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Biotransformation of Doxorubicin Promotes Resilience in Simplified Intestinal Microbial Communities.MSphere Jun 2021Chemotherapeutic drugs can cause harmful gastrointestinal side effects, which may be modulated by naturally occurring members of our microbiome. We constructed...
Chemotherapeutic drugs can cause harmful gastrointestinal side effects, which may be modulated by naturally occurring members of our microbiome. We constructed simplified gut-associated microbial communities to test the hypothesis that bacteria-mediated detoxification of doxorubicin (i.e., a widely used chemotherapeutic) confers protective effects on the human microbiota. Mock communities composed of up to five specific members predicted by genomic analysis to be sensitive to the drug or resistant via biotransformation and/or efflux were grown over three generational stages to characterize community assembly, response to perturbation (doxorubicin exposure), and resilience. Bacterial growth and drug concentrations were monitored with spectrophotometric assays, and strain relative abundances were evaluated with 16S rRNA gene sequencing. Bacteria with predicted resistance involving biotransformation significantly lowered concentrations of doxorubicin in culture media, permitting growth of drug-sensitive strains in monoculture. Such protective effects were not produced by strains with drug resistance conferred solely by efflux. In the mixed communities, resilience of drug-sensitive members depended on the presence and efficiency of transformers, as well as drug exposure concentration. Fitness of bacteria that were resistant to doxorubicin via efflux, though not transformation, also improved when the transformers were present. Our simplified community uncovered ecological relationships among a dynamic consortium and highlighted drug detoxification by a keystone species. This work may be extended to advance probiotic development that may provide gut-specific protection to patients undergoing cancer treatment. While chemotherapy is an essential intervention for treating many forms of cancer, gastrointestinal side effects may precede infections and risks for additional health complications. We developed an model to characterize key changes in bacterial community dynamics under chemotherapeutic stress and the role of bacterial interactions in drug detoxification to promote microbiota resilience. Our findings have implications for developing bio-based strategies to promote gut health during cancer treatment.
Topics: Antibiotics, Antineoplastic; Bacteria; Biotransformation; Doxorubicin; Drug Resistance, Bacterial; Gastrointestinal Microbiome; Humans; Phylogeny; RNA, Ribosomal, 16S
PubMed: 34192503
DOI: 10.1128/mSphere.00068-21 -
The Journal of Antibiotics Jan 2022A double disulfide tethering depsipeptide dimer, romipeptide A (1) was prepared by NaOH catalyzed dimerization of romidepsin. Its structure was determined by analysis of...
A double disulfide tethering depsipeptide dimer, romipeptide A (1) was prepared by NaOH catalyzed dimerization of romidepsin. Its structure was determined by analysis of NMR and HR-ESI-MS data as well as single crystal X-ray diffraction. Bioassay results showed that 1 exhibited good cytotoxic activity against two tumor cell lines B16 and HCT116. This study reported the single crystal data of 1 for the first time. The facile preparation of 1 afforded enough amount for its further biological evaluations.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Crystallography, X-Ray; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Magnetic Resonance Spectroscopy; Melanoma, Experimental; Molecular Structure; Spectrometry, Mass, Electrospray Ionization; X-Ray Diffraction
PubMed: 34824376
DOI: 10.1038/s41429-021-00487-2 -
International Journal of Nanomedicine 2024While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still...
BACKGROUND
While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still an essential problem.
METHODS
We exploited nanoparticle coordination between ferric (Fe) ions and telomerase-targeting hairpin DNA structures to encapsulate doxorubicin (DOX) and fabricated Fe-DNA@DOX nanoparticles (BDDF NPs). This work studied the NIR fluorescence imaging and pharmacokinetic studies targeting the ability and biodistribution of BDDF NPs. In vitro and vivo studies investigated the nano formula's toxicity, imaging, and synergistic therapeutic effects.
RESULTS
The enhanced permeability and retention (EPR) effect and tumor targeting resulted in prolonged blood circulation times and high tumor accumulation. Significantly, BDDF NPs could reduce DOX-mediated cardiac toxicity by improving the antioxidation ability of cardiomyocytes based on the different telomerase activities and iron dependency in normal and tumor cells. The synergistic treatment efficacy is enhanced through Fe-mediated ferroptosis and the β-catenin/p53 pathway and improved the tumor inhibition rate.
CONCLUSION
Harpin DNA-based nanoplatforms demonstrated prolonged blood circulation, tumor drug accumulation via telomerase-targeting, and synergistic therapy to improve antitumor drug efficacy. Our work sheds new light on nanomaterials for future synergistic chemotherapy.
Topics: Doxorubicin; Animals; Humans; Telomerase; Cell Line, Tumor; Mice; DNA; Tissue Distribution; Nanoparticles; Neoplasms; Ferroptosis; Antibiotics, Antineoplastic; Mice, Inbred BALB C; Drug Carriers
PubMed: 38882546
DOI: 10.2147/IJN.S461774 -
Journal of the American Chemical Society Feb 2020The family of anthraquinone-fused enediyne antitumor antibiotics was established by the discovery of dynemicin A and deoxy-dynemicin A. It was then expanded, first by...
The family of anthraquinone-fused enediyne antitumor antibiotics was established by the discovery of dynemicin A and deoxy-dynemicin A. It was then expanded, first by the isolation of uncialamycin, and then by the addition to the family of tiancimycins A-F and yangpumicin A. This family of natural products provides opportunities in total synthesis, biology, and medicine due to their novel and challenging molecular structures, intriguing biological properties and mechanism of action, and potential in targeted cancer therapies. Herein, the total syntheses of tiancimycins A and B, yangpumicin A, and a number of related anthraquinone-fused enediynes are described. Biological evaluation of the synthesized compounds revealed extremely potent cytotoxicities against a number of cell lines, thus enriching the structure-activity relationships within this class of compounds. The findings of these studies may facilitate future investigations directed toward antibody-drug conjugates for targeted cancer therapies and provide inspiration for further advances in total synthesis and chemical biology.
Topics: Anthraquinones; Antibiotics, Antineoplastic; Enediynes; Humans; Structure-Activity Relationship
PubMed: 31976660
DOI: 10.1021/jacs.9b12522 -
Nanotechnology Apr 2021Doxorubicin (DOX) is a commonly used anticancer drug, but it is inefficient as a therapeutic due to a lack of targeting. Peptide-tuned self-assembly of DOX offers a...
Doxorubicin (DOX) is a commonly used anticancer drug, but it is inefficient as a therapeutic due to a lack of targeting. Peptide-tuned self-assembly of DOX offers a strategy to improve targeting for greater efficacy. In this work, we designed and prepared an amphiphilic tumor cell-targeting peptide, P14 (AAAAFFFHHHGRGD), able to encapsulate DOX by self-assembly to form tumor cell-targeting and pH-sensitive nano-micelles. The results showed a critical P14-micelle concentration of 1.758 mg land an average particle size of micelles of 121.64 nm, with entrapment and drug-loading efficiencies of 28.02% ± 1.35% and 12.06% ± 0.59%, respectively. The prepared micelles can release 73.52 ± 1.27% DOX within 24 h in pH 4.5 medium, and the drug cumulative release profile of micelles can be described by the first-order model. Compared with free DOX, the micelles exhibited an increased ability to inhibit tumor cell growth and cause tumor apoptosis, with ICvalues of DOX and P14-DOX micelles against human breast cancer cells (MCF-7) of 0.91 ± 0.07 and 0.75 ± 0.06g ml, respectively, and cellular apoptotic rates of DOX and P14-DOX micelles of 70.3% and 42.4%, respectively. Cellular uptake experiments revealed high concentrations of micelles around and inside MCF-7 cells, demonstrating that micelles can target tumor cells. These results indicate the excellent potential for the application of this amphiphilic peptide as a carrier for small-molecule drugs and suggest a strategy for the design of effective anti-tumor drugs.
Topics: Antibiotics, Antineoplastic; Apoptosis; Doxorubicin; Drug Carriers; Drug Compounding; Drug Liberation; Humans; Hydrogen-Ion Concentration; Kinetics; MCF-7 Cells; Micelles; Molecular Targeted Therapy; Nanostructures; Peptides
PubMed: 33711826
DOI: 10.1088/1361-6528/abee49 -
International Journal of Biological... Sep 2021A novel chitosan-dipeptide hydrogel was fabricated through a combination of self-assembly of 9-fluorenylmethoxycarbonyl-modified diphenylalanine (Fmoc-FF) and its... (Comparative Study)
Comparative Study
A novel chitosan-dipeptide hydrogel was fabricated through a combination of self-assembly of 9-fluorenylmethoxycarbonyl-modified diphenylalanine (Fmoc-FF) and its electrostatic interaction with glycol chitosan (GCS). Hydrogel strength and stability depended on its composition. The highest gel strength was observed at a Fmoc-FF mass fraction (ϕ) of 0.85, whereby the highest combined strength of the two interactions was achieved. As the ϕ increased above 0.6, gel stability decreased in buffered solution at pH 7.46. The incorporation of doxorubicin (DOX) as a cationic model drug significantly increased the stability of the complex hydrogels. DOX-loaded hydrogels exhibited slow DOX release, probably due to the drug's strong binding to Fmoc-FF via electrostatic attraction and the high gel stability. These hydrogels also exhibited excellent thixotropic features that facilitated the development of injectable self-healing drug delivery systems. Notably, DOX release was significantly accelerated as the pH of the medium decreased from 7.46 to 5.5 and 4.0, possibly due to hydrogel components' protonation. The DOX-loaded hydrogel exhibited notable cytotoxicity against A549 human lung cancer cells, which suggests the newly developed hydrogel to be a promising candidate vehicle for the localized and controlled drug delivery in cancer therapy.
Topics: A549 Cells; Antibiotics, Antineoplastic; Cell Survival; Chitosan; Doxorubicin; Drug Carriers; Drug Compounding; Drug Liberation; Humans; Hydrogels; Hydrogen-Ion Concentration; Lung Neoplasms; Phenylalanine
PubMed: 34314799
DOI: 10.1016/j.ijbiomac.2021.07.134 -
Journal of Materials Chemistry. B Nov 2021Tumor-selective drug delivery could enhance anticancer efficacy and avoid drug side effects. However, because of tumor heterogeneity, current nanoparticle-based drug...
Tumor-selective drug delivery could enhance anticancer efficacy and avoid drug side effects. However, because of tumor heterogeneity, current nanoparticle-based drug delivery systems rarely improve clinical outcomes significantly, commonly only reducing systemic toxicity. In this work, a new tumor-specific, tyrosinase-responsive cascade amplification release nanoparticle (TR-CARN) was developed to fulfill the needs for tumor-specific drug delivery and high efficacy cancer treatment. Tyrosinase (Tyr) is specifically expressed in melanomas and can catalyze acetaminophen (APAP) to increase reactive oxygen species (ROS). It was therefore utilized here to initiate the ROS amplification procedure. In TR-CARN, a ROS-responsive prodrug BDOX was loaded into an amphiphilic polymer, and APAP was linked to the polymer through a ROS-cleavable thioether bond. TR-CARN caused reduced side effects during the delivery because of the low toxicity of BDOX. Once TR-CARN entered into the tumor, endogenous ROS triggered initial APAP and BDOX release. Tyr-mediated ROS synthesis by APAP then accelerated APAP and BDOX release and toxification. Consequently, TR-CARN achieved melanoma-specific treatment of high efficacy through the cascade amplification strategy with enhanced biosafety.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Cell Survival; Doxorubicin; Drug Delivery Systems; Drug Liberation; Humans; Melanoma; Monophenol Monooxygenase; Nanoparticles; Prodrugs
PubMed: 34746946
DOI: 10.1039/d1tb01893k -
ACS Applied Bio Materials Mar 2021Cancer cannot be controlled by the usage of drugs alone, and thus, nanotechnology is an important technique that can provide the drug with an impetus to act more... (Review)
Review
Cancer cannot be controlled by the usage of drugs alone, and thus, nanotechnology is an important technique that can provide the drug with an impetus to act more effectively. There is adequate availability of anticancer drugs that are classified as alkylating agents, hormones, or antimetabolites. Nanoparticle (NP) carriers increase the residence time of the drug, thereby enhancing the survival rate of the drug, which otherwise gets washed off owing to the small size of the drug particles by the excretory system. For example, for enhancing the circulation, a coating of nonfouling polymers like PEG and dextran is done. Famous drugs such as doxorubicin (DOX) are commonly encapsulated inside the nanocomposite. The various classes of nanoparticles are used to enhance drug delivery by aiding it to fight against the tumor. Targeted therapy aims to attack the cells with features common to the cancer cells while minimizing damage to the normal cell, and these therapies work in one in four ways. Some block the cancer cells from reproducing newer cells, others release toxic substances to kill the cancer cells, some stimulate the immune system to destroy the cancer cells, and some block the growth of more blood vessels around cancer cells, which starve the cells of the nutrients, which is needed for their growth. This review aims to testify the advancements nanotechnology has brought in cancer therapy, and its statements are supported with recent research findings and clinical trial results.
Topics: Antibiotics, Antineoplastic; Biocompatible Materials; Cell Proliferation; Doxorubicin; Drug Carriers; Humans; Materials Testing; Nanoparticles; Nanotechnology; Neoplasms; Particle Size
PubMed: 35014353
DOI: 10.1021/acsabm.1c00020 -
Carbohydrate Polymers May 2021Doxorubicin (DOX), an anthracycline drug, is widely used for the treatment of several cancers like osteosarcoma, cervical carcinoma, breast cancer, etc. DOX lacks target... (Review)
Review
Doxorubicin (DOX), an anthracycline drug, is widely used for the treatment of several cancers like osteosarcoma, cervical carcinoma, breast cancer, etc. DOX lacks target specificity; thereby it also affects normal cells thus resulting in several side-effects. A drug delivery system (DDS) can be used to deliver the drug in a controlled and sustained manner at a targeted site within the body. Various DDS like nanoemulsions, polymeric nanoparticles, and liposomes are used for loading DOX. Alginate, a polysaccharide is widely used for fabricating DDS due to its biodegradable and bio-compatible properties. Alginates, in combination with other biomaterials, have been extensively used as a novel drug delivery carrier for DOX. Alginate provides a platform for drug delivery in different forms like hydrogels, nanogels, nanoparticles, microparticles, graphene oxide systems, magnetic systems, etc. Herein, we briefly describe alginate in combination with other materials as a nanocarrier for targeted delivery of DOX for anti-cancer treatment.
Topics: Alginates; Animals; Antibiotics, Antineoplastic; Cell Survival; Doxorubicin; Drug Carriers; Humans; Hydrogels; Nanogels; Neoplasms
PubMed: 33673985
DOI: 10.1016/j.carbpol.2021.117696 -
Critical Reviews in Oncology/hematology Sep 2019Cancer and heart diseases are the leading causes of morbidity and mortality in many countries worldwide. Recent advancement in chemotherapy and targeted therapies has... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cancer and heart diseases are the leading causes of morbidity and mortality in many countries worldwide. Recent advancement in chemotherapy and targeted therapies has led to an improvement in cancer survival rates, but at a cost of higher cardiac side effects. However, report on antineoplastic-related cardiotoxicities incidence in Asia is lacking.
METHODS
We systematically searched multiple databases to identify studies reporting incidence of antineoplastic-related cardiovascular toxicity in Asia published from inception to November 2018. Pre-specified subgroups were performed to explore heterogeneity and study quality assessed and reported according to PRISMA guidelines.
RESULTS
A total of 61 studies across 11 countries in Asia reported 8 types of cardiovascular toxicities were included. These studies mostly reported on adult populations, and usually examined cardiotoxicities related to anthracycline use. The most frequently reported cardiotoxicities were heart failure, electrocardiogram abnormalities and left ventricular dysfunction. The pooled estimated incidence of cardiotoxicity was 4.27% (95% CI: 3.53-5.07). Subgroup analysis showed higher incidence in middle income countries compared to high income countries.
CONCLUSIONS
Although robust incidence studies are sparse, cardiovascular complications affects approximately one in twenty cancer patients in Asia. This highlights a unique opportunity of cancer patients caring that need cardiologists and oncologist to become familiar with this emerging sub-specialty.
Topics: Adult; Anthracyclines; Antibiotics, Antineoplastic; Asia; Cardiotoxicity; Heart Diseases; Humans; Incidence; Neoplasms
PubMed: 31272046
DOI: 10.1016/j.critrevonc.2019.05.017