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International Journal of Molecular... Jul 2022Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to...
Due to its noninvasive nature, site-confined irradiation, and high tissue penetrating capabilities, ultrasound (US)-driven sonodynamic treatment (SDT) has been proven to have broad application possibilities in neoplastic and non-neoplastic diseases. However, the inefficient buildup of sonosensitizers in the tumor site remarkably impairs SDT efficiency. The present work proposes a deep-penetrating sonochemistry nanoplatform (Pp18-lipos@SRA737&DOX, PSDL) comprising Pp18 liposomes (Pp18-lipos, Plipo), SRA737 (a CHK1 inhibitor), and doxorubicin (DOX) for the controlled formation of reactive oxygen species (ROS) and release of DOX and SRA737 upon US activation, therefore increasing chemotherapeutic effectiveness and boosting SDT efficacy. Therein, the antitumor activities of DOX have been attributed to its intercalation into the nucleus DNA and induction of cell apoptosis. CHK1 evolved to respond to DNA damage and repair the damage via cell cycle progression. SRA737 is a potent and orally bioavailable clinical drug candidate for inhibiting CHK1, demonstrating adjuvant anticancer effect in vitro and in vivo. It was interesting to find that SRA737 carried into Plipo@DOX could significantly alleviate G2/M cell cycle arrest and aggravate DNA double-strand injuries, resulting in significant cell death. The developed US-switchable nanosystem provides a promising strategy for augmenting sono-chemotherapy against breast cancer controllably and precisely.
Topics: Cell Death; Cell Line, Tumor; Doxorubicin; Humans; Liposomes; Nanoparticles; Reactive Oxygen Species; Triple Negative Breast Neoplasms
PubMed: 35887326
DOI: 10.3390/ijms23147981 -
Nanomedicine : Nanotechnology, Biology,... Nov 2020CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute...
CPX-351, a liposomal encapsulation of cytarabine and daunorubicin at a synergistic 5:1 molar ratio, is indicated for adults with newly diagnosed, therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In preclinical species, this article demonstrated (1) similar release of cytarabine and daunorubicin by CPX-351 in plasma; (2) similar patterns of metabolism of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal cytarabine/daunorubicin combination; (3) prolonged tissue exposure to CPX-351; (4) dramatically different tissue distribution of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination (tissue:plasma ratios generally <1 versus >1, respectively); and (5) dramatically lower unbound plasma and tissue concentrations of cytarabine and daunorubicin following administration of CPX-351 versus non-liposomal combination. Together, these results provide insight into the safety profile of CPX-351, as well as mechanisms that drive the improved efficacy observed for CPX-351 versus the conventional 7 + 3 cytarabine/daunorubicin regimen in clinical studies.
Topics: Animals; Antineoplastic Agents; Area Under Curve; Bile; Chromatography, High Pressure Liquid; Cytarabine; Daunorubicin; Dogs; Drug Combinations; Feces; Female; Half-Life; Limit of Detection; Male; Mice; Rats; Spectrometry, Fluorescence; Spectrophotometry, Ultraviolet; Tissue Distribution
PubMed: 32750494
DOI: 10.1016/j.nano.2020.102275 -
ACS Applied Bio Materials Aug 2022The design of simple and versatile synthetic routes to accomplish triggered-release properties in carriers is of particular interest for drug delivery purposes. In this...
The design of simple and versatile synthetic routes to accomplish triggered-release properties in carriers is of particular interest for drug delivery purposes. In this context, the programmability and adaptability of DNA nanoarchitectures in combination with liposomes have great potential to render biocompatible hybrid carriers for triggered cargo release. We present an approach to form a DNA mesh on large unilamellar liposomes incorporating a stimuli-responsive DNA building block. Upon incubation with a single-stranded DNA trigger sequence, a hairpin closes, and the DNA building block is allowed to self-contract. We demonstrate the actuation of this building block by single-molecule Förster resonance energy transfer (FRET), fluorescence recovery after photobleaching, and fluorescence quenching measurements. By triggering this process, we demonstrate the elevated release of the dye calcein from the DNA-liposome hybrid carriers. Interestingly, the incubation of the doxorubicin-laden active hybrid carrier with HEK293T cells suggests increased cytotoxicity relative to a control carrier without the triggered-release mechanism. In the future, the trigger could be provided by peritumoral nucleic acid sequences and lead to site-selective release of encapsulated chemotherapeutics.
Topics: DNA; Doxorubicin; Drug Delivery Systems; HEK293 Cells; Humans; Liposomes
PubMed: 35838663
DOI: 10.1021/acsabm.2c00225 -
British Journal of Cancer May 2022Combined chemoradiotherapy is the standard of care for locally advanced solid tumours. However, systemic toxicity may limit the delivery of planned chemotherapy. New... (Review)
Review
Combined chemoradiotherapy is the standard of care for locally advanced solid tumours. However, systemic toxicity may limit the delivery of planned chemotherapy. New approaches such as radiation-induced prodrug activation might diminish systemic toxicity, while retaining anticancer benefit. Organic azides have recently been shown to be reduced and activated under hypoxic conditions with clinically relevant doses of radiotherapy, uncaging pazopanib and doxorubicin in preclinical models with similar efficacy as the drug, but lower systemic toxicity. This approach may be relevant to the chemoradiation of glioblastoma and other solid tumours and offers potential for switching on drug delivery from implanted devices. The inclusion of reporters to confirm drug activation, avoidance of off-target effects and synchronisation of irradiation with optimal intratumoral drug concentration will be critical. Further preclinical validation studies of this approach should be encouraged.
Topics: Chemoradiotherapy; Combined Modality Therapy; Doxorubicin; Humans; Neoplasms; Prodrugs
PubMed: 35217798
DOI: 10.1038/s41416-022-01746-1 -
Blood Advances Jan 2022Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is...
Secondary myelodysplastic syndromes and acute myeloid leukemia (sMDS/AML) are rare in children and adolescents and have a dismal prognosis. The mainstay therapy is hematopoietic cell transplantation (HCT), but there has been no innovation in cytoreductive regimens. CP X-351, a fixed 5:1 molar ratio of liposomal cytarabine to daunorubicin, has shown favorable safety and efficacy in elderly individuals with secondary AML and children with relapsed de novo AML. We report the outcomes of 7 young patients (6 with newly diagnosed sMDS/AML and 1 with primary MDS/AML) uniformly treated with CP X-351. Five patients had previously received chemotherapy for osteosarcoma, Ewing sarcoma, neuroblastoma, or T-cell acute lymphoblastic leukemia; 1 had predisposing genomic instability disorder (Cornelia de Lange syndrome) and 1 had MDS-related AML and multiorgan failure. The median age at diagnosis of myeloid malignancy was 17 years (range, 13-23 years). Patients received 1 to 3 cycles of CP X-351 (cytarabine 100 mg/m2 plus daunorubicin 44 mg/m2) on days 1, 3, and 5, resulting in complete morphologic remission without overt toxicity or treatment-related mortality. This approach allowed for adding an FLT3 inhibitor as individualized therapy in 1 patient. Six patients were alive and leukemia-free at 0.5 to 3.3 years after HCT. One patient died as a result of disease progression before HCT. To summarize, CP X-351 is an effective and well-tolerated regimen for cytoreduction in pediatric sMDS/AML that warrants prospective studies.
Topics: Adolescent; Aged; Child; Cytarabine; Daunorubicin; Humans; Leukemia, Myeloid, Acute; Neoplasms, Second Primary; Prospective Studies
PubMed: 34710216
DOI: 10.1182/bloodadvances.2021006139 -
Cells Jul 2023Triple-negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes. Despite being initially responsive to chemotherapy, patients develop...
Triple-negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes. Despite being initially responsive to chemotherapy, patients develop drug-resistant and metastatic tumors. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a secreted protein with a tumor suppressor function due to its anti-proteolytic activity. Nevertheless, evidence indicates that TIMP-1 binds to the CD63 receptor and activates noncanonical oncogenic signaling in several cancers, but its role in mediating TNBC chemoresistance is still largely unexplored. Here, we show that mesenchymal-like TNBC cells express TIMP-1, whose levels are further increased in cells generated to be resistant to cisplatin (Cis-Pt-R) and doxorubicin (Dox-R). Moreover, public dataset analyses indicate that high TIMP-1 levels are associated with a worse prognosis in TNBC subjected to chemotherapy. Knock-down of TIMP-1 in both Cis-Pt-R and Dox-R cells reverses their resistance by inhibiting AKT activation. Consistently, TNBC cells exposed to recombinant TIMP-1 or TIMP-1-enriched media from chemoresistant cells, acquire resistance to both cisplatin and doxorubicin. Importantly, released TIMP-1 reassociates with plasma membrane by binding to CD63 and, in the absence of CD63 expression, TIMP-1-mediated chemoresistance is blocked. Thus, our results identify TIMP-1 as a new biomarker of TNBC chemoresistance and lay the groundwork for evaluating whether blockade of TIMP-1 signal is a viable treatment strategy.
Topics: Humans; Triple Negative Breast Neoplasms; Tissue Inhibitor of Metalloproteinase-1; Cisplatin; Drug Resistance, Neoplasm; Doxorubicin
PubMed: 37443843
DOI: 10.3390/cells12131809 -
International Journal of Molecular... May 2023Doxorubicin is one of the most widely used antitumor drugs and is currently produced via the chemical conversion method, which suffers from high production costs,...
Doxorubicin is one of the most widely used antitumor drugs and is currently produced via the chemical conversion method, which suffers from high production costs, complex product separation processes, and serious environmental pollution. Biocatalysis is considered a more efficient and environment-friendly method for drug production. The cytochrome daunorubicin C-14 hydroxylase (DoxA) is the essential enzyme catalyzing the conversion of daunorubicin to doxorubicin. Herein, the DoxA from subsp. ATCC 27952 was expressed in , and the rational design strategy was further applied to improve the enzyme activity. Eight amino acid residues were identified as the key sites via molecular docking. Using a constructed screening library, we obtained the mutant DoxA(P88Y) with a more rational protein conformation, and a 56% increase in bioconversion efficiency was achieved by the mutant compared to the wild-type DoxA. Molecular dynamics simulation was applied to understand the relationship between the enzyme's structural property and its substrate-binding efficiency. It was demonstrated that the mutant DoxA(P88Y) formed a new hydrophobic interaction with the substrate daunorubicin, which might have enhanced the binding stability and thus improved the catalytic activity. Our work lays a foundation for further exploration of DoxA and facilitates the industrial process of bio-production of doxorubicin.
Topics: Daunorubicin; Molecular Docking Simulation; Cytochrome P-450 Enzyme System; Doxorubicin; Protein Conformation
PubMed: 37176043
DOI: 10.3390/ijms24098337 -
International Journal of Molecular... Jun 2022Variable-Angle Total Internal Reflection Fluorescence Microscopy (VA-TIRFM) is applied in view of early detection of cellular responses to the cytostatic drug...
Variable-Angle Total Internal Reflection Fluorescence Microscopy (VA-TIRFM) is applied in view of early detection of cellular responses to the cytostatic drug doxorubicin. Therefore, we determined cell-substrate topology of cultivated CHO cells transfected with a membrane-associated Green Fluorescent Protein (GFP) in the nanometer range prior to and subsequent to the application of doxorubicin. Cell-substrate distances increased up to a factor of 2 after 24 h of application. A reduction of these distances by again a factor 2 was observed upon cell aging, and an influence of the cultivation time is presently discussed. Applicability of VA-TIRFM was supported by measurements of MCF-7 breast cancer cells after membrane staining and incubation with doxorubicin, when cell-substrate distances increased again by a factor ≥ 2. So far, our method needs well-defined cell ages and staining of cell membranes or transfection with GFP or related molecules. Use of intrinsic fluorescence or even light-scattering methods to various cancer cell lines could make this method more universal in the future, e.g., in the context of early detection of apoptosis.
Topics: Animals; Cell Membrane; Cricetinae; Cricetulus; Doxorubicin; Green Fluorescent Proteins; Microscopy, Fluorescence
PubMed: 35682954
DOI: 10.3390/ijms23116277 -
BMC Cancer Apr 2021Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of...
BACKGROUND
Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of cell death, including apoptosis. Apoptosis is highly regulated programmed cell death that can be initiated mainly via two pathways, through death receptors (extrinsic) or involvement of the mitochondria (intrinsic). Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course.
METHODS
This study investigated the mechanisms of daunorubicin induced apoptosis in the treatment of CCRF-CEM, MOLT-4 (acute T-lymphoblastic leukaemia) and SUP-B15 (acute B-lymphoblastic leukaemia) cells. Cells were treated with daunorubicin for 4 h, and then placed in recovery medium (without daunorubicin) for 4 h, 12 h and 24 h. Apoptotic response was analysing using annexin-V expression, caspase activity, mitochondrial membrane potential change and an array to detect 43 apoptotic proteins.
RESULTS
Daunorubicin induced apoptosis in all leukemic cell lines, but with different levels and duration of response. Both apoptosis levels and caspase activity increased after four hours recovery then declined in CCRF-CEM and MOLT-4 cells. However, SUP-B15 cells displayed initially comparable levels but remained elevated over the 24 h assessment period. Changes in mitochondrial membrane potential occurred in both MOLT-4 and CCRF-CEM cells but not in SUP-B15 cells. Expression of apoptotic proteins, including Bcl-2, Bax, caspase 3 and FADD, indicated that daunorubicin potentially induced both extrinsic and intrinsic apoptosis in both CCRF-CEM and MOLT-4 cells, but only extrinsic apoptosis in SUP-B15 cells.
CONCLUSIONS
This study describes variations in sensitivities and timing of apoptotic responses in different leukaemia cell lines. These differences could be attributed to the lack of functional p53 in coordinating the cells response following cytotoxic treatment with daunorubicin, which appears to delay apoptosis and utilises alternative signalling mechanisms that need to be further explored.
Topics: Annexin A5; Antibiotics, Antineoplastic; Apoptosis; Apoptosis Regulatory Proteins; Caspases; Cell Line, Tumor; Daunorubicin; Humans; Leukemia; Membrane Potential, Mitochondrial
PubMed: 33879127
DOI: 10.1186/s12885-021-08167-y -
Cells Aug 2023Desmosomes play a vital role in providing structural integrity to tissues that experience significant mechanical tension, including the heart. Deficiencies in desmosomal... (Review)
Review
Desmosomes play a vital role in providing structural integrity to tissues that experience significant mechanical tension, including the heart. Deficiencies in desmosomal proteins lead to the development of arrhythmogenic cardiomyopathy (AC). The limited availability of preventative measures in clinical settings underscores the pressing need to gain a comprehensive understanding of desmosomal proteins not only in cardiomyocytes but also in non-myocyte residents of the heart, as they actively contribute to the progression of cardiomyopathy. This review focuses specifically on the impact of desmosome deficiency on epi- and endocardial cells. We highlight the intricate cross-talk between desmosomal proteins mutations and signaling pathways involved in the regulation of epicardial cell fate transition. We further emphasize that the consequences of desmosome deficiency differ between the embryonic and adult heart leading to enhanced erythropoiesis during heart development and enhanced fibrogenesis in the mature heart. We suggest that triggering epi-/endocardial cells and fibroblasts that are in different "states" involve the same pathways but lead to different pathological outcomes. Understanding the details of the different responses must be considered when developing interventions and therapeutic strategies.
Topics: Adult; Humans; Desmosomes; Cardiomyopathies; Cell Differentiation; Epirubicin; Myocytes, Cardiac
PubMed: 37681854
DOI: 10.3390/cells12172122