Abstract
Ethanolic extract of Nelumbo nucifera petals showed preferential cytotoxic activity against HeLa human cervical cancer cell line with a PC50 value of 10.4 μg/mL. This active extract was subjected to a phytochemical investigation study which led to the isolation of nine benzylisoquinoline alkaloids (1–9). The isolated compounds exhibited potent antiausterity activities. Moreover, under nutrient-deprived conditions, (−)-lirinidine (8) induced remarkable alterations in HeLa cell morphology including cell shrinkage and plasma blebbing leading to total cell death within 10 h. Mechanistically, 8 was found to inhibit Akt/mTOR signaling pathway. It also induced apoptosis by promoting caspase-3 activation and inhibiting Bcl-2 expression. Therefore, benzylisoquinoline alkaloids skeleton can be considered as a promising scaffold for the anticancer drug development against cervical cancer.
Funding source: Japan Society for the Promotion of Science
Award Identifier / Grant number: 16K08319
Funding source: Kobayashi International Scholarship Foundation
Award Identifier / Grant number: 2020
Funding source: Khon Kaen University
Award Identifier / Grant number: 60JH211
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Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: This work was supported by the Japanese Society for the Promotion of Science (JSPS), Japan, Kakenhi (16K08319) and Kobayashi International Scholarship to S.A. The authors thank the Graduate School of Khon Kaen University, Thailand for supporting J.M. through Research Fund (ID: 60JH211) and a Ph.D. scholarship from the Faculty of Pharmaceutical Sciences, Khon Kaen University, Thailand.
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Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
References
1. Ginsburg, O, Bray, F, Coleman, MP, Vanderpuye, V, Eniu, A, Kotha, SR, et al.. The global burden of women’s cancers: an unmet grand challenge in global health. Lancet 2018;389:847–60. https://doi.org/10.1016/S0140-6736(16)31392-7.Search in Google Scholar
2. Arbyn, M, Weiderpass, E, Bruni, L, de Sanjosé, S, Saraiya, M, Ferlay, J, et al.. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Global Health 2019;8:191–203. https://doi.org/10.1016/S2214-109X(19)30482-6.Search in Google Scholar
3. Burd, EM. Human papillomavirus and cervical cancer. Clin Microbiol Rev 2003;16:1–17. https://doi.org/10.1128/cmr.16.1.1-17.2003.Search in Google Scholar
4. Šarenac, T, Mikov, M. Cervical cancer, different treatments and importance of bile acids as therapeutic agents in this disease. Front Pharmacol 2019;10:1–29. https://doi.org/10.3389/fphar.2019.00484.Search in Google Scholar
5. Maine, D, Hurlburt, S, Greeson, D. Cervical cancer prevention in the 21st century: cost is not the only issue. Am J Publ Health 2011;101:1549–55. https://doi.org/10.2105/ajph.2011.300204.Search in Google Scholar
6. LaVigne, AW, Triedman, SA, Randall, TC, Trimble, EL. Cervical cancer in low and middle income countries: addressing barriers to radiotherapy delivery. Gynecol Oncol Rep 2017;22:16–20. https://doi.org/10.1016/j.gore.2017.08.004.Search in Google Scholar
7. Varughese, J, Richman, S. Cancer care inequity for woman in resource-poor counties. Rev Obstet Gynecol 2010;3:122–32.Search in Google Scholar
8. Oaknin, A, Rodriguez-Freixinos, V. Bevacizumab in the treatment of cervical cancer – current evidence and next step. Eur Oncol Haematol 2016;12:32–43. https://doi.org/10.17925/eoh.2016.12.01.32.Search in Google Scholar
9. Xiang, M, Kidd, EA. Benefit of cisplatin with definitive radiotherapy in older women with cervical cancer. J Natl Compr Canc Netw 2019;17:969–75. https://doi.org/10.6004/jnccn.2019.7289.Search in Google Scholar
10. Yadav, N, Parveen, S, Banerjee, M. Potential of nana-phytochemicals in cervical cancer therapy. Clin Chim Acta 2020;505:60–72. https://doi.org/10.1016/j.cca.2020.01.035.Search in Google Scholar
11. Izuishi, K, Kato, K, Ogura, T, Kinoshita, T, Esumi, H. Remarkable tolerance of tumor cells to nutrient deprivation: possible new biochemical target for cancer therapy. Cancer Res 2000;60:6201–7.Search in Google Scholar
12. Fathy, M, Awale, S, Nikaido, T. Phosphorylated Akt protein at Ser473 enables HeLa cells to tolerate nutrient-deprived conditions. Asian Pac J Cancer Prev APJCP 2017;18:3255–60. https://doi.org/10.22034/APJCP.2017.18.12.3255.Search in Google Scholar
13. Awale, S, Lu, J, Kalauni, SK, Kurashima, Y, Tezuka, Y, Kadota, S, et al.. Identification of arctigenin as an antitumor agent having the ability to eliminate the tolerance of cancer cells to nutrient starvation. Cancer Res 2006;66:1751–7. https://doi.org/10.1158/0008-5472.can-05-3143.Search in Google Scholar
14. Awale, S, Nakashima, EMN, Kalauni, SK, Tezuka, Y, Kurashima, Y, Lu, J, et al.. Angelmarin, a novel anti-cancer agent able to eliminate the tolerance of cancer cells to nutrient starvation. Bioorg Med Chem Lett 2006;16:581–53. https://doi.org/10.1016/j.bmcl.2005.10.046.Search in Google Scholar
15. Ueda, JY, Athikomkulchai, S, Miyatake, R, Saiki, I, Esumi, H, Awale, S. (+)-grandifloracin, an antiausterity agent, induces autophagic PANC-1 pancreatic cancer cell death. Drug Des Dev Ther 2014;8:39–47. https://doi.org/10.2147/DDDT.S52168.Search in Google Scholar
16. Awale, S, Dibwe, DF, Balachandran, C, Fayez, S, Feineis, D, Lombe, BK, et al.. Ancistrolikokine E3, a 5,8′-coupled naphthylisoquinoline alkaloid, eliminates the tolerance of cancer cells to nutrition starvation by inhibition of the Akt/mTOR/autophagy signaling pathway. J Nat Prod 2018;81:2282–91. https://doi.org/10.1021/acs.jnatprod.8b00733.Search in Google Scholar
17. Sun, S, Phrutivorapongkul, A, Dibwe, DF, Balachandran, C, Awale, S. Chemical constituents of Thai Citrus hystrix and their antiausterity activity against the PANC-1 human pancreatic cancer cell line. J Nat Prod 2018;81:1877–83. https://doi.org/10.1021/acs.jnatprod.8b00405.Search in Google Scholar
18. Tawila, AM, Sun, S, Kim, MJ, Omar, AM, Dibwe, DF, Ueda, JY, et al.. Highly potent antiausterity agents from Callistemon citrinus and their mechanism of action against the PANC-1 human pancreatic cancer cell line. J Nat Prod 2020;83:2221–32. https://doi.org/10.1021/acs.jnatprod.0c00330.Search in Google Scholar
19. Omar, AM, Dibwe, DF, Tawila, AM, Sun, S, Phrutivorapongkul, A, Awale, S. Chemical constituents of Anneslea fragrans and their antiausterity activity against the PANC-1 human pancreatic cancer cell line. J Nat Prod 2019;82:3133–9. https://doi.org/10.1021/acs.jnatprod.9b00735.Search in Google Scholar
20. Omar, AM, Dibwe, DF, Tawila, AM, Sun, S, Kim, MJ, Awale, S. Chemical constituents from Artemisia vulgaris and their antiausterity activities against the PANC-1 human pancreatic cancer cell line. Nat Prod Res 2019:1–7. https://doi.org/10.1080/14786419.2019.1700246.Search in Google Scholar
21. Paudel, KR, Panth, N. Phytochemical profile and biological activity of Nelumbo nucifera. Evid base Compl Alternative Med 2015;2015:1–16. https://doi.org/10.1155/2015/789124.Search in Google Scholar
22. Sheikh, SA. Ethon-medicinal uses and pharmacological activities of lotus (Nelumbo nucifera). J Med Plants Stud 2014;2:42–6.Search in Google Scholar
23. Deng, J, Chen, S, Yin, X, Wang, K, Liu, Y, Liu, S, et al.. Systematic qualitative and quantitative assessment of anthocyanins, flavones adn flavonols in the petals of 108 lotus (Nelumbo nucifera) cultivars. Food Chem 2013;139:307–12. https://doi.org/10.1016/j.foodchem.2013.02.010.Search in Google Scholar
24. Morikawa, T, Kitagawa, N, Tanabe, G, Ninomiya, K, Okugawa, S, Motai, C, et al.. Quantitative determination of alkaloids in lotus flower (flower buds of Nelumbo nucifera) and their melanogenesis inhibitory activity. Molecules 2016;21:930. https://doi.org/10.3390/molecules21070930.Search in Google Scholar
25. Tungmunnithum, D, Pinthong, D, Hano, C. Flavonoids from Nelumbo nucifera Gaertn., a medicinal plant: uses in traditional medicine, phytochemistry and pharmacological activities. Medicines 2018;5:127. https://doi.org/10.3390/medicines5040127.Search in Google Scholar
26. Liu, C, Kao, C, Wu, H, Li, W, Huang, C, Li, H, et al.. Antioxidant and anticancer aporphine alkaloids from the leaves of Nelumbo nucifera Gaertn. Cv. Rosa-plena. Molecules 2014;19:17829–38. https://doi.org/10.3390/molecules191117829.Search in Google Scholar
27. Weon, JB, Ma, CJ. Neuroprotective compounds from the embryo of Nelumbo nucifra seeds. Phcog Mag 2020;16:329–35.Search in Google Scholar
28. Thawabteh, A, Juma, S, Bader, M, Karaman, D, Scrano, L, Bufo, SA, et al.. The biological activity of natural alkaloids against herbivores cancerous cells and pathogens. Toxins 2019;11:656. https://doi.org/10.3390/toxins11110656.Search in Google Scholar
29. Ziyaev, R, Irgashev, T, Israilov, IA, Abdullaev, ND, Yunusov, MS, Yunusov, SY. Alkaloids of Ziziphus jujuba the structure of juziphine adn juzirine. Chem Nat Compd 1977;13:204–7. https://doi.org/10.1007/bf00563948.Search in Google Scholar
30. Bhakuni, DS, Satish, S, Dhar, MM. Absolute configuration of isococlaurine. Tetrahedron 1971;28:1093–5.10.1016/0040-4020(72)80168-6Search in Google Scholar
31. Torres, R, Monache, FD, Bettolo, GBM. Alkaloids from Discaria serratifolia. J Nat Prod 1979;42:430–1. https://doi.org/10.1021/np50004a014.Search in Google Scholar
32. Cabedo, N, Protais, P, Cassels, BK, Cortes, D. Synthesis and dopamine receptor selectivity of the benzyltetrahydroisoquinoline, (R)-(−)-nor-roefractine. J Nat Prod 1998;61:709–12. https://doi.org/10.1021/np980008a.Search in Google Scholar
33. Crabbe, P, Klyne, W. Optical rotatory dispersion and circular dichroism of aromatic compounds: a general survey. Tetrahedron 1971;23:3449–503.10.1016/S0040-4020(01)92310-5Search in Google Scholar
34. Chang, FR, Wei, J, Teng, C, Wu, Y. Two new 7-dehydroaporphine alkaloids and antiplatelet action aoprphines from the leaves of Annona purpurea. Phytochemistry 1998;49:2015–8. https://doi.org/10.1016/s0031-9422(98)00376-8.Search in Google Scholar
35. Chang, F, Chen, C, Hsieh, T, Cho, C, Wu, Y. Chemical constituents from Annona glabra III. J Chin Chem Soc 2000;47:913–20. https://doi.org/10.1002/jccs.200000124.Search in Google Scholar
36. Ziyaev, R, Abdusamatov, A, Ynusov, SY. d-Caaverine and a new alkaloid – lirinidine from liriodendron tulipifera. Chem Nat Compd 1973;9:727–9. https://doi.org/10.1007/bf00565796.Search in Google Scholar
37. Song, G, Ouyang, G, Bao, S. The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 2005;9:59–71. https://doi.org/10.1111/j.1582-4934.2005.tb00337.x.Search in Google Scholar
38. Altomare, AD, Khaled, AR. Homeostasis and the importance for a balance between AKT/mTOR activity and intracellular signaling. Curr Med Chem 2012;19:3748–62. https://doi.org/10.2174/092986712801661130.Search in Google Scholar
Supplementary material
The online version of this article offers supplementary material (https://doi.org/10.1515/znc-2020-0304).
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