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Cucurbit[n]uril-based amphiphiles that self-assemble into functional nanomaterials for therapeutics.Chemical Communications (Cambridge,... Sep 2019Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various... (Review)
Review
Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various nanomaterials such as vesicles, micelles, nanorods, and nanosheets in water. The structures and functions of the nanomaterials can be controlled by supramolecular engineering of the host-guest complexes. In addition, functionalization at the periphery of CB[6] and CB[7] generates CB[n]-based molecular amphiphiles (MAs) that can also self-assemble into vesicles or micelle-like nanoparticles in water. Taking advantage of the molecular cavities of CBs and their strong guest recognition properties, the surface of the self-assembled nanomaterials can be easily decorated with various functional tags in a non-covalent manner. In this feature article, the two types (SAs and MAs) of CB-based amphiphiles, their self-assemblies and their applications for nanotherapeutics and theranostics are presented with future perspectives.
Topics: Antibiotics, Antineoplastic; Bridged-Ring Compounds; Cell Proliferation; Doxorubicin; HeLa Cells; Humans; KB Cells; Nanostructures; Surface-Active Agents
PubMed: 31418758
DOI: 10.1039/c9cc05567c -
Expert Review of Anticancer Therapy 2016Non-muscle invasive bladder cancer (NMIBC) has a high tendency for recurrence and progression. Currently, all known intravesical agents are associated with adverse... (Comparative Study)
Comparative Study Review
Non-muscle invasive bladder cancer (NMIBC) has a high tendency for recurrence and progression. Currently, all known intravesical agents are associated with adverse effects (AEs) and limited efficacy. The combination of hyperthermia (HT) with intravesical Mitomycin C (MMC) chemotherapy has been shown to improve outcomes. The added efficacy of HT to MMC was first shown in preclinical studies. The reports on patients with NMIBC have indicated that the treatment is safe and well tolerated. Several clinical studies reported the efficacy of radiofrequency-induced chemotherapy effect (RITE) in the treatment of patients with NMIBC. This modality was shown to be superior to MMC alone. RITE was effective also in patients with high-risk NMIBC, including those who failed Bacillus Calmette-Guérin (BCG). This study provides an updated review of literature regarding the use of RITE in patients with NMIBC.
Topics: Administration, Intravesical; Animals; Antibiotics, Antineoplastic; Combined Modality Therapy; Humans; Hyperthermia, Induced; Mitomycin; Treatment Outcome; Urinary Bladder Neoplasms
PubMed: 26618756
DOI: 10.1586/14737140.2016.1126515 -
Biotechnic & Histochemistry : Official... May 2021Doxorubicin (Dox) is an anthracycline antibiotic with antineoplastic activity. Acetylsalicylic acid (Asa) is recommended for use as a prophylactic for thromboembolism...
Doxorubicin (Dox) is an anthracycline antibiotic with antineoplastic activity. Acetylsalicylic acid (Asa) is recommended for use as a prophylactic for thromboembolism during treatment of cancers. We investigated liver toxicity due to combined use of Dox and Asa in chemotherapy regimens. We used 140 Swiss albino mice divided into four main groups: control, Dox, Asa, and Dox + Asa. Each group was subdivided into seven subgroups based on time of sacrifice, i.e., 6, 12, 24, 48 h and 7, 14, 21 days. Quantitative and histopathological changes in liver were assessed by light microscopy and stereology. The portal triad area of the Dox and Dox + Asa groups was increased significantly compared to controls at 6 h, whereas in the Asa group, the means were similar to controls. Assessment of histopathology indicated an increased time-dependent degeneration and necrosis of liver tissues in mice in the Dox and Dox + Asa groups. The protective effects of Asa were not evident in Dox + Asa group. When Dox and Asa were administered together, degenerative changes were greater than for in the group that was given Dox alone. We found that Asa and Dox combined therapy increased tissue damage.
Topics: Animals; Antibiotics, Antineoplastic; Aspirin; Chemical and Drug Induced Liver Injury; Doxorubicin; Mice; Oxidative Stress
PubMed: 32643434
DOI: 10.1080/10520295.2020.1788724 -
PloS One 2017Peptides containing the asparagine-glycine-arginine (NGR) motif are recognized by CD13/aminopeptidase N (APN) receptor isoforms that are selectively overexpressed in...
Peptides containing the asparagine-glycine-arginine (NGR) motif are recognized by CD13/aminopeptidase N (APN) receptor isoforms that are selectively overexpressed in tumor neovasculature. Spontaneous decomposition of NGR peptides can result in isoAsp derivatives, which are recognized by RGD-binding integrins that are essential for tumor metastasis. Peptides binding to CD13 and RGD-binding integrins provide tumor-homing, which can be exploited for dual targeted delivery of anticancer drugs. We synthesized small cyclic NGR peptide-daunomycin conjugates using NGR peptides of varying stability (c[KNGRE]-NH2, Ac-c[CNGRC]-NH2 and the thioether bond containing c[CH2-CO-NGRC]-NH2, c[CH2-CO-KNGRC]-NH2). The cytotoxic effect of the novel cyclic NGR peptide-Dau conjugates were examined in vitro on CD13 positive HT-1080 (human fibrosarcoma) and CD13 negative HT-29 (human colon adenocarcinoma) cell lines. Our results confirm the influence of structure on the antitumor activity and dual acting properties of the conjugates. Attachment of the drug through an enzyme-labile spacer to the C-terminus of cyclic NGR peptide resulted in higher antitumor activity on both CD13 positive and negative cells as compared to the branching versions.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Cyclization; Daunorubicin; Humans; Oligopeptides; Spectrometry, Mass, Electrospray Ionization
PubMed: 28575020
DOI: 10.1371/journal.pone.0178632 -
Accounts of Chemical Research Oct 2017(-)-Lomaiviticin A (4) is a complex C-symmetric bacterial metabolite that contains two diazofluorene functional groups. The diazofluorene consists of naphthoquinone,...
(-)-Lomaiviticin A (4) is a complex C-symmetric bacterial metabolite that contains two diazofluorene functional groups. The diazofluorene consists of naphthoquinone, cyclopentadiene, and diazo substituents fused through a σ- and π-bonding network. Additionally, (-)-lomaiviticin A (4) is a potent cytotoxin, with half-maximal inhibitory potency (IC) values in the low nanomolar range against many cancer cell lines. Because of limitations in supply, its mechanism of action had remained a "black box" since its isolation in the early 2000s. In this Account, I describe how studies directed toward the total synthesis of (-)-lomaiviticin A (4) provided a platform to elucidate the emergent properties of this metabolite and thereby connect chemical reactivity with cellular phenotype. We first developed a convergent strategy to prepare the diazofluorene (9 + 10 → 13). We then adapted this chemistry to the synthesis of lomaiviticin aglycon (21/22) and the natural monomeric diazofluorene (-)-kinamycin F (3). The key step in the lomaiviticin aglycon (21/22) synthesis involved the stereoselective oxidative coupling of two monomeric diazofluorenes (2 × 18 → 20) to establish the cojoining carbon-carbon bond of the target. As the absolute stereochemistry of the aglycon and carbohydrate residues of (-)-lomaiviticin A (4) were unknown, we developed a semisynthetic route to the metabolite that proceeds in one step and 42% yield by diazo transfer to the more abundant isolate (-)-lomaiviticin C (6). This allowed us to complete the stereochemical assignment of (-)-lomaiviticin A (4) and provided a renewable source of material. Using this material, we established that the remarkable cytotoxic effects of (-)-lomaiviticin A (4) derive from the induction of highly toxic double-strand breaks (DSBs) in DNA. At the molecular level, 1,7-nucleophilic additions to each electrophilic diazofluorene trigger homolytic decomposition pathways that produce sp radicals at the carbon atoms of each diazo group. These radicals abstract hydrogen atoms from the deoxyribose of DNA, a process known to initiate strand cleavage. NMR spectroscopy and molecular mechanics simulations were used to elucidate the mode of DNA binding. These studies showed that both diazofluorenes of (-)-lomaiviticin A (4) penetrate into the duplex. This mode of non-covalent binding places each diazo carbon atom in close proximity to each DNA strand. Throughout these studies, isolates containing one diazofluorene, such as (-)-lomaiviticin C (6) and (-)-kinamycin C (2), were used as controls. Consistent with our mechanistic model, these compounds do not induce DSBs in DNA and are several orders of magnitude less potent. Reactivity studies suggest that (-)-lomaiviticin A (4) is more electrophilic than simple monomeric diazofluorenes. We attribute this to through-space delocalization of the developing negative charge in the transition state for 1,7-addition. Consistent with this mechanism of action, (-)-lomaiviticin A (4) displays selective low-picomolar potencies toward DNA DSB repair-deficient cell types. The emergent properties of (-)-lomaiviticin A (4) derive from the specific arrangement of diazo, naphthoquinone, cyclopentadiene, and ketone functional groups. These functional groups work together to yield, essentially, a masked vinyl radical that can be exposed under biological conditions. Furthermore, the rotational symmetry of the metabolite, deriving from dimerization, allows it to interact with the antiparallel symmetry of DNA and affect cleavage of the duplex.
Topics: Antibiotics, Antineoplastic; DNA; DNA Breaks, Double-Stranded; Fluorenes; Humans; K562 Cells; Models, Chemical; Molecular Structure; Stereoisomerism
PubMed: 28956437
DOI: 10.1021/acs.accounts.7b00347 -
Journal of Ethnopharmacology Apr 2021Propolis extracts are widely used in traditional folk medicine and exhibit several properties such as antitumor, anti-inflammatory, and antimicrobial. However, these...
ETHNOPHARMACOLOGICAL RELEVANCE
Propolis extracts are widely used in traditional folk medicine and exhibit several properties such as antitumor, anti-inflammatory, and antimicrobial. However, these products have not been investigated in combination with medicines used in clinical practice.
AIM OF THE STUDY
This study aimed to evaluate the chemical composition of propolis extracts from Apis mellifera scutellata and different Meliponini species and characterize their cytotoxicity against tumor cells, antibacterial effects, and interference with the actions of doxorubicin and gentamicin.
MATERIALS AND METHODS
Chromatographic and spectrometric analyses were performed using ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS). Propolis extracts were evaluated for cytotoxicity and synergism using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the antimicrobial activity was examined using the broth microdilution technique and synergism was investigated using checkerboard and time-kill assays.
RESULTS
The chemical characterization revealed the presence of 63 compounds, and the extracts showed selective cytotoxicity against tumor cell lines. Propolis extracts of mandaçaia and mirim exerted selective synergistic cytotoxicity in combination with doxorubicin. Except for the tubuna extract, all evaluated extracts exhibited antibacterial effects on gram-positive strains. Mandaçaia and mirim extracts exerted a synergistic effect with gentamicin; however, only mandaçaia extract exerted a selective effect.
CONCLUSION
Propolis could be a source of antineoplastics and antibiotics. These natural products may reduce the occurrence of doxorubicin and gentamicin related adverse effects, resistance, or both.
Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Bees; Cell Survival; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; HeLa Cells; Hep G2 Cells; Humans; MCF-7 Cells; Propolis; Tandem Mass Spectrometry
PubMed: 33307049
DOI: 10.1016/j.jep.2020.113662 -
Current Drug Metabolism 2015Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites... (Review)
Review
Many clinical studies involving anti-tumor agents neglect to consider how these agents are metabolized within the host and whether the creation of specific metabolites alters drug therapeutic properties or toxic side effects. However, this is not the case for the anthracycline class of chemotherapy drugs. This review describes the various enzymes involved in the one electron (semi-quinone) or two electron (hydroxylation) reduction of anthracyclines, or in their reductive deglycosidation into deoxyaglycones. The effects of these reductions on drug antitumor efficacy and toxic side effects are also discussed. Current evidence suggests that the one electron reduction of anthracyclines augments both their tumor toxicity and their toxicity towards the host, in particular their cardiotoxicity. In contrast, the two electron reduction (hydroxylation) of anthracyclines strongly reduces their ability to kill tumor cells, while augmenting cardiotoxicity through their accumulation within cardiomyocytes and their direct effects on excitation/contraction coupling within the myocytes. The reductive deglycosidation of anthracyclines appears to inactivate the drug and only occurs under rare, anaerobic conditions. This knowledge has resulted in the identification of important new approaches to improve the therapeutic index of anthracyclines, in particular by inhibiting their cardiotoxicity. The true utility of these approaches in the management of cancer patients undergoing anthracycline-based chemotherapy remains unclear, although one such agent (the iron chelator dexrazoxane) has recently been approved for clinical use.
Topics: Animals; Anthracyclines; Antibiotics, Antineoplastic; Benzoquinones; Humans; Hydroxylation; Neoplasms; Oxidation-Reduction; Treatment Outcome
PubMed: 26321196
DOI: 10.2174/1389200216888150915112039 -
Oxidative Medicine and Cellular... 2017The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged... (Review)
Review
The production of reactive species is a core of the redox cycling profile of anthracyclines. However, these molecular characteristics can be viewed as a double-edged sword acting not only on neoplastic cells but also on multiple cellular targets throughout the body. This phenomenon translates into anthracycline cardiotoxicity that is a serious problem in the growing population of paediatric and adult cancer survivors. Therefore, better understanding of cellular processes that operate within but also go beyond cardiomyocytes is a necessary step to develop more effective tools for the prevention and treatment of progressive and often severe cardiomyopathy experienced by otherwise successfully treated oncologic patients. In this review, we focus on oxidative stress-triggered cellular events such as DNA damage, senescence, and cell death implicated in anthracycline cardiovascular toxicity. The involvement of progenitor cells of cardiac and extracardiac origin as well as different cardiac cell types is discussed, pointing to molecular signals that impact on cell longevity and functional competence.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Doxorubicin; Humans; Oxidative Stress
PubMed: 29181122
DOI: 10.1155/2017/1521020 -
Bioorganic & Medicinal Chemistry Mar 2022The construction of multistimuli-responsive nanoaggregate has become one of the increasingly significant research topics in supramolecular chemistry. We herein reported...
The construction of multistimuli-responsive nanoaggregate has become one of the increasingly significant research topics in supramolecular chemistry. We herein reported the pH- and glutathione dual-responsive supramolecular assemblies fabricated by the disulfide-containing pillar[4]arene and tetraphenylethylene derivatives possessing different alkyl chains in length. Morphological characterization experiments showed the binary supramolecular assemblies formed well-defined nanoparticles, which could facilitate their endocytosis in cells. More remarkably, due to the compact nanostructures and the existence of acidifiable carboxyl group and bioreducible disulfide linkage in pillar[4]arene, the obtained nanoaggregates presented high drug-loading efficiency and sustained drug release behaviors, as well as the targeted fluorescence imaging ability in cancer cells. Thus, it can be envisioned that such microenvironment-adaptable supramolecular nanoassemblies featuring dual stimuli-responsiveness and fluorescence-imaging abilities may be developed as more appealing nanosystems for the therapy of refractory disease.
Topics: Antibiotics, Antineoplastic; Calixarenes; Cell Line; Cell Proliferation; Disulfides; Dose-Response Relationship, Drug; Doxorubicin; Drug Liberation; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Optical Imaging; Structure-Activity Relationship
PubMed: 35131545
DOI: 10.1016/j.bmc.2022.116649 -
Cancer Letters Sep 2020The dependency of prostate cancer (PCa) growth on androgen receptor (AR) signaling has been harnessed to develop first-line therapies for high-risk localized and...
The dependency of prostate cancer (PCa) growth on androgen receptor (AR) signaling has been harnessed to develop first-line therapies for high-risk localized and metastatic PCa treatment. However, the occurrence of aberrant expression, mutated or splice variants of AR confers resistance to androgen ablation therapy (ADT), radiotherapy or chemotherapy in AR-positive PCa. Therapeutic strategies that effectively inhibit the expression and/or transcriptional activity of full-length AR, mutated AR and AR splice variants have remained elusive. In this study, we report that mithramycin (MTM), an antineoplastic antibiotic, suppresses cell proliferation and exhibits dual inhibitory effects on expression and transcriptional activity of AR and AR splice variants. MTM blocks AR recruitment to its genomic targets by occupying AR enhancers and causes downregulation of AR target genes, which includes key DNA repair factors in DNA damage repair (DDR). We show that MTM significantly impairs DDR and enhances the effectiveness of ionizing radiation or the radiomimetic agent Bleomycin in PCa. Thus, the combination of MTM treatment with RT or radiomimetic agents, such as bleomycin, may present a novel effective therapeutic strategy for patients with high-risk, clinically localized PCa.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; DNA Damage; DNA Repair; Humans; Male; Plicamycin; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 32485222
DOI: 10.1016/j.canlet.2020.05.027