title: Co-administration of glycyrrhizic acid with the antileishmanial drug sodium antimony gluconate (SAG) cures SAG-resistant visceral leishmaniasis.
abstract: Since there are very few affordable antileishmanial drugs available, antimonial resistance has crippled antileishmanial therapy, thereby emphasising the need for development of novel therapeutic strategies. This study aimed to evaluate the antileishmanial role of combined therapy with sodium antimony gluconate (SAG) and the triterpenoid glycyrrhizic acid (GA) against infection with SAG-resistant Leishmania (GE1F8R). Combination therapy with GA and SAG successfully limited infection with SAG-resistant Leishmania in a synergistic manner (fractional inhibitory concentration index <1.0). At the same time, mice infected with SAG-resistant Leishmania and co-treated with GA and SAG exhibited a significant reduction in hepatic and splenic parasite burden. In probing the mechanism, it was observed that GA treatment suppressed the expression and efflux activity of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1), two host ABC transporters responsible for antimony efflux from host cells infected with SAG-resistant parasites. This suppression correlated with greater intracellular antimony retention during SAG therapy both in vitro and in vivo, which was reflected in the reduced parasite load. Furthermore, co-administration of GA and SAG induced a shift in the cytokine balance towards a Th1 phenotype by augmenting pro-inflammatory cytokines (such as IL-12, IFNγ and TNFα) and inducing nitric oxide generation in GE1F8R-infected macrophages as well as GE1F8R-infected mice. This study aims to provide an affordable leishmanicidal alternative to expensive antileishmanial drugs such as miltefosine and amphotericin B. Furthermore, this report explores the role of GA as a resistance modulator in MRP1- and P-gp-overexpressing conditions.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, India.
authors.forename: Amrita
authors.initials: A
authors.lastname: Bhattacharjee
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, India.
authors.forename: Saikat
authors.initials: S
authors.lastname: Majumder
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, India.
authors.forename: Suchandra Bhattacharyya
authors.initials: SB
authors.lastname: Majumdar
authors.affiliation: Department of In vitro Carcinogenesis and Cellular Chemotherapy, Chittaranjan National Cancer Institute, Kolkata, India.
authors.forename: Soumitra Kumar
authors.initials: SK
authors.lastname: Choudhuri
authors.affiliation: Infectious Diseases and Immunology Division, Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Syamal
authors.initials: S
authors.lastname: Roy
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, India. Electronic address: subrata@bic.boseinst.ernet.in.
authors.forename: Subrata
authors.initials: S
authors.lastname: Majumdar
mesh_terms: D000818:Animals; D000967:Antimony Sodium Gluconate / Q000008:administration & dosage* / Q000494:pharmacology; D000981:Antiprotozoal Agents / Q000008:administration & dosage* / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D004195:Disease Models, Animal; D004351:Drug Resistance; D004359:Drug Therapy, Combination / Q000379:methods; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D019695:Glycyrrhizic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D007891:Leishmania / Q000187:drug effects* / Q000302:isolation & purification; D007898:Leishmaniasis, Visceral / Q000188:drug therapy* / Q000469:parasitology; D008099:Liver / Q000469:parasitology; D008807:Mice, Inbred BALB C; D059208:Parasite Load; D013154:Spleen / Q000469:parasitology; D016896:Treatment Outcome
chemical_list: D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D019695:Glycyrrhizic Acid; D000967:Antimony Sodium Gluconate
keywords: ABC transporter; Antimony; Drug resistance; Immunomodulator; Macrophages