Verapamil and cyclosporin a sensitize human kidney tumor cells to vincristine in absence of membrane P-glycoprotein and without apparent changes in the cytoplasmic free Ca2+ concentration

1990 ◽  
Vol 10 (2) ◽  
pp. 231-237 ◽  
Author(s):  
P. Nygren ◽  
R. Larsson
Keyword(s):  
Cyclosporin A ◽  
Drug Sensitivity ◽  
Human Kidney ◽  
Chemotherapeutic Drug ◽  
Long Term Effects ◽  
Adenocarcinoma Cell Line ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Sensitizing Effect

Vincristine (Vcr) dose dependently inhibited growth of the kidney adenocarcinoma cell line ACHN during 4 days of culture. Verapamil (Ver) at 10 μM and cyclosporin A (CsA) at 1 μg/ml had no effect on cell growth but significantly potentiated the action of Vcr, despite the absence of the multidrug resistance associated membrane P-glycoprotein (P-gp). Neither Ver nor CsA had any acute or long term effects on cytoplasmic free Ca2+ concentration (Ca2+i), except for a small Ver induced increase after 36 h of incubation. The results indicate that Ver and CsA may have a sensitizing effect on chemotherapeutic drug sensitivity also in absence of P-gp. However, these effects are probably not mediated by changes in Ca2+i.

scholarly journals Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

2014 ◽  
Vol 34 (10) ◽  
pp. 1637-1645 ◽  
Author(s):  
Amandine Jullienne ◽  
Jill M Roberts ◽  
Viorela Pop ◽  
M Paul Murphy ◽  
Elizabeth Head ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Amyloid Beta ◽  
Vascular Dysfunction ◽  
Neurovascular Unit ◽  
Early Brain Injury ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Blood Microvessels

In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Aβ) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Aβ clearance. Rodent-Aβ staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood–brain barrier alongside vascular dysfunction and altered Aβ trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

scholarly journals Long-term effects of cyclosporin A on cultured mouse pancreatic islets

Diabetologia ◽  
1984 ◽  
Vol 27 (S1) ◽  
pp. 66-69 ◽  
Author(s):  
A. Andersson ◽  
H. Borg ◽  
A. Hallberg ◽  
C. Hellerstr�m ◽  
S. Sandler ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Pancreatic Islets ◽  
Long Term Effects ◽  
Mouse Pancreatic Islets

Real-Time Measurement of Chemotherapeutic Drug Transport in an Individual Cancer Cell Selected in a Microfluidic Biochip

2009 ◽  
Author(s):  
Yuchun Chen ◽  
Paul C. H. Li
Keyword(s):  
Cancer Cells ◽  
Drug Transport ◽  
Time Measurement ◽  
Chemotherapeutic Drug ◽  
Glycoprotein P ◽  
Main Research ◽  
Real Time Measurement ◽  
P Glycoprotein ◽  
Research Goal ◽  
Retention Study

Multidrug resistance (MDR) is a significant obstacle to effective chemotherapy to many patients. Because of the overexpression of one membrane protein, P-glycoprotein (P-gp), there is an increased efflux of chemotherapeutic drug in the resistant cancer cells. The main research goal of MDR study is to get improved intracellular drug retention inside the cancer cells. So it is important to study the chemotherapeutic drug transport in the cancer cells. In this work, single leukemia CEM MDR cell has been isolated and captured by a microfluidic single-cell biochip for drug transport and retention study.

scholarly journals Follow-up of cyclosporin A treatment in Type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects

Diabetologia ◽  
1991 ◽  
Vol 34 (6) ◽  
pp. 429-434 ◽  
Author(s):  
S. Martin ◽  
G. Schernthaner ◽  
J. Nerup ◽  
F. A. Gries ◽  
V. A. Koivisto ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Cyclosporin A ◽  
Insulin Dependent Diabetes Mellitus ◽  
Insulin Dependent Diabetes ◽  
Dependent Diabetes Mellitus ◽  
Long Term Effects ◽  
Insulin Dependent

Inhibition of P-glycoprotein by cyclosporin A analogues and metabolites

1999 ◽  
Vol 77 (1) ◽  
pp. 47-58 ◽  
Author(s):  
Michel Demeule ◽  
Alain Laplante ◽  
Arash Sepehr-Araé ◽  
Édith Beaulieu ◽  
Diana Averill-Bates ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Cyclosporin A ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Multidrug Resistant ◽  
Hydroxyl Group ◽  
Glycoprotein P ◽  
Ovary Cells ◽  
Psc 833 ◽  
P Glycoprotein

The interaction between P-glycoprotein (P-gp) from membranes isolated from multidrug-resistant Chinese hamster ovary cells and cyclosporin A (CsA) analogues and its metabolites was characterized. Screening of these latter as chemosensitizers was performed using three different assays: (i) vinblastine uptake, (ii) photoaffinity labeling by [125I]iodoaryl azidoprazosin, and (iii) P-gp ATPase activity. Oxidation of the hydroxyl group at position 1 of CsA (200-096), CsG (215-834), or CsD (PSC-833) increased their inhibition of P-gp. CsA analogues (208-032, 208-183) modified at position 11 retained their ability to inhibit P-gp while analogues modified at position 2 (CsC and CsD) lost their efficiency. The inhibitions induced by metabolites of CsA were also compared to those obtained with CsG metabolites. From all the molecules tested, PSC-833 and 280-446 peptolide were the strongest inhibitors. Our results indicate that modifications of CsA analogues at position 1 and 2 are critical for their interaction with P-gp and that CsA metabolites retain a portion of the inhibitory activity of the parent drug.Key words: P-glycoprotein, cyclosporin A, vinblastine uptake, photolabeling, ATPase activity.

scholarly journals Compound 968 reverses adriamycin resistance in breast cancer MCF-7ADR cells via inhibiting P-glycoprotein function independently of glutaminase

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ronghui Yang ◽  
Zihao Guo ◽  
Yiliang Zhao ◽  
Lingdi Ma ◽  
Binghui Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Death ◽  
Chemotherapeutic Agents ◽  
New Combination ◽  
Chemotherapeutic Drug ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Increased Sensitivity ◽  
Mcf 7

AbstractAdriamycin (ADR) is a chemotherapeutic drug widely utilized to treat multiple types of cancers; however, the clinical efficacy of ADR is compromised due to the development of drug resistance in patients. The combination of drugs with ADR may provide a better therapeutic regimen to overcome this obstacle. Glutaminase (GLS) has been explored as a therapeutic cancer target, and its inhibition also results in increased sensitivity of tumor cells to chemotherapeutic agents. This study aimed to investigate whether GLS inhibition could reverse ADR resistance. We treated the ADR-resistant MCF-7 (MCF-7ADR) cells with a GLS inhibitor, compound 968 or CB-839, in combination with ADR. We found that compound 968, rather than CB-839, together with ADR synergistically inhibited the cell viability. These results indicated that compound 968 reversed ADR resistance in MCF-7ADR cells independently of GLS. Moreover, we modified the structure of compound 968 and finally obtained a compound 968 derivative, SY-1320, which was more potent than compound 968 in eliminating the drug resistance in MCF-7ADR cells. Furthermore, using drug affinity responsive target stability and streptavidin–biotin immunoprecipitation assays, we demonstrated that SY-1320 could specifically target P-glycoprotein (P-gp) and increase ADR accumulation through inhibition of P-gp, thereby resulting in cell death in MCF-7ADR cells. Together, our findings indicate that compound 968 or SY-1320 might be a promising drug for new combination chemotherapy in breast cancer to overcome the drug resistance.

scholarly journals Long-term Levothyroxine Treatment Decreases the Oral Bioavailability of Cyclosporin A by Inducing P-glycoprotein in Small Intestine

2005 ◽  
Vol 20 (5) ◽  
pp. 324-330 ◽  
Author(s):  
Mingji Jin ◽  
Tsutomu Shimada ◽  
Miki Shintani ◽  
Koichi Yokogawa ◽  
Masaaki Nomura ◽  
...  
Keyword(s):  
Small Intestine ◽  
Cyclosporin A ◽  
Oral Bioavailability ◽  
P Glycoprotein ◽  
Levothyroxine Treatment

Ovarian Dysfunction in Fetally Irradiated Beagles

1977 ◽  
Vol 35 ◽  
pp. 658-659
Author(s):  
T. M. Seed ◽  
M. H. Sanderson ◽  
D. L. Gutzeit ◽  
T. E. Fritz ◽  
D. V. Tolle ◽  
...  
Keyword(s):  
Gamma Rays ◽  
Low Dose ◽  
Long Term Effects ◽  
Ovarian Dysfunction ◽  
Dose Rates ◽  
Highly Sensitive ◽  
Microscopic Evaluation ◽  
Ovarian Pathology ◽  
Normal Offspring

The developing mammalian fetus is thought to be highly sensitive to ionizing radiation. However, dose, dose-rate relationships are not well established, especially the long term effects of protracted, low-dose exposure. A previous report (1) has indicated that bred beagle bitches exposed to daily doses of 5 to 35 R 60Co gamma rays throughout gestation can produce viable, seemingly normal offspring. Puppies irradiated in utero are distinguishable from controls only by their smaller size, dental abnormalities, and, in adulthood, by their inability to bear young.We report here our preliminary microscopic evaluation of ovarian pathology in young pups continuously irradiated throughout gestation at daily (22 h/day) dose rates of either 0.4, 1.0, 2.5, or 5.0 R/day of gamma rays from an attenuated 60Co source. Pups from non-irradiated bitches served as controls. Experimental animals were evaluated clinically and hematologically (control + 5.0 R/day pups) at regular intervals.

Ultrastructural investigations of MDL 19,660-induced effects on the canine platelet and megakaryocyte

1990 ◽  
Vol 48 (3) ◽  
pp. 374-375
Author(s):  
D.E. Loudy ◽  
J. Sprinkle-Cavallo ◽  
J.T. Yarrington ◽  
F.Y. Thompson ◽  
J.P. Gibson
Keyword(s):  
Antidepressant Drug ◽  
Beagle Dogs ◽  
Long Term Effects ◽  
Short Term ◽  
Platelet Counts ◽  
Toxicological Studies ◽  
Induced Aggregation ◽  
Internal Architecture

Previous short term toxicological studies of one to two weeks duration have demonstrated that MDL 19,660 (5-(4-chlorophenyl)-2,4-dihydro-2,4-dimethyl-3Hl, 2,4-triazole-3-thione), an antidepressant drug, causes a dose-related thrombocytopenia in dogs. Platelet counts started to decline after two days of dosing with 30 mg/kg/day and continued to decrease to their lowest levels by 5-7 days. The loss in platelets was primarily of the small discoid subpopulation. In vitro studies have also indicated that MDL 19,660: does not spontaneously aggregate canine platelets and has moderate antiaggregating properties by inhibiting ADP-induced aggregation. The objectives of the present investigation of MDL 19,660 were to evaluate ultrastructurally long term effects on platelet internal architecture and changes in subpopulations of platelets and megakaryocytes.Nine male and nine female beagle dogs were divided equally into three groups and were administered orally 0, 15, or 30 mg/kg/day of MDL 19,660 for three months. Compared to a control platelet range of 353,000- 452,000/μl, a doserelated thrombocytopenia reached a maximum severity of an average of 135,000/μl for the 15 mg/kg/day dogs after two weeks and 81,000/μl for the 30 mg/kg/day dogs after one week.

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