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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Cytotoxicity Effects of Miltefosine and Niosomal form on Human Umbilical Vein Endothelial Cells: Colorimetric Assay, Apoptosis, and Gene Expression Profiling

Author(s): Fatemeh Sharifi, Fatemeh Seyedi*, Neda Mohamadi, Iraj Sharifi, Abbas Pardakhty, Ahmad Khosravi and Ali Kamali

Volume 20, Issue 12, 2023

Published on: 26 September, 2022

Page: [1936 - 1946] Pages: 11

DOI: 10.2174/1570180819666220816120305

Price: $65


Background: Miltefosine (MIL), hexadecyl phosphocholine, is the only oral medicine used to treat leishmaniasis. This drug has a major limitation and is expensive and potentially teratogenic. Objective: This study aimed to evaluate the toxic effect of MIL and its niosomal form on human umbilical vein endothelial cells (HUVECs), the expression genes, and the profile associated with apoptosis in the mitochondrial permeabilization regulated.

Methods: Miltefosine niosome (MN) prepared by the thin-film hydration method and characterized. HUVECs were treated with MIL (100–1000μg/ml), and MN (10-50μg/ml) for 24, 48, and 72 h, and the persistence was assessed by colorimetric assay flow cytometry and real-time PCR.

Results: Lesser toxicity was detected on cell proliferation for MN while both forms decreased Bcl-2 and elevated the expression of Bak/Bax and caspases-3, -8, and -9. The data demonstrated that MIL significantly exerted its cytotoxicity on HUVECs compared to MN.

Conclusion: This drug should be considered embryotoxic during pregnancy, while in niosomal form, it released slowly and remained safe. The mechanism of action of MIL associated with programmed cell death.

Keywords: Miltefosine, niosome, drug delivery system, colorimetric assay, apoptosis, gene expression profile.

Roatt, B.M.; de Oliveira Cardoso, J.M.; De Brito, R.C.F.; Coura-Vital, W.; de Oliveira Aguiar-Soares, R.D.; Reis, A.B. Recent advances and new strategies on leishmaniasis treatment; Appl. Microbiol. Appl. Microbiol. Biotechnol. APPL, 2020, 104(21), 8965-8917.
Kumar, A.; Pandey, S.C.; Samant, M. Slow pace of antileishmanial drug development. Parasitol. Open, 2018, 4, 4.
Sundar, S.; Chakravarty, J.; Meena, L.P. Leishmaniasis: Treatment, drug resistance and emerging therapies. Expert Opin. Orphan Drugs, 2019, 7(1), 1-10.
Croft, S.L. Kinetoplastida: New therapeutic strategies. Parasite, 2008, 15(3), 522-527.
[] [PMID: 18814734]
Sundar, S.; Jha, T.K.; Thakur, C.P.; Engel, J.; Sindermann, H.; Fischer, C.; Junge, K.; Bryceson, A.; Berman, J. Oral miltefosine for Indian visceral leishmaniasis. N. Engl. J. Med., 2002, 347(22), 1739-1746.
[] [PMID: 12456849]
Singh, S.; Sivakumar, R. Challenges and new discoveries in the treatment of leishmaniasis. J. Infect. Chemother., 2004, 10(6), 307-315.
[] [PMID: 15614453]
Sundar, S.; Chatterjee, M. Visceral leishmaniasis - current therapeutic modalities. Indian J. Med. Res., 2006, 123(3), 345-352.
[PMID: 16778315]
Torres-Guerrero, E.; Quintanilla-Cedillo, M.R.; Ruiz-Esmenjaud, J.; Arenas, R. Leishmaniasis: A review. F1000 Res., 2017, 6, 750.
[] [PMID: 28649370]
Tayyebi, M.; Darchini-Maragheh, E.; Layegh, P.; Kiafar, B.; Goyonlo, V.M. The effect of oral miltefosine in treatment of antimoniate resistant anthroponotic cutaneous leishmaniasis: An uncontrolled clinical trial. PLoS Negl. Trop. Dis., 2021, 15(3), e0009241.
[] [PMID: 33739976]
Tunalı, V.; Harman, M.; Çavuş, İ.; Gündüz, C.; Özbilgin, A.; Turgay, N. Overcoming the challenge; In Vivo efficacy of miltefosine for chronic cutaneous leishmaniasis. Acta Parasitol., 2021, 66(2), 354-360.
[] [PMID: 32996014]
Sunyoto, T.; Potet, J.; Boelaert, M. Why miltefosine-a life-saving drug for leishmaniasis-is unavailable to people who need it the most. BMJ Glob. Health, 2018, 3(3), e000709.
[] [PMID: 29736277]
Ouellette, M.; Drummelsmith, J.; Papadopoulou, B. Leishmaniasis: Drugs in the clinic, resistance and new developments. Drug Resist. Updat., 2004, 7(4-5), 257-266.
[] [PMID: 15533763]
Pijpers, J.; den Boer, M.L.; Essink, D.R.; Ritmeijer, K. The safety and efficacy of miltefosine in the long-term treatment of post-kalaazar dermal leishmaniasis in South Asia - A review and meta-analysis. PLoS Negl. Trop. Dis., 2019, 13(2), e0007173.
[] [PMID: 30742620]
Berman, J. Miltefosine to treat leishmaniasis. Expert Opin. Pharmacother., 2005, 6(8), 1381-1388.
[] [PMID: 16013987]
Chappuis, F.; Sundar, S.; Hailu, A.; Ghalib, H.; Rijal, S.; Peeling, R.W.; Alvar, J.; Boelaert, M. Visceral leishmaniasis: What are the needs for diagnosis, treatment and control? Nat. Rev. Microbiol., 2007, 5(11), 873-882.
[] [PMID: 17938629]
Silva, A.; Costa, A.; Jain, S.; Coelho, E.; Fujiwara, R.; Scher, R.; Nunes, R.; Dolabella, S. Application of poloxamers for the development of drug delivery system to treat leishmaniasis: A review. Curr. Drug Targets, 2021, 22(3), 296-309.
[] [PMID: 33155921]
Bhardwaj, P.; Tripathi, P.; Gupta, R.; Pandey, S. Niosomes: A review on niosomal research in the last decade. J. Drug Deliv. Sci. Technol., 2020, 56, 101581.
Chen, S.; Hanning, S.; Falconer, J.; Locke, M.; Wen, J. Recent advances in non-ionic surfactant vesicles (niosomes): Fabrication, characterization, pharmaceutical and cosmetic applications. Eur. J. Pharm. Biopharm., 2019, 144, 18-39.
[] [PMID: 31446046]
Chaiworapongsa, T.; Romero, R.; Whitten, A.E.; Korzeniewski, S.J.; Chaemsaithong, P.; Hernandez-Andrade, E.; Yeo, L.; Hassan, S.S. The use of angiogenic biomarkers in maternal blood to identify which SGA fetuses will require a preterm delivery and mothers who will develop pre-eclampsia. J. Matern. Fetal Neonatal Med., 2016, 29(8), 1214-1228.
[] [PMID: 26303962]
Khosravi, A.; Sharifi, I.; Tavakkoli, H.; Keyhani, A.R.; Afgar, A.; Salari, Z.; Bamorovat, M.; Sharifi, F.; Khaleghi, T.; Varma, R.S.; Dabiri, S.; Nematollahi-Mahani, S.N.; Babaee, A.; Mostafavi, M.; Hakimi Parizi, M.; Derakhshanfar, A.; Salarkia, E. Toxicopathological effects of meglumine antimoniate on human umbilical vein endothelial cells. Toxicol. In Vitro, 2019, 56, 10-18.
[] [PMID: 30599190]
Zhang, Y.; Ang, C.Y.; Li, M.; Tan, S.Y.; Qu, Q.; Luo, Z.; Zhao, Y. Polymer-coated hollow mesoporous silica nanoparticles for tripleresponsive drug delivery. ACS Appl. Mater. Interfaces, 2015, 7(32), 18179-18187.
[] [PMID: 26221866]
Pandian, S.R.K.; Panneerselvam, T.; Pavadai, P.; Govindaraj, S.; Ravishankar, V.; Palanisamy, P.; Sampath, M.; Sankaranarayanan, M.; Kunjiappan, S. Nano based approach for the treatment of neglected tropical diseases. Front. Nanotechnol., 2021, 3, 49.
Ramdas, S. Cruel disease, cruel medicine: Self-treatment of cutaneous leishmaniasis with harmful chemical substances in Suriname. Soc. Sci. Med., 2012, 75(6), 1097-1105.
[] [PMID: 22704264]
Ge, X.; Wei, M.; He, S.; Yuan, W-E. Advances of non-ionic surfactant vesicles (niosomes) and their application in drug delivery. Pharmaceutics, 2019, 11(2), 55.
[] [PMID: 30700021]
Okwor, I.; Uzonna, J. Social and economic burden of human leishmaniasis. Am. J. Trop. Med. Hyg., 2016, 94(3), 489-493.
[] [PMID: 26787156]
Lynch, M.M.; Amoozegar, J.B.; McClure, E.M.; Squiers, L.B.; Broussard, C.S.; Lind, J.N.; Polen, K.N.; Frey, M.T.; Gilboa, S.M.; Biermann, J. Improving safe use of medications during pregnancy: The roles of patients, physicians, and pharmacists. Qual. Health Res., 2017, 27(13), 2071-2080.
[] [PMID: 28974142]
Pinto-Martinez, A.K.; Rodriguez-Durán, J.; Serrano-Martin, X.; Hernandez-Rodriguez, V.; Benaim, G. Mechanism of action of miltefosine on Leishmania donovani involves the impairment of acidocalcisome function and the activation of the sphingosinedependent plasma membrane Ca2+ channel. Antimicrob. Agents Chemother., 2017, 62(1), e01614-e01617.
[PMID: 29061745]
Mishra, J.; Singh, S. Miltefosine resistance in Leishmania donovani involves suppression of oxidative stress-induced programmed cell death. Exp. Parasitol., 2013, 135(2), 397-406.
[] [PMID: 23968687]
Sampaio, R.N.R.; Silva, J.S.F.E.; Paula, C.D.R.; Porto, C.; Motta, J.O.C.D.; Pereira, L.I.A.; Martins, S.S.; Barroso, D.H.; Freire, G.S.M.; Gomes, C.M. A randomized, open-label clinical trial comparing the long-term effects of miltefosine and meglumine antimoniate for mucosal leishmaniasis. Rev. Soc. Bras. Med. Trop., 2019, 52, e20180292.
[] [PMID: 30942258]
Cope, J.R.; Roy, S.L.; Yoder, J.S.; Beach, M.J. Increased patient survival: Miltefosine for treatment of free-living ameba infections caused by acanthamoeba, balamuthia, and naegleria. Cureus, 2017.
Sundar, S.; Mondal, D.; Rijal, S.; Bhattacharya, S.; Ghalib, H.; Kroeger, A.; Boelaert, M.; Desjeux, P.; Richter-Airijoki, H.; Harms, G. Implementation research to support the initiative on the elimination of kala azar from Bangladesh, India and Nepal–the challenges for diagnosis and treatment; Blackwell Publishing Ltd Oxford: UK, 2008.
Wadhone, P.; Maiti, M.; Agarwal, R.; Kamat, V.; Martin, S.; Saha, B. Miltefosine promotes IFN-γ-dominated anti-leishmanial immune response. J. Immunol., 2009, 182(11), 7146-7154.
[] [PMID: 19454711]
Ware, J.M.; O’Connell, E.M.; Brown, T.; Wetzler, L.; Talaat, K.R.; Nutman, T.B.; Nash, T.E. Efficacy and tolerability of miltefosine in the treatment of cutaneous leishmaniasis. Clin. Infect. Dis., 2020.
[PMID: 33124666]
Zimmermann, K.C.; Green, D.R. How cells die: Apoptosis pathways. J. Allergy Clin. Immunol., 2001, 108(4)(Suppl.), S99-S103.
[] [PMID: 11586274]
Peña‐Blanco, A.; García-Sáez, A.J. Bax, Bak and beyond—mitochondrial performance in apoptosis. FEBS J., 2018, 285(3), 416-431.
Song, C.; Han, Y.; Luo, H.; Qin, Z.; Chen, Z.; Liu, Y.; Lu, S.; Sun, H.; Zhou, C. HOXA10 induces BCL2 expression, inhibits apoptosis, and promotes cell proliferation in gastric cancer. Cancer Med., 2019, 8(12), 5651-5661.
[] [PMID: 31364281]
Basu, A. The interplay between apoptosis and cellular senescence: Bcl-2 family proteins as targets for cancer therapy. Pharmacol. Ther., 2022, 230, 107943.
[] [PMID: 34182005]
Kawiak, A.; Kostecka, A. Regulation of Bcl-2 family proteins in estrogen receptor-positive breast cancer and their implications in endocrine therapy. Cancers (Basel), 2022, 14(2), 279.
[] [PMID: 35053443]
J, B.; M, B.M.; Chanda, K. An overview on the therapeutics of neglected infectious diseases-leishmaniasis and chagas diseases. Front Chem., 2021, 9, 622286.
[] [PMID: 33777895]
Rahman, R.; Goyal, V.; Haque, R.; Jamil, K.; Faiz, A.; Samad, R.; Ellis, S.; Balasegaram, M.; Boer, M.D.; Rijal, S.; Strub-Wourgaft, N.; Alves, F.; Alvar, J.; Sharma, B. Safety and efficacy of short course combination regimens with AmBisome, miltefosine and paromomycin for the treatment of visceral leishmaniasis (VL) in Bangladesh. PLoS Negl. Trop. Dis., 2017, 11(5), e0005635.
[] [PMID: 28558062]
Man, E.; Price, H.P.; Hoskins, C. Current and future strategies against cutaneous parasites. Pharm. Res., 2022, 39(4), 631-651.
[] [PMID: 35313360]
Prasanna, P.; Kumar, P.; Kumar, S.; Rajana, V.K.; Kant, V.; Prasad, S.R.; Mohan, U.; Ravichandiran, V.; Mandal, D. Current status of nanoscale drug delivery and the future of nano-vaccine development for leishmaniasis - A review. Biomed. Pharmacother., 2021, 141, 111920.
[] [PMID: 34328115]
Korade, Z.; Allen, L.B.; Anderson, A.; Tallman, K.A.; Genaro-Mattos, T.C.; Porter, N.A.; Mirnics, K. Trazodone effects on developing brain. Transl. Psychiatry, 2021, 11(1), 85.
[] [PMID: 33526772]
Sunyoto, T.; Boelaert, M.; Meheus, F. Understanding the economic impact of leishmaniasis on households in endemic countries: A systematic review. Expert Rev. Anti Infect. Ther., 2019, 17(1), 57-69.
[] [PMID: 30513027]
Alyami, H.; Abdelaziz, K.; Dahmash, E.Z.; Iyire, A. Nonionic surfactant vesicles (niosomes) for ocular drug delivery: Development, evaluation and toxicological profiling. J. Drug Del. Sci. Tech., 2020, 60, 102069.

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