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Human & Experimental Toxicology 2022Osteosarcoma is the most frequent malignant bone malignancy and the current treatments are ineffective. Ivermectin, an anti-protozoal drug, has been shown to have...
BACKGROUND
Osteosarcoma is the most frequent malignant bone malignancy and the current treatments are ineffective. Ivermectin, an anti-protozoal drug, has been shown to have anti-cancer activity. This work investigated the potential of repurposing ivermectin to augment chemotherapy's efficacy in osteosarcoma.
METHODS
Proliferation, migration and apoptosis assays were performed in ivermectin-treated osteosarcoma cells. Combination studies were performed. Osteosarcoma xenograft mouse model was established to investigate the efficacy of ivermectin. Intracellular reactive oxygen species (ROS) and mitochondrial superoxide, membrane potential, ATP, 8-OHdG level, protein carbonylation and lipid peroxidation were determined after ivermectin treatment.
RESULTS
Ivermectin was effective and acted synergistically with doxorubicin in osteosarcoma cells regardless of cellular origin and genetic profiling. This was achieved through suppressing inhibiting growth and migration, and inducing caspase-dependent apoptosis. Ivermectin also significantly inhibited osteosarcoma growth in vivo and its combination with doxorubicin resulted in much greater efficacy than doxorubicin alone. Importantly, the effective dose of ivermectin was clinically feasible and did not cause significant toxicity in mice. Mechanistical analysis showed that ivermectin induced oxidative stress and damage, and mitochondrial dysfunction.
CONCLUSIONS
Our findings indicate that ivermectin has utility in treating patients with osteosarcoma, especially those resistant to chemotherapy.
Topics: Humans; Mice; Animals; Ivermectin; Cell Line, Tumor; Osteosarcoma; Doxorubicin; Bone Neoplasms
PubMed: 36503300
DOI: 10.1177/09603271221143693 -
International Journal of Environmental... May 2022A large number of drugs are used to treat different diseases, and thus to improve the quality of life for humans. These represent a real ecological threat, as they end...
A large number of drugs are used to treat different diseases, and thus to improve the quality of life for humans. These represent a real ecological threat, as they end up in soil or ground waters in amounts that can affect the environment. Among these drugs, doxorubicin is a highly cytotoxic compound used as anticancer medicine. Doxorubicin can be efficiently removed from wastewater or polluted water using a simple enzymatic (biocatalytic) system, employing the oxidoreductase enzyme laccase and a stable organic nitroxide-free radical, TEMPO. Results presented in this work (as percentage of removal) were obtained at pH 5 and 7, after 2, 4, 6, and 24 h, using different ratios between doxorubicin, laccase, and TEMPO. It was shown that longer time, as well as an increased amount of catalyst, led to a higher percentage of removal, up to 100%. The influence of all these parameters is also discussed. In this way it was shown that the laccase-TEMPO biocatalytic system is highly efficient in the removal of the anticancer drug doxorubicin from wastewaters.
Topics: Cyclic N-Oxides; Doxorubicin; Humans; Laccase; Quality of Life; Wastewater
PubMed: 35682229
DOI: 10.3390/ijerph19116645 -
Cell Proliferation May 2023Cancer cell spheroids have been shown to mimic in vivo tumour microenvironment and are therefore suitable for in vitro drug screening. Microfluidic technology can...
Cancer cell spheroids have been shown to mimic in vivo tumour microenvironment and are therefore suitable for in vitro drug screening. Microfluidic technology can provide conveniences for spheroid assays such as high-throughput, simplifying manual operation and saving reagent. Here, we propose a concentration gradient generator based on microfluidic technology for cell spheroid culture and assay. The chip consists of upper microchannels and lower microwells. After partitioning HepG2 suspension into the microwells with concave and non-adhesive bottoms, spheroids can spontaneously form. By controlling the fluid replacement and flow in microchannels, the doxorubicin solution is diluted automatically into a series of concentration gradients, which spanning more than one order of magnitude. And then the effect of doxorubicin on spheroids is measured in situ by fluorescent staining. This chip provides a very promising approach to achieve the high-throughput and standardized anti-cancer drug screening in future.
Topics: Spheroids, Cellular; Cell Culture Techniques; Antineoplastic Agents; Drug Evaluation, Preclinical; Doxorubicin
PubMed: 37199072
DOI: 10.1111/cpr.13473 -
Nano Letters Aug 2021Pharmacotherapy of vascular anomalies has limited efficacy and potentially limiting toxicity. Targeted nanoparticle (NP) drug delivery systems have the potential to...
Pharmacotherapy of vascular anomalies has limited efficacy and potentially limiting toxicity. Targeted nanoparticle (NP) drug delivery systems have the potential to accumulate within tissues where the vasculature is impaired, potentially leading to high drug levels (increased efficacy) in the diseased tissue and less in off-target sites (less toxicity). Here, we investigate whether NPs can be used to enhance drug delivery to bioengineered human vascular networks (hVNs) that are a model of human vascular anomalies. We demonstrate that intravenously injected phototargeted NPs enhanced accumulation of NPs and the drug within hVNs. With phototargeting we demonstrate 17 times more NP accumulation within hVNs than was detected in hVNs without phototargeting. With phototargeting there was 10-fold more NP accumulation within hVNs than in any other organ. Phototargeting resulted in a 6-fold increase in drug accumulation (doxorubicin) within hVNs in comparison to animals injected with the free drug. Nanoparticulate approaches have the potential to markedly improve drug delivery to vascular anomalies.
Topics: Animals; Doxorubicin; Drug Delivery Systems; Humans; Nanoparticles
PubMed: 34296614
DOI: 10.1021/acs.nanolett.1c02027 -
International Journal of Molecular... Jun 2023Herein, we report the design and synthesis of novel 7-aza-coumarine-3-carboxamides via scaffold-hopping strategy and evaluation of their in vitro anticancer activity....
Herein, we report the design and synthesis of novel 7-aza-coumarine-3-carboxamides via scaffold-hopping strategy and evaluation of their in vitro anticancer activity. Additionally, the improved non-catalytic synthesis of 7-azacoumarin-3-carboxylic acid is reported, which features water as the reaction medium and provides a convenient alternative to the known methods. The anticancer activity of the most potent 7-aza-coumarine-3-carboxamides against the HuTu 80 cell line is equal to that of reference Doxorubicin, while the selectivity towards the normal cell line is 9-14 fold higher.
Topics: Antineoplastic Agents; Structure-Activity Relationship; Doxorubicin; Coumarins; Cell Line, Tumor; Drug Screening Assays, Antitumor
PubMed: 37373075
DOI: 10.3390/ijms24129927 -
Advanced Science (Weinheim,... Mar 2023Electrically powered micro- and nanomotors are promising tools for in vitro single-cell analysis. In particular, single cells can be trapped, transported, and...
Electrically powered micro- and nanomotors are promising tools for in vitro single-cell analysis. In particular, single cells can be trapped, transported, and electroporated by a Janus particle (JP) using an externally applied electric field. However, while dielectrophoretic (DEP)-based cargo manipulation can be achieved at high-solution conductivity, electrical propulsion of these micromotors becomes ineffective at solution conductivities exceeding ≈0.3 mS cm . Here, JP cargo manipulation and transport capabilities to conductive near-physiological (<6 mS cm ) solutions are extended successfully by combining magnetic field-based micromotor propulsion and navigation with DEP-based manipulation of various synthetic and biological cargos. Combination of a rotating magnetic field and electric field results in enhanced micromotor mobility and steering control through tuning of the electric field frequency. In addition, the micromotor's ability of identifying apoptotic cell among viable and necrotic cells based on their dielectrophoretic difference is demonstrated, thus, enabling to analyze the apoptotic status in the single-cell samples for drug discovery, cell therapeutics, and immunotherapy. The ability to trap and transport live cells towards regions containing doxorubicin-loaded liposomes is also demonstrated. This hybrid micromotor approach for label-free trapping, transporting, and sensing of selected cells within conductive solutions opens new opportunities in drug delivery and single-cell analysis, where close-to-physiological media conditions are necessary.
Topics: Electric Conductivity; Magnetic Fields; Drug Delivery Systems; Single-Cell Analysis; Doxorubicin
PubMed: 36507618
DOI: 10.1002/advs.202204931 -
Scientific Reports Apr 2023Kidneys are complex organs, and reproducing their function and physiology in a laboratory setting remains difficult. During drug development, potential compounds may... (Review)
Review
Kidneys are complex organs, and reproducing their function and physiology in a laboratory setting remains difficult. During drug development, potential compounds may exhibit unexpected nephrotoxic effects, which imposes a significant financial burden on pharmaceutical companies. As a result, there is an ongoing need for more accurate model systems. The use of renal organoids to simulate responses to nephrotoxic insults has the potential to bridge the gap between preclinical drug efficacy studies in cell cultures and animal models, and the stages of clinical trials in humans. Here we established an accessible fluorescent whole-mount approach for nuclear and membrane staining to first provide an overview of the organoid histology. Furthermore, we investigated the potential of renal organoids to model responses to drug toxicity. For this purpose, organoids were treated with the chemotherapeutic agent doxorubicin for 48 h. When cell viability was assessed biochemically, the organoids demonstrated a significant, dose-dependent decline in response to the treatment. Confocal microscopy revealed visible tubular disintegration and a loss of cellular boundaries at high drug concentrations. This observation was further reinforced by a dose-dependent decrease of the nuclear area in the analyzed images. In contrast to other approaches, in this study, we provide a straightforward experimental framework for drug toxicity assessment in renal organoids that may be used in early research stages to assist screen for potential adverse effects of compounds.
Topics: Animals; Humans; Doxorubicin; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Kidney; Organoids
PubMed: 37061575
DOI: 10.1038/s41598-023-33110-5 -
Drug Discovery Today Feb 2022P-glycoprotein (P-gp) is a drug efflux transporter that triggers doxorubicin (DOX) resistance. In this review, we highlight the molecular avenues regulating P-gp, such... (Review)
Review
P-glycoprotein (P-gp) is a drug efflux transporter that triggers doxorubicin (DOX) resistance. In this review, we highlight the molecular avenues regulating P-gp, such as Nrf2, HIF-1α, miRNAs, and long noncoding (lnc)RNAs, to reveal their participation in DOX resistance. These antitumor compounds and genetic tools synergistically reduce P-gp expression. Furthermore, ATP depletion impairs P-gp activity to enhance the antitumor activity of DOX. Nanoarchitectures, including liposomes, micelles, polymeric nanoparticles (NPs), and solid lipid nanocarriers, have been developed for the co-delivery of DOX with anticancer compounds and genes enhancing DOX cytotoxicity. Surface modification of nanocarriers, for instance with hyaluronic acid (HA), can promote selectivity toward cancer cells. We discuss these aspects with a focus on P-gp expression and activity.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Doxorubicin; Drug Resistance, Neoplasm; Micelles; Nanoparticles
PubMed: 34624510
DOI: 10.1016/j.drudis.2021.09.020 -
Journal of Clinical Oncology : Official... Mar 2022To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment.
PURPOSE
To establish a patient-specific polygenic score derived from cytarabine (ara-C) pathway pharmacogenomic evaluation to personalize acute myeloid leukemia (AML) treatment.
MATERIALS AND METHODS
Single nucleotide polymorphisms (SNPs) in the ara-C-pathway genes were analyzed with outcome in patients from the multicenter-AML02 trial (N = 166). Multi-SNP predictor modeling was used to develop 10-SNP Ara-C_SNP score (ACS10) using top SNPs predictive of minimal residual disease and event-free survival (EFS) from the AML02-cohort and four SNPs previously associated with ara-C triphosphate levels in the AML97 trial. ACS10 was evaluated for association with outcomes in each clinical trial arms: the standard low-dose ara-C (LDAC, n = 91) and augmented high-dose ara-C (HDAC, n = 75) arms of AML02 and the standard Ara-C, daunorubicin and etoposide (ADE) (n = 465) and the augmented ADE + gemtuzumab ozogamicin (GO; n = 466) arms of AAML0531 trial.
RESULTS
In the standard LDAC-arm of AML02 cohort, the low-ACS10 score group (≤ 0) had significantly worse EFS (ACS10 low high hazard ratio [HR] = 2.81; 95% CI, 1.45 to 5.43; = .002) and overall survival (OS; HR = 2.98; 95% CI, 1.32 to 6.75; = .009) compared with the high-ACS10 group (score > 0). These results were validated in the standard-ADE arm of AAML0531, with poor outcome in the low-ASC10 group compared with the high-ACS10 group (EFS: HR = 1.35, 95% CI, 1.04 to 1.75, = .026; OS: HR = 1.64, 95% CI, 1.2 to 2.22, = .002). Within the augmented arms (AML02-HDAC and AAML0531-ADE + GO), EFS and OS did not differ between low- and high-ACS10 score groups. In both cohorts, patients with low-ACS10 consistently showed a 10-percentage point improvement in 5-year EFS with augmented therapy (AML02-HDAC or AAML0531-ADE + GO arms) than with standard therapy (AML02-LDAC or AAML0531-ADE arms).
CONCLUSION
Patients with low-ACS10 score experienced significantly poor outcome when treated on standard regimen. Augmentation with either high-dose ara-C or GO addition improved outcome in low-ACS10 group. A polygenic ACS10 score can identify patients with unfavorable pharmacogenetic characteristics and offers a potential for an elective augmented therapy option.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Child; Child, Preschool; Cytarabine; Daunorubicin; Etoposide; Female; Follow-Up Studies; Gemtuzumab; Humans; Induction Chemotherapy; Infant; Infant, Newborn; Leukemia, Myeloid, Acute; Male; Polymorphism, Single Nucleotide; Prognosis; Survival Rate; Young Adult
PubMed: 34990262
DOI: 10.1200/JCO.21.01422 -
Bioscience Reports Apr 2020Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about...
Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment.
Topics: Antibiotics, Antineoplastic; Apoptosis; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Daunorubicin; Disease Progression; Drug Resistance, Neoplasm; Healthy Volunteers; Humans; Leukemia, Myeloid, Acute; Lithium Chloride; RNA, Small Interfering; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wnt Signaling Pathway
PubMed: 32232394
DOI: 10.1042/BSR20194334