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Asian Pacific Journal of Tropical... Jun 2012The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat... (Review)
Review
The control of Leishmania infection relies primarily on chemotherapy till date. Resistance to pentavalent antimonials, which have been the recommended drugs to treat cutaneous and visceral leishmaniasis, is now widespread in Indian subcontinents. New drug formulations like amphotericin B, its lipid formulations, and miltefosine have shown great efficacy to treat leishmaniasis but their high cost and therapeutic complications limit their usefulness. In addition, irregular and inappropriate uses of these second line drugs in endemic regions like state of Bihar, India threaten resistance development in the parasite. In context to the limited drug options and unavailability of either preventive or prophylactic candidates, there is a pressing need to develop true antileishmanial drugs to reduce the disease burden of this debilitating endemic disease. Notwithstanding significant progress of leishmanial research during last few decades, identification and characterization of novel drugs and drug targets are far from satisfactory. This review will initially describe current drug regimens and later will provide an overview on few important biochemical and enzymatic machineries that could be utilized as putative drug targets for generation of true antileishmanial drugs.
Topics: Aminoquinolines; Amphotericin B; Antigens, Protozoan; Antimony Sodium Gluconate; Antiprotozoal Agents; Caspase Inhibitors; Cyclin-Dependent Kinases; Drug Discovery; Enzyme Inhibitors; Folic Acid Antagonists; Humans; Leishmaniasis; Macrophages; Microbodies; Mitogen-Activated Protein Kinase Kinases; Paromomycin; Pentamidine; Phosphorylcholine; Polyamines; Protease Inhibitors; Sterols; Sulfhydryl Compounds; Topoisomerase Inhibitors
PubMed: 22575984
DOI: 10.1016/S1995-7645(12)60084-4 -
Acta Poloniae Pharmaceutica 2012The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic...
The amino analogues of pentamidine with a polymethylene (n = 3 - 6) chain and their chlorambucil derivatives were synthesized. The obtained compounds revealed cytotoxic effect on MCF-7 human breast cancer cell line (IC50 = 22 - 95 +/- 2 pM), mainly by the induction of apoptosis. The topoisomerase I/II inhibition assay and the ethidium displacement assay with the use of pBR322 plasmid DNA were used to the study of mechanism by which the obtained compounds could act. All the compounds are able to bind with DNA and interfere in vitro with the activity of topoisomerase (I and II). The determination of association constants with the use of calf thymus DNA, T4 coliphage DNA, poly(dA-dT)2 and poly(dG-dC)2 showed that the tested compounds bind within minor groove of B-DNA, but not selectively. The alkylating activity of chlorambucil derivatives determined in vitro using a Preussmann test was similar to the activity of chlorambucil. The influence of all the compounds on the amidolytic activity of plasmin and trypsin was also examined. The plasmin activity was inhibited by pentamidine, chlorambucil and aromatic bis-amines (IC50 = 0.1 - 8 mM), whereas the trypsin activity was influenced only by pentamidine.
Topics: Antifibrinolytic Agents; Antineoplastic Agents, Alkylating; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Chlorambucil; DNA; Dose-Response Relationship, Drug; Female; Humans; Inhibitory Concentration 50; Molecular Structure; Pentamidine; Structure-Activity Relationship; Topoisomerase I Inhibitors; Topoisomerase II Inhibitors; Trypsin Inhibitors
PubMed: 22574508
DOI: No ID Found -
International Journal of Pharmaceutics Sep 2019Nanoparticles of polymeric complexes made of hyaluronic acid and polyarginine were investigated for the encapsulation of the cationic hydrophilic drug pentamidine...
Nanoparticles of polymeric complexes made of hyaluronic acid and polyarginine were investigated for the encapsulation of the cationic hydrophilic drug pentamidine isethionate. The interaction between the anionic hyaluronic acid and the cationic pentamidine resulting in the formation of polyelectrolyte complexes was firstly studied. Then, nanoparticles made of hyaluronic acid and polyarginine loaded with pentamidine were developed. These drug delivery systems consist of a monodisperse population of negatively charged pentamidine-loaded nanoparticles with a high drug encapsulation rate (80%). Such high encapsulation efficiency coming from ion exchange was confirmed by measurements of the counterion isethionate released from pentamidine during nanoparticles formation. Besides, freeze-dried pentamidine-loaded nanoparticles kept their integrity after their reconstitution in water. In vitro studies on human lung (A549) and breast (MDA-MB-231) cancer cell lines showed that pentamidine-loaded nanoparticles were more cytotoxic in comparison to the free drug, suggesting an enhanced internalization of encapsulated drug by cancer cells.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Drug Delivery Systems; Drug Liberation; Drug Stability; Freeze Drying; Humans; Hyaluronic Acid; Nanoparticles; Pentamidine; Peptides; Solubility
PubMed: 31323370
DOI: 10.1016/j.ijpharm.2019.118526 -
Archives of Biochemistry and Biophysics Sep 2020Metastasis-associated S100A4 protein is a small calcium-binding protein typically overexpressed in several tumor forms, and it is widely accepted that S100A4 plays a...
Metastasis-associated S100A4 protein is a small calcium-binding protein typically overexpressed in several tumor forms, and it is widely accepted that S100A4 plays a significant role in the metastasis of cancer. Tumor suppressor p53 is one of the S100A4's main targets. Previous reports show that through p53, S100A4 regulates collagen expression and cell proliferation. When S100A4 interacts with p53, the S100A4 destabilizes wild type p53. In the current study, based on H-N HSQC NMR experiments and HADDOCK results, S100A4 interacts with the intrinsically unstructured transactivation domain (TAD) of the protein p53 and the pentamidine molecules in the presence of calcium ions. Our results suggest that the p53 TAD and pentamidine molecules share similar binding sites on the S100A4 protein. This observation indicates that a competitive binding mechanism can interfere with the binding of S100A4-p53 and increase the level of p53. Also, we compare different aspects of p53 activity in the WST-1 test using MCF 7 cells. We found that the presence of a pentamidine molecule results in higher p53 activity, which is also reflected in less cell proliferation. Collectively, our results indicate that disrupting the S100A4-p53 interaction would prevent cancer progression, and thus S100A4-p53 inhibitors provide a new avenue for cancer therapy.
Topics: Antineoplastic Agents; Binding Sites; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; MCF-7 Cells; Pentamidine; Protein Binding; Protein Multimerization; S100 Calcium-Binding Protein A4; Tumor Suppressor Protein p53
PubMed: 32649952
DOI: 10.1016/j.abb.2020.108442 -
The Indian Journal of Medical Research Mar 2006Major therapeutic obstacles in the treatment of visceral leishmaniasis (VL) include the alarming increase in antimonial unresponsiveness especially in Bihar, India and... (Review)
Review
Major therapeutic obstacles in the treatment of visceral leishmaniasis (VL) include the alarming increase in antimonial unresponsiveness especially in Bihar, India and relapses in HIV-Leishmania co-infected patients. The therapeutic armamentarium for VL is currently plagued with several limitations as the available drugs are toxic, majority are effective only parenterally and need to be administered for extended periods. The first orally effective drug, miltefosine has been approved for treating VL. In antimony refractory zones, pentavalent antimony has been largely replaced by amphotericin B deoxycholate, but prolonged hospitalization, toxic effects, and requirement for monitoring greatly hamper its widespread application in endemic regions. Lipid formulations of amphotericin B, a remarkable advance in amphotericin B therapy, have greatly reduced toxicity enabling large doses to be delivered over a short period. Even a single dose treatment with liposomal amphotericin B cures > 90 per cent patients; however, the stumbling block is its prohibitive cost that precludes its widespread accessibility in endemic countries. Studies using paromomycin in VL are encouraging, and judging by the preliminary results of a recently concluded phase III trial, it could be an extremely useful and affordable antileishmanial drug. Other orally effective drugs include the azoles and allopurinol but these have met with limited success owing to either poor efficacy or unacceptable toxicity. Sitamaquine has undergone limited evaluation, and the data suggest effective antileishmanial activity; its role has to be delineated for which additional developmental studies are proposed. This review highlights the progress made in the treatment of VL, including the multiple mechanisms of action of antileishmanial drugs with a view to enable the researcher to undertake the challenge of providing affordable and effective chemotherapy.
Topics: Administration, Oral; Amphotericin B; Animals; Antimony Sodium Gluconate; Antineoplastic Agents; Antiprotozoal Agents; Humans; Immunologic Factors; Leishmania; Leishmaniasis, Visceral; Pentamidine
PubMed: 16778315
DOI: No ID Found -
PLoS Pathogens Feb 2016The chemotherapeutic arsenal against human African trypanosomiasis, sleeping sickness, is limited and can cause severe, often fatal, side effects. One of the classic and...
The chemotherapeutic arsenal against human African trypanosomiasis, sleeping sickness, is limited and can cause severe, often fatal, side effects. One of the classic and most widely used drugs is pentamidine, an aromatic diamidine compound introduced in the 1940s. Recently, a genome-wide loss-of-function screen and a subsequently generated trypanosome knockout strain revealed a specific aquaglyceroporin, TbAQP2, to be required for high-affinity uptake of pentamidine. Yet, the underlying mechanism remained unclear. Here, we show that TbAQP2 is not a direct transporter for the di-basic, positively charged pentamidine. Even though one of the two common cation filters of aquaglyceroporins, i.e. the aromatic/arginine selectivity filter, is unconventional in TbAQP2, positively charged compounds are still excluded from passing the channel. We found, instead, that the unique selectivity filter layout renders pentamidine a nanomolar inhibitor of TbAQP2 glycerol permeability. Full, non-covalent inhibition of an aqua(glycero)porin in the nanomolar range has not been achieved before. The remarkable affinity derives from an electrostatic interaction with Asp265 and shielding from water as shown by structure-function evaluation and point mutation of Asp265. Exchange of the preceding Leu264 to arginine abolished pentamidine-binding and parasites expressing this mutant were pentamidine-resistant. Our results indicate that TbAQP2 is a high-affinity receptor for pentamidine. Taken together with localization of TbAQP2 in the flagellar pocket of bloodstream trypanosomes, we propose that pentamidine uptake is by endocytosis.
Topics: Animals; Aquaglyceroporins; Drug Resistance; Humans; Pentamidine; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 26828608
DOI: 10.1371/journal.ppat.1005436 -
The National Medical Journal of India 1992
Topics: Amphotericin B; Antimony Sodium Gluconate; Antiprotozoal Agents; Humans; India; Leishmaniasis, Visceral; Meglumine; Meglumine Antimoniate; Organometallic Compounds; Pentamidine
PubMed: 1338871
DOI: No ID Found -
Cell Proliferation Jan 2020We investigated the anti-cancer activity of pentamidine, an anti-protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable...
OBJECTIVES
We investigated the anti-cancer activity of pentamidine, an anti-protozoal cationic aromatic diamidine drug, in prostate cancer cells and aimed to provide valuable insights for improving the efficacy of prostate cancer treatment.
MATERIALS AND METHODS
Prostate cancer cell lines and epithelial RWPE-1 cells were used in the study. Cell viability, wound-healing, transwell and apoptosis assays were examined to evaluate the influences of pentamidine in vitro. RNA-seq and qPCR were performed to analyse changes in gene transcription levels upon pentamidine treatment. Mitochondrial changes were assessed by measuring mitochondrial DNA content, morphology, membrane potential, cellular glucose uptake, ATP production and ROS generation. Nude mouse xenograft models were used to test anti-tumour effects of pentamidine in vivo.
RESULTS
Pentamidine exerted profound inhibitory effects on proliferation, colony formation, migration and invasion of prostate cancer cells. In addition, the drug suppressed growth of xenograft tumours without exhibiting any obvious toxicity in nude mice. Mechanistically, pentamidine caused mitochondrial DNA content reduction and induced mitochondrial morphological changes, mitochondrial membrane potential dissipation, ATP level reduction, ROS production elevation and apoptosis in prostate cancer cells.
CONCLUSIONS
Pentamidine can efficiently suppress prostate cancer progression and may serve as a novel mitochondria-targeted therapeutic agent for prostate cancer.
Topics: Animals; Cell Proliferation; DNA, Mitochondrial; DNA, Neoplasm; Humans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Nude; Mitochondria; PC-3 Cells; Pentamidine; Prostatic Neoplasms; Xenograft Model Antitumor Assays
PubMed: 31721355
DOI: 10.1111/cpr.12718 -
Frontiers in Cellular and Infection... 2018Enterobacteriaceae cause different types of community- and hospital-acquired infections. Moreover, the spread of multidrug-resistant Enterobacteriaceae is a public...
Activity of Pentamidine Alone and in Combination With Aminoglycosides, Tigecycline, Rifampicin, and Doripenem Against Clinical Strains of Carbapenemase-Producing and/or Colistin-Resistant Enterobacteriaceae.
Enterobacteriaceae cause different types of community- and hospital-acquired infections. Moreover, the spread of multidrug-resistant Enterobacteriaceae is a public health problem and the World Health Organization pointed them among the pathogens in which the search of new antibiotics is critical. The objective of this study was to analyze the activity of pentamidine alone and in combination with gentamicin, tobramycin, amikacin, tigecycline, rifampicin, or doripenem against eight clinical strains of carbapenemase-producing and/or colistin-resistant Enterobacteriaceae: five carbapenemase-producing , one carbapenemase-producing , and two colistin-resistant . MIC and MBC were determined following standard protocols. MIC results were interpreted for all the antibiotics according to the EUCAST breakpoints but for rifampicin in which the French FSM breakpoint was used. Bactericidal and synergistic activity of pentamidine alone and in combination with antibiotics at concentrations of 1xMIC was measured by time-kill curves. For one selected strain, OXA-48/CTX-M-15 time-kill curves were performed also at 1/2xMIC of pentamidine. All studies were performed in triplicate. Pentamidine MIC range was 200-800 μg/mL. The 50, 12.5, 62.5, 87.5, and 62.5% of the strains were susceptible to gentamicin, tobramycin, amikacin, tigecycline, and doripenem, respectively. Only the two strains were susceptible to rifampicin. Pentamidine alone at 1xMIC showed bactericidal activity against all strains, except for the 32 strain. The bactericidal activity of pentamidine alone was also observed in combination. The combinations of pentamidine were synergistic against 32 with amikacin and tobramycin at 24 h and with tigecycline at 8 h. Pentamidine plus rifampicin was the combination that showed synergistic activity against more strains (five out of eight). Pentamidine plus doripenem did not show synergy against any strain. At 1/2xMIC, pentamidine was synergistic with all the studied combinations against the K. pneumoniae OXA-48/CTX-M-15 strain. In summary, pentamidine alone and in combination shows activity against carbapenemase-producing and/or colistin-resistant Enterobacteriaceae. Pentamidine appears to be a promising option to treat infections caused by these pathogens.
Topics: Anti-Bacterial Agents; Carbapenem-Resistant Enterobacteriaceae; Colistin; Drug Resistance, Bacterial; Drug Synergism; Enterobacteriaceae Infections; Humans; Microbial Sensitivity Tests; Microbial Viability; Pentamidine
PubMed: 30406040
DOI: 10.3389/fcimb.2018.00363 -
Journal of Pharmaceutical Sciences Mar 2020Initially developed as a synthetic analogue of insulin, pentamidine (PTM) is an antimicrobial drug that has recently shown in vitro and in vivo anticancer activity....
Initially developed as a synthetic analogue of insulin, pentamidine (PTM) is an antimicrobial drug that has recently shown in vitro and in vivo anticancer activity. Nevertheless, systemic administration of PTM causes severe side effects, especially nephrotoxicity. Here we propose the association of PTM to different biocompatible nanosystems in order to compare the physicochemical characteristics of the loaded nanocarriers and their influence on the drug cytotoxicity toward cancer cells. In particular, PTM (as free base or with different counterions) was encapsulated into liposomes and poly(lactide-co-glycolide) (PLGA) nanoparticles and all the formulations have been deeply characterized concerning mean diameter, polydispersity index, zeta potential, stability, morphology, PTM loading, and drug release profile. The anticancer activity was evaluated on a human ovarian cancer cell line over 72 h. Results showed that PTM is efficiently loaded into liposomes with a transmembrane citrate or sulfate gradient; concerning PLGA nanoparticles, important association occurred, thanks to ionic interactions between the drug and the polymer. The in vitro studies confirmed the anticancer activity of PTM, which was gradually released with different profiles depending on the drug form and the nanocarrier structure.
Topics: Drug Carriers; Drug Delivery Systems; Humans; Lipids; Nanoparticles; Particle Size; Pentamidine; Polymers
PubMed: 31751563
DOI: 10.1016/j.xphs.2019.11.011