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Cancer Chemotherapy and Pharmacology 1994Argon ion laser irradiation at 514.1 nm and 488 nm dramatically increased doxorubicin cytotoxicity in an L929 cell clonogenic survival assay. The cytotoxicity was...
Argon ion laser irradiation at 514.1 nm and 488 nm dramatically increased doxorubicin cytotoxicity in an L929 cell clonogenic survival assay. The cytotoxicity was dependent on both the drug concentration and the total light energy delivered such that at 5 micrograms doxorubicin/ml and 800 J/cm2, cytotoxicity was enhanced by a factor of > 10(4) relative to that achieved with drug alone. Irradiation times in excess of 2 min and power densities in excess of 100 J/cm2 were required to produce the effect. Beyond this 2-min limit, cytotoxicity was not related to the duration of exposure if the total energy delivered was held constant. The ability of catalase and superoxide dismutase to abolish completely the increase in cytotoxicity produced by laser irradiation suggests that the cytotoxic mechanism may depend on the generation of active oxygen species by the photodynamically excited drug.
Topics: Animals; Cells, Cultured; Doxorubicin; Lasers; Mice; Photochemotherapy
PubMed: 7987973
DOI: 10.1007/BF00686279 -
European Journal of Pharmaceutical... Jan 2023In this study, we prepared a C6 cell membrane-coated doxorubicin conjugated manganese dioxide biomimetic nanomedicine system (MnO-DOX-C6) for the treatment of glioma. In...
In this study, we prepared a C6 cell membrane-coated doxorubicin conjugated manganese dioxide biomimetic nanomedicine system (MnO-DOX-C6) for the treatment of glioma. In the glioma microenvironment, manganese dioxide could alleviate tumor hypoxia by promoting the decomposition of hydrogen peroxide (HO) to generate oxygen and, through a Fenton-like reaction, increase ROS levels in tumor cells, thus inducing oxidative stress to further kill cancer cells. Doxorubicin and manganese dioxide were connected through a hydrazone bond so that doxorubicin could be released only in the acidic environment of the tumor, which helped to reduce the toxicity and side effects of doxorubicin. Encapsulation of glioma C6 cancer cell membrane in MnO-DOX-C6 made MnO-DOX possess the homologous targeting ability and also regulated drug release rate. In vitro release experiments showed that the cumulative release of doxorubicin from MnO-DOX-C6 at a pH of 5.0 for 48 h was 66.84 ± 3.81%, proving that it had pH sensitivity and a sustained-release effect. Cellular uptake experiments showed that MnO-DOX-C6 had a good ability to target syngeneic tumor cells. MTT, flow cytometry, Western blot, cell immunofluorescence staining and in vivo antitumor experiments demonstrated that MnO-DOX-C6 could promote C6 cell apoptosis and inhibit its proliferative ability. These results clearly suggested that MnO-DOX-C6 may be a promising bionic nanosystem agent for the treatment of glioma.
Topics: Humans; Manganese Compounds; Oxides; Hydrogen Peroxide; Doxorubicin; Glioma; Nanoparticles; Cell Membrane; Cell Line, Tumor; Tumor Microenvironment
PubMed: 36410571
DOI: 10.1016/j.ejps.2022.106338 -
Veterinary Medicine and Science Aug 2020Opioid receptor activation was shown to enhance the efficacy of anti-neoplastic drugs in several human cancer cell lines. In these cell lines, doxorubicin increased the...
Opioid receptor activation was shown to enhance the efficacy of anti-neoplastic drugs in several human cancer cell lines. In these cell lines, doxorubicin increased the number of opioid receptors and methadone concurrently enhanced cellular doxorubicin uptake. Triggered through lay press and media, animal owners started to challenge veterinary oncologists with questions about methadone use in anti-cancer therapy. Especially in veterinary medicine, where side effects of chemotherapy are tolerated to a lesser extent and hence smaller doses are given, agents potentiating chemotherapeutic agents would be an optimal approach to treatment. Canine transitional cell carcinoma cells (TCC, K9TCC), canine osteosarcoma cells (OSA, Abrams) and canine hemangiosarcoma cells (HSA, DAL-4) were incubated with different combinations of methadone, buprenorphine and doxorubicin, in order to test inhibition of cell proliferation. Opioid receptor density was assessed with fluorescence-activated cell sorting in drug native and doxorubicin pretreated cells. In TCC and OSA cell lines opioid receptor density increased after doxorubicin pretreatment. In combination treatment, however, we did not find significant potentiation of doxorubicin's inhibitory effect on proliferation in these cell lines. Neither was there a significant increase of the effect of doxorubicin when the opioids were added 24 hr before doxorubicin. Hence, we could not confirm the hypothesis that opioids increase the anti-proliferative effect of the anti-neoplastic drug doxorubicin in any of these canine tumour cell lines. The lack of effect on a cellular level does not warrant a clinical approach to use opioids together with doxorubicin in dogs with cancer.
Topics: Animals; Antineoplastic Agents; Buprenorphine; Cell Line, Tumor; Cell Proliferation; Dogs; Doxorubicin; Methadone
PubMed: 32306524
DOI: 10.1002/vms3.266 -
European Biophysics Journal : EBJ Sep 2009Based on molecular and physiological resemblance, the mechanism that controls drug bioavailability and toxicity also shares strong similarities to the one that controls... (Comparative Study)
Comparative Study Review
Toward a mechanical control of drug delivery. On the relationship between Lipinski's 2nd rule and cytosolic pH changes in doxorubicin resistance levels in cancer cells: a comparison to published data.
Based on molecular and physiological resemblance, the mechanism that controls drug bioavailability and toxicity also shares strong similarities to the one that controls drug resistance. In both cases, this mechanism relies on the expression of drug transporters and the physico-chemical properties of drugs, which together alter the intracellular accumulation of chemicals in cells or tissues. However, a parameter that is central and has received great attention in the field of bioavailability, but almost none in the field of drug resistance, is the molecular weight of drugs. In the former area, it is well known that to achieve a reasonable bioavailability, drugs must have-among other properties-a molecular weight less than 500, known as Lipinski's 2nd rule. Accordingly, it is worth questioning whether a similar rule exists in the field of drug resistance and what subsequent mechanism would control the membrane permeability to drugs as a function of their molecular weight. I demonstrate here that cytosolic pH fixes the molecular weight of drugs entering cells, by altering the cell membrane mechanical properties and that, both cytosolic pH and membrane mechanical properties are needed and sufficient to explain doxorubicin resistance levels in different cancerous cell lines. Finally, I discuss the efficiency of a drug handling activity by transporters in MDR and suggest ways to control drug delivery mechanically. In addition, and for the first time, the literal expression of a Law similar to Lipinski's 2nd rule will be described as a function of cytosolic pH and lipid number asymmetry.
Topics: Animals; Biomechanical Phenomena; Cytosol; Doxorubicin; Drug Resistance, Neoplasm; Humans; Hydrogen-Ion Concentration; Neoplasms
PubMed: 19296096
DOI: 10.1007/s00249-009-0429-x -
Cardiovascular Drugs and Therapy Jan 1988Three hours after the intravenous infusion of doxorubicin (3 mg/kg over 15 min) to anesthetized dogs, the drug concentration was found much higher in the myocardium than...
Three hours after the intravenous infusion of doxorubicin (3 mg/kg over 15 min) to anesthetized dogs, the drug concentration was found much higher in the myocardium than in the plasma (about 4,000 ng/g, i.e., 50 times higher). After the intravenous infusion of doxorubicin (1.5 mg/kg over 15 min) to conscious dogs, the drug concentration appeared to decline very slowly in the myocardium, since it was close to 200 ng/g at the 7th day, whereas the plasma concentration had fallen to zero, and the drug was still detected in the cardiac tissue 21 days after the administration. As myocardial concentrations of doxorubicin persist long after plasma clearance is complete, the hazards of repeated administration, based on plasma kinetic patterns, must be emphasized.
Topics: Animals; Dogs; Doxorubicin; Heart; Infusions, Intravenous; Myocardium
PubMed: 3154684
DOI: 10.1007/BF02125741 -
Molecular Cancer Therapeutics Jul 2014Doxorubicin is a widely used chemotherapy for solid tumors and hematologic malignancies, but its use is limited due to cardiotoxicity. Geranylgeranylacetone (GGA), an...
Doxorubicin is a widely used chemotherapy for solid tumors and hematologic malignancies, but its use is limited due to cardiotoxicity. Geranylgeranylacetone (GGA), an antiulcer agent used in Japan for 30 years, has no significant adverse effects, and unexpectedly reduces ovarian cancer progression in mice. Because GGA reduces oxidative stress in brain and heart, we hypothesized that GGA would prevent oxidative stress of doxorubicin cardiac toxicity and improve doxorubicin's chemotherapeutic effects. Nude mice implanted with MDA-MB-231 breast cancer cells were studied after chronic treatment with doxorubicin, doxorubicin/GGA, GGA, or saline. Transthoracic echocardiography was used to monitor systolic heart function and xenografts evaluated. Mice were euthanized and cardiac tissue evaluated for reactive oxygen species generation, TUNEL assay, and RHO/ROCK pathway analysis. Tumor metastases were evaluated in lung sections. In vitro studies using Boyden chambers were performed to evaluate GGA effects on RHO pathway activator lysophosphatidic acid (LPA)-induced motility and invasion. We found that GGA reduced doxorubicin cardiac toxicity, preserved cardiac function, prevented TUNEL-positive cardiac cell death, and reduced doxorubicin-induced oxidant production in a nitric oxide synthase-dependent and independent manner. GGA also reduced heart doxorubicin-induced ROCK1 cleavage. Remarkably, in xenograft-implanted mice, combined GGA/doxorubicin treatment decreased tumor growth more effectively than doxorubicin treatment alone. As evidence of antitumor effect, GGA inhibited LPA-induced motility and invasion by MDA-MB-231 cells. These anti-invasive effects of GGA were suppressed by geranylgeraniol suggesting GGA inhibits RHO pathway through blocking geranylation. Thus, GGA protects the heart from doxorubicin chemotherapy-induced injury and improves anticancer efficacy of doxorubicin in breast cancer.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Diterpenes; Doxorubicin; Drug Interactions; Female; Heart Diseases; Humans; Mice; Mice, Nude; Xenograft Model Antitumor Assays; rho-Associated Kinases
PubMed: 24737026
DOI: 10.1158/1535-7163.MCT-13-0965 -
Molecules (Basel, Switzerland) Jul 2018A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was...
A heterobifunctional reactive oxygen species (ROS)-responsive linker for directed drug assembly onto and delivery from a quantum dot (QD) nanoparticle carrier was synthesized and coupled to doxorubicin using -(3-dimethylaminopropyl)-'-ethylcarbodiimide hydrochloride (EDC)/sulfo⁻NHS coupling. The doxorubicin conjugate was characterized using ¹H NMR and LC-MS and subsequently reacted under conditions of ROS formation (Cu/H₂O₂) resulting in successful and rapid thioacetal oxidative cleavage, which was monitored using ¹H NMR.
Topics: Doxorubicin; Magnetic Resonance Spectroscopy; Molecular Structure; Nanoparticles; Oxidation-Reduction; Peptides; Quantum Dots; Reactive Oxygen Species
PubMed: 30037071
DOI: 10.3390/molecules23071809 -
Cancer Chemotherapy and Pharmacology 1992The pharmacokinetics of doxorubicin (DOX) and doxorubicinol (DOXol) was studied in six patients with various advanced neoplastic diseases who received 28-72 mg/m2 DOX...
The pharmacokinetics of doxorubicin (DOX) and doxorubicinol (DOXol) was studied in six patients with various advanced neoplastic diseases who received 28-72 mg/m2 DOX (nine courses). Plasma and parotid saliva were collected over a 48-h period, and DOX and DOXol were quantified by high-performance liquid chromatography with fluorescence detection. As reported previously, a wide range of plasma levels were found among our patients. It appears that in addition to being quickly cleared from the plasma, both DOX and DOXol are excreted in detectable amounts in parotid saliva, a route of elimination that has been given little attention, if any. Excretion in the saliva exposes the mucosa of the upper gastrointestinal tract to drug and may play a role in causing stomatitis in patients receiving DOX by the i.v. route. Since huge interindividual and pronounced intraindividual differences were found in S/P ratios that mostly were not systematically related to the plasma drug concentration, the concentration in parotid saliva was not useful in predicting the level of free DOX and DOXol in plasma. For the parent drug and its metabolite, the S/P ratios increased significantly with time during the 48-h period after dosing.
Topics: Adult; Aged; Doxorubicin; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasms; Parotid Gland; Saliva
PubMed: 1628370
DOI: 10.1007/BF00686315 -
Biochemical and Biophysical Research... Aug 2020The limited effectiveness and high toxicity of current treatments in osteosarcoma necessitate new therapeutic strategy. Cobimetinib is a FDA-approved MEK inhibitor and...
The limited effectiveness and high toxicity of current treatments in osteosarcoma necessitate new therapeutic strategy. Cobimetinib is a FDA-approved MEK inhibitor and is clinically used in combination with standard of care to treat melanomas. Here, we report that targeted MEK inhibition by cobimetinib enhances doxorubicin's efficacy in osteosarcoma models. We found that cobimetinib potently inhibited growth and survival of osteosarcoma cells. We revealed that cobimetinib had anti-metastasis activity as it inhibited osteosarcoma cell migration. Notably, the effective concentrations of cobimetinib are clinically achievable. We further found that cells with the most sensitivity had highest p-ERK and cells with the least sensitivity had lowest p-ERK, suggesting the possible correlation of ERK activation with cobimetinib sensitivity in osteosarcoma. We further confirmed that inhibition of MEK/ERK signaling pathway is the mechanism of cobimetinib's action in osteosarcoma, leading to inhibition of focal adhesion kinase (FAK) and anti-apoptotic pathway, as well as activation of pro-apoptotic pathway. Using xenograft mice model, we found that cobimetinib at the tolerable dose significantly inhibited osteosarcoma formation and growth. In addition, the combination of cobimetinib and doxorubicin at sublethal dose completely arrested tumor growth without further progression. The ability of cobimetinib in enhancing doxorubicin's efficacy in osteosarcoma models makes cobimetinib as a useful addition to the treatment armamentarium for osteosarcoma. Our findings also emphasize the therapeutic value of MEK/ERK pathway to improve the clinical management of osteosarcoma.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Azetidines; Cell Line, Tumor; Cell Movement; Cell Proliferation; Doxorubicin; Drug Synergism; Humans; Male; Mice, Nude; Mitogen-Activated Protein Kinase Kinases; Osteosarcoma; Piperidines; Xenograft Model Antitumor Assays
PubMed: 32736683
DOI: 10.1016/j.bbrc.2020.06.082 -
Asian Pacific Journal of Cancer... Dec 2022Targeting breast cancer stem cells with the CD44+/CD24- phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and...
BACKGROUNDS
Targeting breast cancer stem cells with the CD44+/CD24- phenotype is critical for complete eradication of cancer cells due to its Self-renewal, differentiation, and therapeutic resistance ability. Quercetin is a popular flavonoid with lower adverse effects and has anti-tumor properties. Therefore, we assessed the anticancer activity of Quercetin and Doxorubicin alone and in combination in the T47D cells of human breast cancer and their isolated Cancer stem cells (CSCs).
MATERIALS AND METHODS
The human breast cancer cell line T47D was used for this experiment. T47D CSCs were isolated by magnetic bead sorting using the MACS system. The anticancer activity of Quercetin and Doxorubicin alone and in combination were evaluated using MTT cytotoxicity assay and cell cycle distribution and apoptosis induction by flow cytometry analysis.
RESULTS
We have shown that almost 1% of T47D cell populations are made up of CD44+/CD24- cells, which considered as cancer stem cells. Quercetin and Doxorubicin alone or in combination inhibited cell proliferation and induced apoptosis in breast cancer T47D cells and in lower extent in CD44+/CD24- cells. Quercetin significantly strengthened Doxorubicin's cytotoxicity and apoptosis induction in both cell populations. Quercetin and Doxorubicin and their combination induced G2/M arrest in the T47D cells and to a lesser extent in isolated CSCs. A value of p < 0.05 was considered as indicating a statistically significant difference.
CONCLUSION
These outcomes suggested that CSCs are a minor population of cancer cells, which play a significant role in drug resistance by being quiescent, slow cycling and resistance to apoptosis. Furthermore, our data showed that adding Quercetin to Doxorubicin is an effective approach for the treatment of both CSCs and bulk tumor cells.
Topics: Humans; Female; Quercetin; Apoptosis; Cell Line, Tumor; G2 Phase Cell Cycle Checkpoints; Doxorubicin; Cell Cycle Checkpoints; Breast Neoplasms; Cell Proliferation; Cell Cycle; Neoplastic Stem Cells
PubMed: 36579996
DOI: 10.31557/APJCP.2022.23.12.4145