|LETTER TO EDITOR
|Year : 2015 | Volume
| Issue : 1 | Page : 69-70
Hypothesis: The potential application of doxorubicin against cutaneous leishmaniasis
Masoud Keighobadi1, Mahdi Fakhar2, Saeed Emami1
1 Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
2 Department of Parasitology and Mycology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
|Date of Web Publication||22-Jan-2015|
Department of Parasitology and Mycology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Keighobadi M, Fakhar M, Emami S. Hypothesis: The potential application of doxorubicin against cutaneous leishmaniasis. Trop Parasitol 2015;5:69-70
DNA topoisomerases (TOP) have been used as chemotherapeutic targets for antibacterial and antiprotozoal diseases. They are ubiquitous enzymes that play an important role in many essential processes (such as DNA replication, transcription, and recombination). They are classified as TOP type I, type II that cleavage single stranded and double stranded DNA, respectively. 
Topoisomerases I (EC 126.96.36.199) have been characterized from Leishmania donovani and Trypanosoma cruzi. The enzyme was found to be independent of ATP.  Inhibitors of TOP I include anti-Leishmania compounds such as sodium stibogluconate (glucantime). TOP II (EC 188.8.131.52) has been identified from Trypanosoma brucei,  T. cruzi and L. donovani.  TOP II inhibitor, 9-anilinoacridine; antitumor agent, and other acridine derivatives inhibited Leishmania and Trypanosoma effectively. 
The structure of L. donovani topoisomerase I, bound to nicked DNA captured as a vandate complex has been elucidated.  The structural analysis of these enzymes will give us an insight into their catalytic mechanisms and will also enable us to design specific inhibitors against Leishmania parasites. Doxorubicin is available in liposome-encapsulated forms as Doxil. Also known as hydroxyl daunorubicin that is commonly used in the treatment of a wide range of cancers. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines. The Food and Drug Administration approved a generic version of Doxil in February 2013. The drug is administered intravenously, as the hydrochloride salt. Recently has been demonstrated that acute inflammation induced by doxorubicin is associated with apoptosis of macrophages in the mouse model and that it is specific for doxorubicin, an imuunogenic chemotherapeutic target.  Doxorubicin interacts with DNA by inhibition of macromolecular biosynthesis. This inhibits the progression of the enzyme TOP II, which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the TOP II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thus stopping the process of replication. , Accordingly, Doxorubicin could be effective against Leishmania parasite. Hence, combination of the Doxil, as a liposomal formulation of doxorubicin, preferable as a topical formulation with glucantime (as a drug of choice) could integrate for treatment and also decrease the resistance of Leishmania against current available drugs. It would be desirable because liposome-encapsulated doxorubicin is fewer side-effects than unencapsulated doxorubicin in the same treatment regimen. Moreover, since liposome labor to deliver the drug by diffusion rather than by direct cell fusion, this form allowing doxorubicin to pass freely through the membrane and gave an effective drug delivery. Our remark favorable utility of it for clinical trials and also in vitro and or in vivo experiments in the future.
| References|| |
Chawla B, Madhubala R. Drug targets in Leishmania.
J Parasit Dis 2010;34:1-13.
Das A, Dasgupta A, Sengupta T, Majumder HK. Topoisomerases of kinetoplastid parasites as potential chemotherapeutic targets. Trends Parasitol 2004;20:381-7.
Strauss PR, Wang JC. The TOP2 gene of Trypanosoma brucei
: A single-copy gene that shares extensive homology with other TOP2 genes encoding eukaryotic DNA topoisomerase II. Mol Biochem Parasitol 1990;38:141-50.
Fragoso SP, Goldenberg S. Cloning and characterization of the gene encoding Trypanosoma
cruzi DNA topoisomerase II. Mol Biochem Parasitol 1992;55:127-34.
Das A, Dasgupta A, Sharma S, Ghosh M, Sengupta T, Bandopadhyay S, et al.
Characterisation of the gene encoding type II DNA topoisomerase from Leishmania donovani
: A key molecular target in antileishmanial therapy. Nucleic Acids Res 2001;29:1844-51.
Figgitt D, Denny W, Chavalitshewinkoon P, Wilairat P, Ralph R. In vitro
study of anticancer acridines as potential antitrypanosomal and antimalarial agents. Antimicrob Agents Chemother 1992;36:1644-7.
Davies DR, Mushtaq A, Interthal H, Champoux JJ, Hol WG. The structure of the transition state of the heterodimeric topoisomerase I of Leishmania donovani
as a vanadate complex with nicked DNA. J Mol Biol 2006;357:1202-10.
Krysko DV, Kaczmarek A, Krysko O, Heyndrickx L, Woznicki J, Bogaert P, et al.
TLR-2 and TLR-9 are sensors of apoptosis in a mouse model of doxorubicin-induced acute inflammation. Cell Death Differ 2011;18:1316-25.
Fornari FA, Randolph JK, Yalowich JC, Ritke MK, Gewirtz DA. Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Mol Pharmacol 1994;45: 649-56.
Momparler RL, Karon M, Siegel SE, Avila F. Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer Res 1976;36:2891-5.
|This article has been cited by|
||Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum
| ||Susiany P. Lopes,Lina M. Yepes,Yunierkis Pérez-Castillo,Sara M. Robledo,Damião P. de Sousa |
| ||Molecules. 2020; 25(14): 3178 |
|[Pubmed] | [DOI]|
||Promising antileishmanial effectiveness of doxorubicin and Doxil against Leishmania major : An in vitro assay
| ||Azar Shokri,Javad Akhtari,Masoud Keighobadi,Mahdi Fakhar,Saeed Hosseini Teshnizi,Saeed Emami,Sajede Sadjjadian |
| ||Asian Pacific Journal of Tropical Medicine. 2017; |
|[Pubmed] | [DOI]|
||Case Report: No Response to Liposomal Daunorubicin in a Patient with Drug-Resistant HIV-Associated Visceral Leishmaniasis
| ||Nicholas J. Gow,Robert N. Davidson,Rob Ticehurst,Andrew Burns,Mark G. Thomas,Carlos Franco-Paredes |
| ||PLOS Neglected Tropical Diseases. 2015; 9(8): e0003983 |
|[Pubmed] | [DOI]|