Amaryllidaceae alkaloids in skin cancer management: Photoprotective effect on human keratinocytes and anti-proliferative activity in melanoma cells (2024)

J Appl Biomed 21:36-47, 2023|DOI:10.32725/jab.2023.004

Amaryllidaceae alkaloids in skin cancer management: Photoprotective effect on human keratinocytes and anti-proliferative activity in melanoma cells

Carol Castañeda¹, Karent Bravo¹, Natalie Cortés^{1, 2}, Janeth Bedoya³, Warley de S. Borges⁴, Jaume Bastida⁵, Edison Osorio^{1, *}

¹Universidad de Antioquía, Facultad de Ciencias Farmacéuticas y Alimentarias, Grupo de Investigación en Sustancias Bioactivas, Medellín, Colombia

²Universidad de Ibagué, Facultad de Ciencias Naturales y Matemáticas, Ibagué, Colombia

³Universidad de Antioquia, Facultad de Medicina, Grupo Medicina Molecular y de Translación, Medellín, Colombia

⁴Universidade Federal do Espírito Santo, Departamento de Química, Vitória, Espírito Santo, Brazil

⁵Universitat de Barcelona, Facultat de Farmàcia i Ciències de l'Alimentació, Departament de Biologia, Sanitat i Medi Ambient, Barcelona, Spain

Skin cancer has high rates of mortality and therapeutic failure. In this study, to develop a multi-agent strategy for skin cancer management, the selective cytotoxicity of several alkaloid fractions and pure alkaloids isolated from Amaryllidaceae species was evaluated in melanoma cells. In addition, UVB-stimulated keratinocytes (HaCaT) were exposed to seven alkaloid fractions characterized by GC-MS, and the production of intracellular reactive oxygen species (ROS) and IL-6, were measured to evaluate their photoprotection effects. The Eucharis caucana (bulb) alkaloid fraction (20 μg/ml) had a clear effect on the viability of melanoma cells, reducing it by 45.7% without affecting healthy keratinocytes. This alkaloid fraction and tazettine (both at 2.5 μg/ml) suppressed UVB-induced ROS production by 31.6% and 29.4%, respectively. The highest anti-inflammatory potential was shown by the Zephyranthes carinata (bulb) alkaloid fraction (10 μg/ml), which reduced IL-6 production by 90.8%. According to the chemometric analysis, lycoramine and tazettine had a photoprotective effect on the UVB-exposed HaCaT cells, attenuating the production of ROS and IL-6. These results suggest that Amaryllidaceae alkaloids have photoprotective and therapeutic potential in skin cancer management, especially at low concentrations.

Keywords: Amaryllidaceae alkaloids; Eucharis caucana; Photoprotection; Skin cancer; Zephyranthes carinata

Grants and funding:

This investigation received financial support from MINCIENCIAS (agreement # 614-2018). The authors would like to expresstheir gratitude to the Iberian-American Programme for Cooperation and Development (CYTED) (Ref. 416RT0511) –BIFRENES Thematic Network and Foundation of Support to Research and Innovation of Espírito Santo (FAPES UniversalNo. 80708382/18). We would also like to acknowledge INCTBioNat (CNPq 465637/2014-0 and FAPESP 2014/50926-0)for the additional support. The authors are especially grateful to the University of Antioquia (UdeA) for its important contributionin the development of this work. None of these institutions had anything to do with the preparation of the article, the study design, collection, analysis, and interpretation of data, or with the writing of the report and the decision to submit the article for publication.

Conflicts of interest:

The authors have no conflict of interests to declare.

Received: December 22, 2021; Revised: January 18, 2023; Accepted: March 17, 2023; Prepublished online: March 31, 2023; Published: April 1, 2023 Show citation

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1. Afaq F (2011). Natural agents: Cellular and molecular mechanisms of photoprotection. Arch Biochem Biophys 508(2): 144-151. DOI: 10.1016/j.abb.2010.12.007. Go to original source... Go to PubMed...
2. Apalla Z, Lallas A, Sotiriou E, Lazaridou E, Ioannides D (2017b). Epidemiological trends in skin cancer. Dermatol Pract Concept 7(2): 1-6. DOI: 10.5826/dpc.0702a01. Go to original source... Go to PubMed...
3. Apalla Z, Nashan D, Weller RB, Castellsagué X (2017a). Skin cancer: Epidemiology, disease burden, pathophysiology, diagnosis, and therapeutic approaches. Dermatol Ther (Heidelb) 7(Suppl. 1): 5-19. DOI: 10.1007/s13555-016-0165-y. Go to original source... Go to PubMed...
4. Atanasov AG, Zotchev SB, Dirsch VM, International Natural Product Sciences Taskforce, Supuran CT (2021). Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 20(3): 200-216. DOI: 10.1038/s41573-020-00114-z. Go to original source... Go to PubMed...
5. Bastida J, Lavilla R, Viladomat F (2006). Chapter 3 Chemical and Biological Aspects of Narcissus Alkaloids. Alkaloids Chem Biol 63: 87-179. DOI: 10.1016/s1099-4831(06)63003-4. Go to original source... Go to PubMed...
6. Berkov S, Osorio E, Viladomat F, Bastida J (2020). Chemodiversity, chemotaxonomy and chemoecology of Amaryllidaceae alkaloids. Alkaloids Chem Biol 83: 113-185. DOI: 10.1016/bs.alkal.2019.10.002. Go to original source... Go to PubMed...
7. Bessa CDPB, de Andrade JP, de Oliveira RS, Domingos E, Santos H, Romão W, et al. (2017). Identification of alkaloids from Hippeastrum aulicum (Ker Gawl.) Herb. (Amaryllidaceae) using CGC-MS and ambient ionization mass spectrometry (PS-MS and LS-MS). J Braz Chem Soc 28(5): 819-830. DOI: 10.21577/0103-5053.20160234. Go to original source...
8. Bhatt VR, Shostrom V, Holstein SA, Al-Kadhimi ZS, Maness LJ, Berger A, et al. (2020). Survival of older adults with newly diagnosed acute myeloid leukemia: Effect of using multiagent versus single-agent chemotherapy. Clin Lymphoma Myeloma Leuk 20(5): e239-e258. DOI: 10.1016/j.clml.2020.01.015. Go to original source... Go to PubMed...
9. Biswas SK (2016). Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox?. Oxid Med Cell Longev 2016: 5698931. DOI: 10.1155/2016/5698931. Go to original source... Go to PubMed...
10. Bolton NM, Maerz AH, Brown RE, Bansal M, Bolton JS, Conway WC (2019). Multiagent neoadjuvant chemotherapy and tumor response are associated with improved survival in pancreatic cancer. Hpb (Oxford) 21(4): 413-418. DOI: 10.1016/j.hpb.2018.08.013. Go to original source... Go to PubMed...
11. Cao Z, Yu D, Fu S, Zhang G, Pan Y, Bao M, et al. (2013). Lycorine hydrochloride selectively inhibits human ovarian cancer cell proliferation and tumor neovascularization with very low toxicity. Toxicol Lett 218(2): 174-185. DOI: 10.1016/j.toxlet.2013.01.018. Go to original source... Go to PubMed...
12. Chorachoo J, Saeloh D, Srichana T, Amnuaikit T, Musthafa KS, Sretrirutchai S, Voravuthikunchai SP (2016). Rhodomyrtone as a potential anti-proliferative and apoptosis inducing agent in HaCaT keratinocyte cells. Eur J Pharmacol 772: 144-151. DOI: 10.1016/j.ejphar.2015.12.005. Go to original source... Go to PubMed...
13. Cortes N, Castañeda C, Osorio EH, Cardona-Gomez GP, Osorio E (2018). Amaryllidaceae alkaloids as agents with protective effects against oxidative neural cell injury. Life Sci 203: 54-65. DOI: 10.1016/j.lfs.2018.04.026. Go to original source... Go to PubMed...
14. Cragg GM, Pezzuto JM (2016). Natural products as a vital source for the discovery of cancer chemotherapeutic and chemopreventive agents. Med Princ Pract 25(Suppl. 2): 41-59. DOI: 10.1159/000443404. Go to original source... Go to PubMed...
15. Cunningham JJ, Gatenby RA, Brown JS (2011). Evolutionary dynamics in cancer therapy. Mol Pharm 8(6): 2094-2100. DOI: 10.1021/mp2002279. Go to original source... Go to PubMed...
16. Dasari R, Banuls LMY, Masi M, Pelly SC, Mathieu V, Green IR, et al. (2014). C1,C2-ether derivatives of the Amaryllidaceae alkaloid lycorine: Retention of activity of highly lipophilic analogues against cancer cells. Bioorganic Med Chem Lett 24(3): 923-927. DOI: 10.1016/j.bmcl.2013.12.073. Go to original source... Go to PubMed...
17. Duque L, Bravo K, Osorio E (2017). A holistic anti-aging approach applied in selected cultivated medicinal plants: A view of photoprotection of the skin by different mechanisms. Ind Crops Prod 97: 431-439. DOI: 10.1016/j.indcrop.2016.12.059. Go to original source...
18. Gordon R (2013). Skin cancer: An overview of epidemiology and risk factors. Semin Oncol Nurs 29(3): 160-169. DOI: 10.1016/j.soncn.2013.06.002. Go to original source... Go to PubMed...
19. Gonring-Salarini K, Conti R, de Andrade JP, Borges BJ, Aguiar AC, de Souza J, et al. (2019). In vitro antiplasmodial activities of alkaloids isolated from roots of Worsleya procera (Lem.) Traub (Amaryllidaceae). J Braz Chem Soc 30(8): 51-58. DOI: 10.21577/0103-5053.20190061. Go to original source...
20. Howes MJR (2018). The evolution of anticancer drug discovery from plants. Lancet Oncol 19(3): 293-294. DOI: 10.1016/S1470-2045(18)30136-0. Go to original source... Go to PubMed...
21. Ingrassia L, Lefranc F, Dewelle J, Pottier L, Mathieu V, Spiegl-Kreinecker S, et al. (2009). Structure-activity relationship analysis of novel derivatives of narciclasine (an Amaryllidaceae isocarbostyril derivative) as potential anticancer agents. J Med Chem 52(4): 1100-1114. DOI: 10.1021/jm8013585. Go to original source... Go to PubMed...
22. Kornienko A, Evidente A (2008). Chemistry, biology, and medicinal potential of narciclasine and its congeners. Chem Rev 108(6): 1982-2014. DOI: 10.1021/cr078198u. Go to original source... Go to PubMed...
23. Kozma B, Eide MJ (2014). Photocarcinogenesis: An epidemiologic perspective on ultraviolet light and skin cancer. Dermatol Clin 32(3): 301-313. DOI: 10.1016/j.det.2014.03.004. Go to original source... Go to PubMed...
24. Kucheryavskiy S (2021). Getting started with mdatools for R. [online] [cit. 2021-11-20]. Available from: https://mdatools.com/docs/
25. Lee JH, An HT, Chung JH, Kim KH, Eun HC, Cho KC (2002). Acute effects of UVB radiation on the proliferation and differentiation of keratinocytes. Photodermatol Photoimmunol Photomed 18(5): 253-261. DOI: 10.1034/j.1600-0781.2002.02755.x. Go to original source... Go to PubMed...
26. Lee WR, Lin YK, Alalaiwe A, Wang PW, Liu PY, Fang JY (2020). Fractional laser-mediated siRNA delivery for mitigating psoriasis-like lesions via IL-6 silencing. Mol Ther Nucleic Acids 19: 240-251. DOI: 10.1016/j.omtn.2019.11.013. Go to original source... Go to PubMed...
27. Lianza M, Verdan MH, de Andrade JP, Poli F, de Almeida LC, Costa-Lotufo LV, et al. (2020). Isolation, absolute configuration and cytotoxic activities of alkaloids from Hippeastrum goianum (Ravenna) Meerow (Amaryllidaceae). J Braz Chem Soc 31: 2135-2145. DOI: 10.21577/0103-5053.20200116. Go to original source...
28. Lu JJ, Wang YT (2020). Identification of anti-cancer compounds from natural products. Chin J Nat Med 18(7): 481-482. DOI: 10.1016/S1875-5364(20)30057-1. Go to original source... Go to PubMed...
29. Maier MJ (2015). Package 'REdaS'. [online] [cit. 2021-11-20]. Available from: https://cran.r-project.org/web/packages/REdaS/REdaS.pdf
30. Masi M, Van Slambrouck S, Gunawardana S, van Rensburg MJ, James PC, Mochel JG, et al. (2019). Alkaloids isolated from Haemanthus humilis Jacq., an indigenous South African Amaryllidaceae: Anticancer activity of coccinine and montanine. South African J Bot 126: 277-281. DOI: 10.1016/j.sajb.2019.01.036. Go to original source...
31. Mevik BH, Wehrens R, Liland KH, Hiemstra P (2019). Package 'pls': Partial least squares and principal component regression. [online] [cit. 2021-11-20]. Available from: https://github.com/bhmevik/pls
32. Montes de Oca MK, Pearlman RL, McClees SF, Strickland R, Afaq F (2017). Phytochemicals for the prevention of photocarcinogenesis. Photochem Photobiol 93(4): 956-974. DOI: 10.1111/php.12711. Go to original source... Go to PubMed...
33. Muramatsu S, Kubo R, Nishida E, Shintani Y, Morita A (2016). Serum interleukin-6 levels in response to biologic treatment in patients with psoriasis. Mod Rheumatol 27(1): 137-141. DOI: 10.3109/14397595.2016.1174328. Go to original source... Go to PubMed...
34. Nair JJ, Bastida J, van Staden J (2016b). In vivo cytotoxicity studies of Amaryllidaceae alkaloids. Nat Prod Commun 11(1): 121-132. Go to original source...
35. Nair JJ, Bastida J, Viladomat F, van Staden J (2012). Cytotoxic agents of the crinane series of Amaryllidaceae alkaloids. Nat Prod Commun 7(12): 1677-1688. Go to original source...
36. Nair JJ, van Staden J, Bastida J (2016a). Cytotoxic alkaloid constituents of the Amaryllidaceae. Stud Nat Prod Chem 49: 107-156. DOI: 10.1016/B978-0-444-63601-0.00003-X. Go to original source...
37. Newman DJ, Cragg GM (2020). Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 83(3): 770-803. DOI: 10.1021/acs.jnatprod.9b01285. Go to original source... Go to PubMed...
38. Nichols JA, Katiyar SK (2010). Skin photoprotection by natural polyphenols: Anti-inflammatory, antioxidant and DNA repair mechanisms. Arch Dermatol Res 302(2): 71-83. DOI: 10.1007/s00403-009-1001-3. Go to original source... Go to PubMed...
39. Nieweg OE, Gallegos-Hernández JF (2016). Cutaneous melanoma and the new drugs. Cir Cir (English Ed) 83(2): 175-180. DOI: 10.1016/j.circen.2015.08.016. Go to original source...
40. Oak ASW, Athar M, Yusuf N, Elmets CA (2018). UV and Skin: Photocarcinogenesis. In: Environment and Skin. Switzerland: Springer International Publishing. pp. 67-103. DOI: 10.1007/978-3-319-43102-4_8. Go to original source...
41. Qiao P, Guo W, Ke Y, Fang H, Zhuang Y, Jiang M, et al. (2019). Mechanical stretch exacerbates psoriasis by stimulating keratinocyte proliferation and cytokine production. J Invest Dermatol 139(7): 1470-1479. DOI: 10.1016/j.jid.2018.12.019. Go to original source... Go to PubMed...
42. Qiu S, Sun H, Zhang AH, Xu HY, Yan GL, Han Y, Wang XJ (2014). Natural alkaloids: Basic aspects, biological roles, and future perspectives. Chin J Nat Med 12(6): 401-406. DOI: 10.1016/S1875-5364(14)60063-7. Go to original source... Go to PubMed...
43. Real FX, López C (2016). Medicina Interna. Madrid: Elsevier, pp. 1191-1202.
44. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010). Oxidative stress, inflammation, and cancer: How are they linked? Exp Ther 49(11): 1603-1616. DOI: 10.1016/j.freeradbiomed.2010.09.006. Go to original source... Go to PubMed...
45. Roussi F, Gueritte F, Fahy J (2012). The vinca alkaloids. In: Cragg GM, Kingston DGI, Newman DJ (Eds). Anticancer agents from natural products. Second ed. CRC/Taylor & Francis, Boca Raton, pp. 177-198.
46. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancer in 185 countries. CA Cancer J Clin 71(3): 209-249. DOI: 10.3322/caac.21660. Go to original source... Go to PubMed...
47. Traykova M, Traykov T, Hadjimitova V, Krikorian K, Bojadgieva N (2003). Antioxidant properties of galantamine hydrobromide. Z Naturforsch C J Biosci 58(5-6): 361-365. DOI: 10.1515/znc-2003-5-613. Go to original source... Go to PubMed...
48. Voiculescu VM, Lisievici CV, Lupu M, Vajaitu C, Draghici CC, Popa AV, et al. (2019). Mediators of inflammation in topical therapy of skin cancers. Mediators Inflamm 2019: 8369690. DOI: 10.1155/2019/8369690. Go to original source... Go to PubMed...
49. Wang C, Wang Q, Li X, Jin Z, Xu P, Xu N, et al. (2016). Lycorine induces apoptosis of bladder cancer T24 cells by inhibiting phospho-Akt and activating the intrinsic apoptotic cascade. Biochem Biophys Res Commun 483(1): 197-202. DOI: 10.1016/j.bbrc.2016.12.168. Go to original source... Go to PubMed...
50. Wu D, Yotnda P (2011). Production and detection of reactive oxygen species (ROS) in cancers. J Vis Exp (57): e3357. DOI: 10.3791/3357. Go to original source... Go to PubMed...
51. Ying X, Huang A, Xing Y, Lan L, Yi Z, He P (2017). Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway. Sci China Life Sci 60(4): 417-428. DOI: 10.1007/s11427-016-0368-y. Go to original source... Go to PubMed...