cytochrome P450 enzymes: a status report summarizing their reactions, substrates, inducers and inhibitors. Drug Metab Rev 1997; 29: 413-580
  CrossrefPubMedGoogle Scholar
• 67 Sharom FJ. The P-glycoprotein multidrug transporter. Essays Biochem 2011; 50: 161-178
  CrossrefPubMedGoogle Scholar
• 68 Stafford GI, Birer C, Brodin B, Christensen SB, Eriksson AH, Jäger AK, Rønsted N. Serotonin transporter protein (SERT) and P-glycoprotein (P-gp) binding activity of montanine and coccinine from three species of Haemanthus L. (Amaryllidaceae). S Afr J Bot 2013; 88: 101-106
  CrossrefPubMedGoogle Scholar
• 69 Abdel-Halim OB, Morikawa T, Ando S, Matsuda H, Yoshikawa M. New crinine-type alkaloids with inhibitory effect on induction of inducible nitric oxide synthase from Crinum yemense . J Nat Prod 2004; 67: 1119-1124
  CrossrefPubMedGoogle Scholar
• 70 Xu W, Liu LZ, Loizidou M, Ahmed M, Charles IG. The role of nitric oxide in cancer. Cell Res 2002; 12: 311-320
  CrossrefPubMedGoogle Scholar
• 71 Champoux JJ. DNA topoisomerases: structure, function and mechanism. Annu Rev Biochem 2001; 70: 369-413
  CrossrefPubMedGoogle Scholar
• 72 Sarıkaya BB, Zencir S, Somer NU, Kaya GI, Onur MA, Bastida J, Berenyi A, Zupko I, Topcu Z. The effects of arolycoricidine and narciprimine on tumor cell killing and topoisomerase activity. Rec Nat Prod 2012; 6: 381-385
  PubMedGoogle Scholar
• 73 Nino J, Hincapié GM, Correa YM, Mosquera OM. Alkaloids of Crinum x powellii “Album” (Amaryllidaceae) and their topoisomerase inhibitory activity. Z Naturforsch 2007; 62c: 223-226
  CrossrefPubMedGoogle Scholar
• 74 Evidente A, Kireev AS, Jenkins AR, Romero AE, Steelant WFA, van Slambrouck S, Kornienko A. Biological evaluation of structurally diverse Amaryllidaceae alkaloids and their synthetic derivatives: discovery of novel leads for anticancer drug design. Planta Med 2009; 75: 501-507
  Article in Thieme ConnectPubMedGoogle Scholar
• 75 Stock AM, Troost G, Niggemann B, Zänker KS, Entschladen F. Targets for anti-metastatic drug development. Curr Pharm Des 2013; 19: 5127-5134
  CrossrefPubMedGoogle Scholar
• 76 Kovalevich J, Langford D. Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol 2013; 1078: 9-21
  CrossrefPubMedGoogle Scholar
• 77 Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860-867
  CrossrefPubMedGoogle Scholar
• 78 Park JB. Synthesis and characterization of norbelladine, a precursor of Amaryllidaceae alkaloid, as an anti-inflammatory/anti-COX compound. Bioorg Med Chem Lett 2014; 24: 5381-5384
  CrossrefPubMedGoogle Scholar
• 79 Nair JJ, van Staden J, Bastida J. Apoptosis-inducing effects of Amaryllidaceae alkaloids. Curr Med Chem 2016; 23: 161-185
  CrossrefPubMedGoogle Scholar
• 80 Wang S, Yin J, Chen D, Nie F, Song X, Fei C, Miao H, Jing C, Ma W, Wang L, Xie S, Li C, Zeng R, Pan W, Hao X, Li L. Small-molecule modulation of Wnt signaling via modulating the Axin-LRP5/6 interaction. Nat Chem Biol 2013; 9: 579-585
  CrossrefPubMedGoogle Scholar
• 81 Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell 2012; 149: 1192-1205
  CrossrefPubMedGoogle Scholar
• 82 Cohen GM. Caspases: the executioners of apoptosis. Biochem J 1997; 326: 1-16
  CrossrefPubMedGoogle Scholar
• 83 Van Goietsenoven G, Andolfi A, Lallemand B, Cimmino A, Lamoral-Theys D, Gras T, Abou-Donia A, Dubois J, Lefranc F, Mathieu V, Kornienko A, Kiss R, Evidente A. Amaryllidaceae alkaloids belonging to different structural subgroups display activity against apoptosis-resistant cancer cells. J Nat Prod 2010; 73: 1223-1227
  CrossrefPubMedGoogle Scholar
• 84 Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science 2002; 298: 1912-1934
  CrossrefPubMedGoogle Scholar
• 85 Luo J. Glycogen synthase kinase 3b (GSK3b) in tumorigenesis and cancer chemotherapy. Cancer Lett 2009; 273: 194-200
  CrossrefPubMedGoogle Scholar
• 86 Bolanos-Garcia VM. Aurora kinases. Int J Biochem Cell Biol 2005; 37: 1572-1577
  CrossrefPubMedGoogle Scholar
• 87 Milazzo G, Mercatelli D, Di Muzio G, Triboli L, De Rosa P, Perini G, Giorgi FM. Histone deacetylases (HDACs): evolution, specificity, role in transcriptional complexes, and pharmacological actionability. Genes (Basel) 2020; 11: 556/1-556/49
  CrossrefPubMedGoogle Scholar
• 88 Li L, Dai HJ, Ye M, Wang SL, Xiao XJ, Zheng J, Chen HY, Luo YH, Liu J. Lycorine induces cell cycle arrest in the G₀/G₁ phase in K562 cells via HDAC inhibition. Cancer Cell Int 2012; 12: 49-54
  CrossrefPubMedGoogle Scholar
• 89 Holmes DIR, Zachary I. The vascular endothelial growth factor (VEGF) family: angiogenic factors in health and disease. Genome Biol 2005; 6: 209/1-209/10
  PubMedGoogle Scholar
• 90 Penning TM, Byrns MC. Steroid hormone transforming aldo-keto reductases and cancer. Ann N Y Acad Sci 2009; 1155: 33-42
  CrossrefPubMedGoogle Scholar
• 91 Stahl SM. Mechanism of action of serotonin selective reuptake inhibitors: serotonin receptors and pathways mediate therapeutic effects and side effects. J Affect Disord 1998; 51: 215-235
  CrossrefPubMedGoogle Scholar
• 92 Sarrouilhe D, Mesnil M. Serotonin and human cancer: a critical view. Biochimie 2019; 161: 46-50
  CrossrefPubMedGoogle Scholar
• 93 Shinka T, Onodera D, Tanaka T, Miyazaki T, Moriuchi T, Fukumoto T. Serotonin synthesis and metabolism-related molecules in a human prostate cancer cell line. Oncol Lett 2011; 2: 211-215
  CrossrefPubMedGoogle Scholar

• Supplementary Material