scholarly journals In vitro potentiation of doxorubicin by unseeded controlled non-inertial ultrasound cavitation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Cécile Fant ◽  
Maxime Lafond ◽  
Bernadette Rogez ◽  
Ivan Suarez Castellanos ◽  
Jacqueline Ngo ◽  
...  

Abstract Ultrasound-generated non-inertial cavitation has the ability to potentiate the therapeutic effects of cytotoxic drugs. We report a novel strategy to induce and regulate unseeded (without nucleation agents) non-inertial cavitation, where cavitation is initiated, monitored and regulated using a confocal ultrasound setup controlled by an instrumentation platform and a PC programmed feedback control loop. We demonstrate, using 4T1 murine mammary carcinoma as model cell line, that unseeded non-inertial cavitation potentiates the cytotoxicity of doxorubicin, one of the most potent drugs used in the treatment of solid tumors including breast cancer. Combined treatment with doxorubicin and unseeded non-inertial cavitation significantly reduced cell viability and proliferation at 72 h. A mechanistic study of the potential mechanisms of action of the combined treatment identified the presence of cavitation as required to enhance doxorubicin efficacy, but ruled out the influence of changes in doxorubicin uptake, temperature increase, hydroxyl radical production and nuclear membrane modifications on the treatment outcome. The developed strategy for the reproducible generation and maintenance of unseeded cavitation makes it an attractive method as potential preclinical and clinical treatment modality to locally potentiate doxorubicin.

2020 ◽  
Author(s):  
Felix Benjamin Meyer ◽  
Sophie Goebel ◽  
Sonja Barbara Spangel ◽  
Christiane Leovsky ◽  
Doerte Hoelzer ◽  
...  

Abstract Background Despite considerable medical proceedings, cancer is still a leading cause of death. Major problems for tumor therapy are chemoresistance as well as toxic side effects. In recent years, the additional treatment with the antidiabetic drug metformin during chemotherapy showed promising results in some cases. The aim of this study was to develop an in vitro tumor therapy model in order to further investigate the potential of a combined chemotherapy with metformin. Methods Cytotoxic effects of a combined treatment on BALB/c fibroblasts were proven by the resazurin assay. Based on the BALB/c cell transformation assay, the BALB/c tumor therapy model was established successfully with four different chemotherapeutics (Doxorubicin, Docetaxel, Mitomycin C and 5-Fluorouracil). Moreover, glucose consumption in the medium supernatant was measured and protein expressions were determined by Western Blotting. Results Initial tests for the combined treatment with metformin indicated unexpected results as metformin could partly mitigate the cytotoxic effects of the chemotherapeutic agents. These results were further confirmed as metformin induced resistance to some of the drugs when applied simultaneously in the tumor therapy model. Mechanistically, an increased glucose consumption was observed in non-transformed cells as well as in the mixed population of malignant transformed cell foci and non-transformed monolayer cells, suggesting that metformin could also increase glucose consumption in transformed cells. Conclusion In conclusion, this study suggests a cautious use of metformin during chemotherapy. Moreover, the BALB/c tumor therapy model offers a potent tool for further mechanistic studies of drug-drug interactions during cancer therapy.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1835-1835
Author(s):  
Larisa Balaian ◽  
Edward D. Ball

Abstract Binding of CD33 on AML cells by monoclonal antibodies (mAb) mediates cytotoxicicity on AML cells modulated by the protein tyrosine kinase Syk and the phosphatase SHP-1. We have demonstrated that Syk- negative AML cells are relatively resistant to the effects CD33 ligation, but after exposure to the hypomethylating agent 5-azacytidine (5-aza) they become sensitive to the effects of both unconjugated and chemically-conjugated (gemtuzumab ozogamycin, GO) anti-CD33 mAb. Here we tested a panel of 40 primary AML samples for the expression of SHP-1. In 13% of the cases SHP-1 was undetectable. Anti-CD33 mAb and GO induced growth inhibition more effectively in AML cells that expressed SHP-1. Among SHP-1-positive samples, 69% demonstrated significant growth inhibition in response to CD33 ligation. In contrast, none of the SHP-1-negative samples responded to anti-CD33 mAb. These results show a correlation between SHP-1 expression and responsiveness of AML cells to CD33 ligation. However, 5-aza treatment restored SHP-1 expression and, therefore, increased the anti-proliferative effects of anti-CD33 mAb and GO. In 40% of SHP-1-negative samples, the AML cells were only marginally inhibited by 5-aza or anti-CD33 mAb alone, whereas the combination produced a more than additive effect in AML cells where 5-aza induced re-expression of SHP-1. The effect of GO was more than doubled by 5-aza in these cells. Total inhibition of DNA synthesis in the presence of 5-aza plus anti-CD33 mAb or GO reached 60–70% and was similar in SHP-1-positive and SHP-1-negative cells. Moreover, 5-aza significantly enhanced of GO-mediated cytotoxicity in AML progenitor cells. In a NOD/scid mouse model, which permits growth of human AML cells and allows measurement of in vivo therapeutic effects of therapeutic strategies for AML, we tested whether combined treatment of the mice with 5-aza would enhance the cytotoxicity of anti-CD33 mAb and GO. Suboptimal doses of 5-aza by itself, as well as treatment with murine anti-CD33 mAb alone did not cause significant cytoreduction. However, combined treatment of mice with anti-CD33 mAb and 5-aza, resulted in a significant response. Treatment with GO mediated up to 60% inhibition of AML cell proliferation. Combined treatment of mice with GO and 5-aza resulted in reduction of leukemia cells by >80%. These data show an interaction of 5-aza and anti-CD33/GO in an in vivo AML model. Based on these data, we hypothesize that the combination of 5-aza and GO may be a potent therapy for patients with AML. Moreover, Syk and SHP-1 may serve as biomarkers of leukemia cell response. Therefore, we initiated a clinical trial of 5-aza and GO combined therapy. Six patients with relapsed AML have been treated in a dose escalation of 5-aza preceeding GO (6 mg/m2 times two). All 6 were Syk-positive, while SHP-1 expression was detected in 4 samples and absent in two. 2 days of 5-aza treatment in vivo induced re-expression of SHP-1 in both previously SHP-1 negative patient cells. Moreover, significant increases were observed in the levels of Syk protein in one baseline positive sample and 1 SHP-baseline positive sample. Study of the effects of 5-aza alone ex vivo on the baseline patient cells showed no significant effect on leukemia cell proliferation. However, importantly, in all 6 samples 5-aza more than doubled the AML cells’ response to cytotoxic effects of GO and naked anti-CD33 mAb. These results suggest that 5-aza may augment the effects of anti-CD33 mAb therapy through demethylation of SYK, SHP-1, and possibly other genes. The clinical efficacy of the combined therapy requires further study.


BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Felix B. Meyer ◽  
Sophie Goebel ◽  
Sonja B. Spangel ◽  
Christiane Leovsky ◽  
Doerte Hoelzer ◽  
...  

Abstract Background Despite considerable medical proceedings, cancer is still a leading cause of death. Major problems for tumor therapy are chemoresistance as well as toxic side effects. In recent years, the additional treatment with the antidiabetic drug metformin during chemotherapy showed promising results in some cases. The aim of this study was to develop an in vitro tumor therapy model in order to further investigate the potential of a combined chemotherapy with metformin. Methods Cytotoxic effects of a combined treatment on BALB/c fibroblasts were proven by the resazurin assay. Based on the BALB/c cell transformation assay, the BALB/c tumor therapy model was established successfully with four different and widely used chemotherapeutics from different categories. Namely, Doxorubicin as a type-II isomerase inhibitor, Docetaxel as a spindle toxin, Mitomycin C as an alkylating agent and 5-Fluorouracil as an antimetabolite. Moreover, glucose consumption in the medium supernatant was measured and protein expressions were determined by Western Blotting. Results Initial tests for the combined treatment with metformin indicated unexpected results as metformin could partly mitigate the cytotoxic effects of the chemotherapeutic agents. These results were further confirmed as metformin induced resistance to some of the drugs when applied simultaneously in the tumor therapy model. Mechanistically, an increased glucose consumption was observed in non-transformed cells as well as in the mixed population of malignant transformed cell foci and non-transformed monolayer cells, suggesting that metformin could also increase glucose consumption in transformed cells. Conclusion In conclusion, this study suggests a cautious use of metformin during chemotherapy. Moreover, the BALB/c tumor therapy model offers a potent tool for further mechanistic studies of drug-drug interactions during cancer therapy. Graphical abstract


1976 ◽  
Vol 35 (01) ◽  
pp. 049-056 ◽  
Author(s):  
Christian R Klimt ◽  
P. H Doub ◽  
Nancy H Doub

SummaryNumerous in vivo and in vitro experiments, investigating the inhibition of platelet aggregation and the prevention of experimentally-induced thrombosis, suggest that anti-platelet drugs, such as aspirin or the combination of aspirin and dipyridamole or sulfinpyrazone, may be effective anti-thrombotic agents in man. Since 1971, seven randomized prospective trials and two case-control studies have been referenced in the literature or are currently being conducted, which evaluate the effects of aspirin, sulfinpyrazone, or dipyridamole in combination with aspirin in the secondary prevention of myocardial infarction. A critical review of these trials indicates a range of evidence from no difference to a favorable trend that antiplatelet drugs may serve as anti-thrombotic agents in man. To date, a definitive answer concerning the therapeutic effects of these drugs in the secondary prevention of coronary heart disease is not available.


Materials ◽  
2020 ◽  
Vol 14 (1) ◽  
pp. 19
Author(s):  
Chan-Gi Pack ◽  
Bjorn Paulson ◽  
Yeonhee Shin ◽  
Min Kyo Jung ◽  
Jun Sung Kim ◽  
...  

Controlling the uptake of nanoparticles into cells so as to balance therapeutic effects with toxicity is an essential unsolved problem in the development of nanomedicine technologies. From this point of view, it is useful to use standard nanoparticles to quantitatively evaluate the physical properties of the nanoparticles in solution and in cells, and to analyze the intracellular dynamic motion and distribution of these nanoparticles at a single-particle level. In this study, standard nanoparticles are developed based on a variant silica-based nanoparticle incorporating fluorescein isothiocyanate (FITC) or/and rhodamine B isothiocyanate (RITC) with a variety of accessible diameters and a matching fluorescent cobalt ferrite core-shell structure (Fe2O4/SiO2). The physical and optical properties of the nanoparticles in vitro are fully evaluated with the complementary methods of dynamic light scattering, electron microscopy, and two fluorescence correlation methods. In addition, cell uptake of dual-colored and core/shell nanoparticles via endocytosis in live HeLa cells is detected by fluorescence correlation spectroscopy and electron microscopy, indicating the suitability of the nanoparticles as standards for further studies of intracellular dynamics with multi-modal methods.


Author(s):  
Zhigeng Zou ◽  
Wei Zheng ◽  
Hongjun Fan ◽  
Guodong Deng ◽  
Shih-Hsin Lu ◽  
...  

Abstract Background Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. Methods We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. Results ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. Conclusions ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.


2021 ◽  
Vol 64 (1) ◽  
Author(s):  
Senthil Nagarajan ◽  
Jae Kwon Lee

AbstractSesamolin is one of the lignans derived from sesame oil. It has demonstrated significant antioxidant, anti-aging, and anti-mutagenic properties. It also reportedly augments natural killer (NK) cell lysis activity. We previously reported that sesamolin also exerts anticancer effects in vitro and induces enhanced NK cell cytolytic activity against tumor cells. Herein, we aimed to determine the mechanism by which sesamolin prevents and retards tumorigenesis in BALB/c mouse models of leukemia induced by murine (BALB/c) myelomonocytic leukemia WEHI-3B cells. Banded neutrophils, myeloblasts, and monocytic leukemic cells were more abundant in the leukemia model than in normal mice. Sesamolin decreased the number of leukemic cells by almost 60% in the leukemia model mice in vivo; additionally, sesamolin and the positive control drug, vinblastine, similarly hindered neoplastic cell proliferation. Spleen samples were ~ 4.5-fold heavier in leukemic mice than those obtained from normal mice, whereas spleen samples obtained from leukemic mice treated with sesamolin had a similar weight to those of normal mice. Moreover, sesamolin induced a twofold increase in the cytotoxic activity of leukemic mouse NK cells against WEHI-3B cells. These results indicated that sesamolin exerts anti-leukemic effects in vivo.


2021 ◽  
Vol 1 (1) ◽  
pp. 84-95
Author(s):  
Patience O. Obi ◽  
Jennifer E. Kent ◽  
Maya M. Jeyaraman ◽  
Nicole Askin ◽  
Taiana M. Pierdoná ◽  
...  

Asthma is the most common pediatric disease, characterized by chronic airway inflammation and airway hyperresponsiveness. There are several management options for asthma, but no specific treatment. Extracellular vesicles (EVs) are powerful cellular mediators of endocrine, autocrine and paracrine signalling, and can modulate biophysiological function in vitro and in vivo. A thorough investigation of therapeutic effects of EVs in asthma has not been conducted. Therefore, this systematic review is designed to synthesize recent literature on the therapeutic effects of EVs on physiological and biological outcomes of asthma in pre-clinical studies. An electronic search of Web of Science, EMBASE, MEDLINE, and Scopus will be conducted on manuscripts published in the last five years that adhere to standardized guidelines for EV research. Grey literature will also be included. Two reviewers will independently screen the selected studies for title and abstract, and full text based on the eligibility criteria. Data will be extracted, narratively synthesized and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. This systematic review will summarize the current knowledge from preclinical studies investigating the therapeutic effects of EVs on asthma. The results will delineate whether EVs can mitigate biological hallmarks of asthma, and if so, describe the underlying mechanisms involved in the process. This insight is crucial for identifying key pathways that can be targeted to alleviate the burden of asthma. The data will also reveal the origin, dosage and biophysical characteristics of beneficial EVs. Overall, our results will provide a scaffold for future intervention and translational studies on asthma treatment.


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