Pamidronate, a promising repositioning drug to treat leishmaniasis, displays antileishmanial and immunomodulatory potential

Ribeiro, Juliana Martins; Rodrigues-Alves, Marina L.; Oliveira, Edward; Guimarães, Pedro Pires Goulart; Santi, Ana Maria Murta; Teixeira-Carvalho, Andréa; Murta, Silvane Maria Fonseca; Peruhype-Magalhães, Vanessa; Souza-Fagundes, Elaine Maria de

doi:10.1016/j.intimp.2022.108952

Cited by 6 publications

(4 citation statements)

References 40 publications

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“…Given that cytotoxic activity of CD8 T cells against cancer cells, these CD20-posivite T cells could play role in cancer suppression as well, which requires further studies. Our finding is in agreement with previous publications demonstrating that anti-CD20 treatment decreases tumor growth in various cancer models (42,43) and ZOL effects on B cell (53,54).…”

Section: Discussionsupporting

confidence: 94%

CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases

et al. 2023

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IntroductionBisphosphonates (BPs) are bone-protecting osteoclast inhibitors, typically used in the treatment of osteoporosis and skeletal complications of malignancies. When given in the adjuvant setting, these drugs may also prevent relapses and prolong overall survival in early breast cancer (EBC), specifically among postmenopausal patients. Because of these findings, adjuvant nitrogen-containing BPs (N-BPs), such as zoledronate (ZOL), are now the standard of care for high-risk EBC patients, but there are no benefit-associated biomarkers, and the efficacy remains low. BPs have been demonstrated to possess anti-tumor activities, but the mechanisms by which they provide the beneficial effects in EBC are not known. MethodsWe used stably transfected 4T1 breast cancer cells together with suppression of CD73 (sh-CD73) or control cells (sh-NT). We compared ZOL effects on tumor growth and infiltrating lymphocytes (TILs) into tumors and lung metastases using two mouse models. B cell depletion was performed using anti-CD20 antibody.ResultsSh-CD73 4T1 cells were significantly more sensitive to the growth inhibitory effects of n-BPs in vitro. However, while ZOL-induced growth inhibition was similar between the tumor groups in vivo, ZOL enhanced B and T lymphocyte infiltration into the orthotopic tumors with down-regulated CD73. A similar trend was detected in lung metastases. ZOL-induced tumor growth inhibition was found to be augmented with B cell depletion in sh-NT tumors, but not in sh-CD73 tumors. As an internal control, ZOL effects on bone were similar in mice bearing both tumor groups.DiscussionTaken together, these results indicate that ZOL modifies TILs in breast cancer, both in primary tumors and metastases. Our results further demonstrate that B cells may counteract the growth inhibitory effects of ZOL. However, all ZOL-induced TIL effects may be influenced by immunomodulatory characteristics of the tumor.

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Section: Discussionsupporting

confidence: 94%

CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases

et al. 2023

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“…Employing molecular dynamics simulations, an in silico study scrutinized the binding patterns of two innovative inhibitors targeting the crucial Leishmania enzyme, pteridine reductase 1 (PTR1). The inhibitors' ability to establish enduring interactions with the enzyme suggests their potential as exceptional candidates for pioneering Cutaneous Leishmaniasis (CL) drug development [ 19 ]. In the quest for prospective therapeutic targets in CL, a combined in silico analysis encompassing network-based and machine-learning methodologies was conducted to identify pivotal proteins and disease-associated pathways.…”

Section: Introductionmentioning

confidence: 99%

Computational investigation of turmeric phytochemicals targeting PTR1 enzyme of Leishmania species

Ullah,

Wu,

Malak

et al. 2024

Heliyon

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“…Leishmania has a dimorphic life cycle, with the promastigote form present in the phlebotomine vector sand fly, while the amastigote form is present in the mammalian host [4] . Currently, available medicines for leishmaniasis, such as miltefosine, amphotericin B, pentamidine, and paromomycin, have multiple disadvantages, including difficult access, handling, high toxicity, drug resistance, prolonged parenteral administration, etc [5] . To date, no effective drug or vaccine is available to effectively treat leishmaniasis [6] .…”

Section: Introductionmentioning

confidence: 99%

“…[4] Currently, available medicines for leishmaniasis, such as miltefosine, amphotericin B, pentamidine, and paromomycin, have multiple disadvantages, including difficult access, handling, high toxicity, drug resistance, prolonged parenteral administration, etc. [5] To date, no effective drug or vaccine is available to effectively treat leishmaniasis. [6] Given the escalating resistance to the current therapeutic agents, identifying a novel therapeutic agent is crucial to treat leishmaniasis.…”

Section: Introductionmentioning

confidence: 99%

5‐Arylidene‐2,4‐thiazolidinediones as Cysteine Protease Inhibitors against Leishmania Donovani

Sharma,

Anjaneyulu Yakkala,

Beg

et al. 2023

ChemistrySelect

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A series of 5‐arylidene‐2,4‐thiazolidinediones were synthesized using Knoevenagel condensation and evaluated for their anti‐leishmanial activity against L. donovani promastigotes and axenic amastigotes. Among the compounds tested, three were the most active, with IC50 values of 0.82–1.42 μM against L. donovani promastigotes and 0.69–1.19 μM against L. donovani amastigote. (Z)‐5‐(4‐(trifluoromethyl)benzylidene)thiazolidine‐2,4‐dione was the most prominent among all the tested compounds and demonstrated better anti‐leishmanial properties when compared to the standard drug miltefosine (1.26 μM against L. donovani promastigotes and 1.17 μM against L. donovani amastigotes). It was insignificantly toxic compared to the standard miltefosine in THP‐1 human monocytic cells. It was further evaluated for its in vitro cysteine protease (papain) inhibitory activity using Z‐RR‐AMC fluorogenic peptide substrate. It demonstrated promising inhibitory activity with the IC50 value of 3.42 μM. In silico docking studies also supported that the (Z)‐5‐(4‐(trifluoromethyl)benzylidene)thiazolidine‐2,4‐dione is bound to cysteine protease proteins′ catalytic active binding site. Anti‐leishmanial properties of this class of compounds have been evaluated for the first time, and (Z)‐5‐(4‐(trifluoromethyl)benzylidene)thiazolidine‐2,4‐dione emerged as a lead molecule from the library of compounds tested. This may serve as a template for further drug discovery in Leishmania.

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Pamidronate, a promising repositioning drug to treat leishmaniasis, displays antileishmanial and immunomodulatory potential

Cited by 6 publications

References 40 publications

CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases

CD73 regulates zoledronate-induced lymphocyte infiltration in triple-negative breast cancer tumors and lung metastases

Computational investigation of turmeric phytochemicals targeting PTR1 enzyme of Leishmania species

5‐Arylidene‐2,4‐thiazolidinediones as Cysteine Protease Inhibitors against Leishmania Donovani

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