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PubMed2003

Multidrug resistance in Serratia marcescens and cloning of genes responsible for the resistance.

Six clinically isolated strains of Serratia marcescens were tested for their drug resistance. All showed fairly high resistance to many antimicrobial agents tested including norfloxacin, streptomycin, ampicillin, erythromycin, tetracycline, chloramphenicol, and antimicrobial dyes. Using the drug-hypersensitive strain of Escherichia coli KAM32 as the host, we cloned the genes responsible for multidrug resistance from chromosomal DNA of one of the strains of S. marcescens, NUSM8906. We obtained 28 hybrid plasmids that made host cells resistant to several antimicrobial agents. Many of the transformants harboring each of the plasmids showed multidrug resistance, and some showed resistance to specific drugs. The hybrid plasmids were classified into several groups based on their drug specificity. It appears that each class of plasmid carries different types of drug resistance genes. Analysis of such genes will reveal the multiple mechanisms involved in multidrug resistance in S. marcescens.

Anti-Bacterial Agents↗

PubMed2026

Drug-resistant genes, virulence characteristics, and molecular typing of clindamycin-resistant Streptococcus agalactiae in late pregnancy.

BACKGROUND: Streptococcus agalactiae increases the risk of adverse pregnancy outcomes and neonatal infections. Clindamycin is a key alternative for intrapartum prophylaxis in penicillin-allergic women, but the prevalence of clindamycin-resistant S. agalactiae is increasing, posing a significant clinical challenge. METHODS: A total of 178 strains isolated from tertiary hospitals in Jinan and Qingdao, Shandong Province, China, were characterized using antimicrobial susceptibility testing, whole-genome sequencing, multilocus sequence typing, serotyping, and analysis of resistance and virulence genes. RESULTS: All strains were susceptible to penicillin, ampicillin, linezolid, vancomycin, and tigecycline. In contrast, resistance rates to erythromycin, levofloxacin, and tetracycline were 95.5%, 60.1%, and 56.7%, respectively. Six serotypes and 15 sequence types belonging to eight clonal complexes were identified. Notable regional differences were observed. The Ib-ST10-CC12 lineage dominated in Jinan, whereas V-ST529-CC327 was predominant in Qingdao. The resistance gene mreA was ubiquitous (100%), followed by ermB (80.3%). The key virulence genes cylE, hylB, and pavA, were detected in all strains. fbsA (99.4%), the alpha protein family (98.9%), cfb (98.3%), the Pilus Island gene cluster (94.9%), and lmb (92.7%) were also highly prevalent. The two major clindamycin resistance genes, erm and lnuB, exhibited distinctly different enrichment patterns among S. agalactiae clonal complexes, despite a certain overlap in CC19 and CC327. Specifically, erm was significantly enriched in CC12 (serotype Ib), CC19 (III/V), and CC327 (III/V). In contrast, lnuB was predominantly restricted to CC19 and CC327, where it defined a unique phylogenetic subcluster. Significant differences in resistance and virulence gene profiles were observed across different clonal complexes. CONCLUSION: Clindamycin-resistant S. agalactiae in late-pregnancy women in Shandong Province, China exhibits a broad resistance spectrum, diverse molecular types, and significant regional heterogeneity. These findings underscore the need for continued surveillance and region-specific strategies for preventing neonatal S. agalactiae infections.

Humans↗

PubMed2004

Characterization of a bifunctional aminoglycoside-modifying enzyme with novel substrate specificity and its gene from a clinical isolate of methicillin-resistant Staphylococcus aureus with high arbekacin resistance.

A clinical isolate (designated PRC104) of methicillin-resistant Staphylococcus aureus was discovered with a novel aminoglycoside resistance profile, including unusually high resistance (MIC 128 microg/ml) to arbekacin (an effective anti-MRSA drug in Japan). We characterized the activity and gene of its bifunctional aminoglycoside-modifying enzyme, AAC(6')/APH(2"), in comparison with those of a regular one that has been known as the critical resistance basis to both gentamicin and arbekacin in methicillin-resistant Staphylococcus aureus. The aac(6')/aph(2") gene of strain PRC104 contained a single base alteration at a novel site (G1126A) resulting in one amino acid substitution (S376N) in the phosphorylation catalytic motif. The phosphorylation activity of the PRC104 enzyme was enhanced for arbekacin and reduced for gentamicin. Both strain PRC104 and S. aureus RN4220 containing the cloned gene were identical in terms of the substrate specificity of the enzyme as well as the aminoglycoside resistance profile, although both mRNA and aminoglycoside resistance levels were markedly high in strain PRC104. Therefore, the cloned aac(6')/aph(2") gene may represent the molecular basis for the novel aminoglycoside modification capability as well as novel aminoglycoside resistance profile of S. aureus PRC104.

Amino Acid Sequence↗

PubMed1997

[Resistant antibiotic analysis of methicillin-resistant staphylococcus].

Methicillin-resistant staphylococcus aureus is one of the important patholonic bacteria which cause nosocomial infection. In order to investigate the resistant antibiotic circumstances of this organism and hence provide foundations of prevention and treatment, we determined the resistant rates of 88 staphylococcus strains for methicillin and for other 14 kinds of commonly used antibiotics, and we determined the engendering beta-lactamase. The results showed that the isolation rate of methicillin-resistant staphylococcus aureus (MRSA) was 56%; the rate of methicillin-resistant staphylococcus coagulase-negative (MRSCoN) was 47.6%; the resistance rate and the multi-resistant rate of methicillin-resistant staphylococcus (MRS) for the 14 kinds of antibiotics were higher as compared with those of methicillin-sensitive (MSSA). Among all the tested strains, MRSA was the highest to engender beta-lactamase (92.9%); Methicillin-sensitive staphylococcus coagulase-negative (MSSCoN) was the lowest (39.4%). MRS was sensitive to vancomycin and furantoin. These suggest that when treating this bacterium, we should select these two antibiotics first.

Anti-Bacterial Agents↗

PubMed1999

[Localization of genes conferring resistance to selected groups of antibiotics in methicillin-resistant strains of Staphylococcus aureus].

Localization of genes conferring resistance to MLS, tetracyclines, chloramphenicol, gentamycin and neomycin in 80 MRSA strains isolated from hospital specimens was determined. The obtained results were compared to DNA patterns of the examined strains after digestion with SmaI and separation in pulsed field electrophoresis (PFGE). It was shown that genes of resistance to MLS (ErmI+) in the case of 13 strains were located on chromosome and in the case of 37 strains on plasmids (16 strains had ErmI+ and 21 strains had ErmI-). Genes determining resistance to tetracyclines were localised on chromosome in the case of 39 (23 strains possessed TetK, 11 strains had TetM and 5 strains possessed both TetK and TetM determinants) and in the case of 32 strains on plasmids. Chloramphenicol resistance genes were localised on plasmids in all 30 resistant strains. Genes conferring resistance to gentamycin were present in 31 of the investigated strains on chromosome and in two strains on plasmids. Neomycin resistance genes were plasmid in 34 strains. It was shown that the localization of the resistance genes and the PFGE patterns of the investigated strains were highly correlated.

Drug Resistance, Microbial↗

PubMedDate not supplied

Single- and multidrug resistance mutations to reverse transcriptase and protease inhibitors: human immunodeficiency virus type 1-infected patients from two geographical areas in Spain. Spanish Groups for Antiretroviral Resistance Studies.

OBJECTIVES: To describe the prevalence of genotypic resistance mutations, including single and multidrug resistance (MDR) to reverse transcriptase (RT) and protease (PR) inhibitors in treated and untreated patients from two geographical areas in Spain (Madrid and Galicia). STUDY DESIGN/METHODS: Resistance mutations to RT inhibitors were studied by line probe assay (LiPA) or by automated sequencing in 468 patients (Madrid, 268; Galicia, 200), and resistance mutations to PR inhibitors were studied by automated sequencing in 295 patients (Madrid, 85; Galicia, 210). RESULTS: The proportion of resistance mutations in treated and untreated patients results were higher by the LiPA method than by sequencing. By sequencing, we detected resistance mutations to nucleoside analogue RT (NRT) inhibitors and NRT inhibitors plus nonnucleoside RT (NNRT) inhibitors in 35.4% and 17.2% of treated patients, respectively. We also detected MDR to zidovudine plus lamivudine in 13.9% of treated patients from Galicia, in 1.7% from Madrid (p < 0.001), and in 1.5% of untreated patients from Galicia. Also, we detected MDR to NRT inhibitors in 3.8% and to NNRT inhibitors in 9.1%. We found resistance mutations to PR inhibitors in 38.1% of treated patients and in 0.9% of untreated patients. CONCLUSIONS: These findings reinforce the usefulness of testing for resistance mutations in some cases to evaluate their prevalence in a given population and in the follow-up of treated patients.

Cohort Studies↗

PubMed2000

[Establishment of cisplatin-induced multidrug resistant human epithelial ovarian cancer cell line 3AO/cDDP and its expressions of multidrug resistance proteins].

OBJECTIVE: To establish multidrug resistant ovarian cancer cell line 3AO/cDDP by exposing parent cell line intervally and repeatedly to high-level concentration of cisplatin, and to detect expressions of lung resistance protein (LRP), multidrug resistance-associated protein(MRP) and P-glycoprotein (P-gp). METHODS: Using the corresponding dose calculated from clinical chemotherapy, we established 3AO/cDDP, with 3AO exposed intervally and repeatedly to high-level concentration of cisplatin at 10 micrograms/ml for 24 hours each time; LRP, MRP and P-gp expressions were detected with flow cytometry(FCM). RESULTS: 3AO/cDDP was established after 4.5 months with stable resistance and the drug resistant index was 1.62 which was similar to clinical resistance degree. Low expression levels of MRP and P-gp were found in both 3AO and 3AO/cDDP, and no statistical difference between the two lines (P > 0.05). However, LRP expression level in 3AO/cDDP was significantly higher than that in 3AO with FCM detection (P < 0.01). CONCLUSIONS: 3AO/cDDP, induced by exposing 3AO to high-level concentration of cisplatin intervally and repeatedly, is an ideal model for investigation of cisplatin resistance. Cisplatin resistance in 3AO/cDDP could be related to high LRP expression and be not associated with MRP or P-gp.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

A novel 7-modified camptothecin analog overcomes breast cancer resistance protein-associated resistance in a mitoxantrone-selected colon carcinoma cell line.

We selected a mitoxantrone-resistant HT29 colon carcinoma cell line (HT29/MIT) that exhibited a very high degree of resistance to the selecting agent and marked resistance to topotecan and SN38, but limited resistance to doxorubicin. The development of drug resistance was independent of expression of P-glycoprotein or multidrug resistance-associated protein but was associated with high up-regulation of the breast carcinoma resistance protein (BCRP) as shown by Western blot analysis. BCRP overexpression was associated with a reduced intracellular accumulation of topotecan, a known substrate for BCRP. Conversely, a lipophilic 7-modified camptothecin analogue (ST1481) displayed a complete lack of cross-resistance in HT29/MIT cells, suggesting that the drug was not a substrate for BCRP because no defects in intracellular accumulation were found. This conclusion is consistent with the antitumor efficacy of ST1481 against a BCRP-expressing tumor. These results may have therapeutic implications because the antitumor efficacy of ST1481 is in part related to a good bioavailability after oral administration, and the drug is currently under Phase I clinical evaluation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

[Methicillin-resistant Staphylococcus aureus (MRSA) with high resistance to mupirocin in hospitals of the Gdańsk region].

Occurrence of high-level mupirocin resistance in methicillin-resistant Staphylococcus aureus (MRSA) strains isolated from 18 hospitals in Gdańsk area was determined. The study was carried out on 190 MRSA isolated in 1997-2000 from various clinical samples. The strains were tested for high-level mupirocin resistance by 200 micrograms mupirocin disc. The minimum inhibitory concentrations (MIC) for methicillin were estimated by agar dilution. Sensitivity to other antibiotics was determined in disc-diffusion method and to vancomycin in agar dilution method additionally. The strains were typed by set of 10 experimental phages and compared by the method of PCR-RFLP analysis of coagulase gen restriction fragment length polymorphism. There were low frequency of high-level mupirocin resistance in MRSA strains (4.7%) that were found only in 3 hospitals, in 6 patients. All of them were high-resistant also to methicillin and resistant to doxycyclin, gentamycin, erytromycin, klindamycin, ciprofloksacin, rifampicin, resistant or intermediate sensitive to fusidic acid but sensitive to vancomycin, teikoplanin and bacitracin. The origin all of the MRSA strains high-resistant to mupirocin probably was the same, except one strain, because they were belonged to one genetic type and possessed the same phage pattern.

Bacteriophage Typing↗

PubMed1995

[Establishment of adriamycin-resistant human ovarian carcinoma cell line and its mechanism of multidrug resistance].

A multidrug-resistant cell line (A2780/ADM) of human ovarian carcinoma which can resist 0.8 microgram.ml-1 of adriamycin (ADM) was obtained by step-wise selection exposure to increasing doses of ADM. A2780/ADM cells showed 17-fold higher resistance to ADM than A2780 cells. The doubling times were 43.8 h in A2780/ADM and 26.3 h in A2780 cells. Colony formation rates were 15%-20% in A2780/ADM and 65%-75% in A2780 cells. A2780/ADM cell line was also shown to significantly cross-resistant to vincristine (VCR) and VP-16, but no cross-resistance was found to 5-Fu, PDD or Mel. A further investigation showed that intracellular accumulation of ADM in A2780/ADM was significantly decreased. Expressions of P-glycoprotein and GST-pi were increased in A2780/ADM by means of immunohistochemical method. Verapamil (Ver) combined with ADM was found to increase the sensitivity and reverse the resistance to ADM in A2780/ADM. This study indicates that A2780 ADM has the peculiarity of multidrug resistance and there may be other mechanism of drug-resistance besides MDR related to P-170.

Doxorubicin↗

PubMed1998

Vascular wall reactivity in conductance and resistance arteries: differential effects of insulin resistance.

Insulin resistance is associated with an increased risk of cardiovascular disease that is probably related to abnormalities of vascular wall function. The JCR:LA-cp rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular disease, and allows study of the relationships between insulin resistance and vascular function. Conductance and resistance arteries serve different functions, thus vascular disease may affect these types of artery differently. Concentration-response curves to norepinephrine, phenylephrine, and acetylcholine were studied in conductance vessels (aortic rings) and resistance vessels (mesenteric arteries) from 12-week-old male obese and lean JCR:LA-cp rats. The aortic rings and mesenteric arteries from obese rats showed increased maximal response to phenylephrine compared with those from lean rats, whereas only the mesenteric arteries from obese rats showed increased maximal response to norepinephrine. In aortic rings, relaxation to acetylcholine was similar for both genotypes, but the mesenteric arteries of obese rats showed impaired relaxation to acetylcholine. We conclude that the sensitivity to vasoconstriction is enhanced in aortic rings and mesenteric arteries of obese male JCR:LA-cp rats, but endothelial function is impaired only in the mesenteric resistance arteries of these animals. Hence functional aberrations in the obese, insulin-resistant state are more pronounced in mesenteric resistance arteries than in a major conductance artery.

Acetylcholine↗

PubMedDate not supplied

Co-transfection of MDR1 and MRP antisense RNAs abolishes the drug resistance in multidrug-resistant human lung cancer cells.

The resistance of lung cancer cells to the therapeutic actions of anticancer drugs is a serious clinical problem often encountered during cancer chemotherapy. It is very important, therefore, to investigate how to prevent and/or reverse this drug resistance. To this end, we took advantage of the fact that the overexpression of MDR1 and MRP genes, two genes known to be associated with the development of drug resistance, is very common in lung cancer. We used antisense RNA in an attempt to prevent expression of the protein products of these genes. Using a retrovirus, we introduced the antisense RNAs of MDR1 and MRP genes into doxorubicin-selected, multidrug-resistant GAOK cells, a cell which overexpresses both MDR1 and MRP genes. The expression levels of the products of the MDR1 gene (Pgp) and MRP gene (Mrp) in the transfected cells were analyzed using flow cytometry, and the drug resistances of the transfected cells were detected by a cell viability (MTT) assay. The expression of Pgp and Mrp in the transfected cells was almost completely inhibited by the antisense RNAs: expression levels decreased 64% and 93%, respectively. In parallel, the drug resistance of these cells decreased about 99% to doxorubicin, 98% to vinblastine, and 97% to colchicine. These results show that: a) antisense RNAs can attenuate drug resistance, an inhibition that might lead to new treatments for patients who are, or become, refractory to conventional chemotherapy; b) MDR1 and MRP appear to be cooperating to confer drug resistance in GAOK cells.

3T3 Cells↗

PubMed1998

[Multicellular resistance: another mechanisms of pleiotropic resistance?].

Cells cultured as spheroids present an heterogeneity similar to that of tumours in vivo. In the spheroid peripheral layers, cells are proliferating, deeper cells are non-cycling, when in the aggregate centre, cells from often a necrotic core. A multicellular resistance appears in spheroids, it is a result of the cell contact to other cells (homogeneous or heterogeneous cells) and/or to the extracellular matrix. The mechanism of this resistance is not known, nevertheless, it can be hypothesised to be linked to the spheroid centre hypoxia, to the quiescence of a large fraction of the cell population and to the apoptosis inhibition due to the cell contact. The "classical" or "unicellular" mechanisms of resistance, as mdr1, MRP, can coexist with the multicellular resistance, but are not responsible for this resistance. The spheroid model of culture is a good opportunity to study a resistance type which looks close to the tumour resistance found in vivo in mice and in patients. A new class of therapeutic molecules appears that can reverse this multicellular resistance, inhibit tumours growth and preclude metastases. The principal mechanism of action of this new pharmacological class appears to be the disruption of the intercellular adhesion forces. Preliminary results obtained with these compounds in patients are promising.

Cell Cycle↗

PubMed2026

Occurrence of antibiotic-resistant E. coli and antibiotic resistance genes from culturable bacteria in drinking water sources along the Upper Mahaweli River, Sri Lanka.

Antibiotic-resistant Escherichia coli (AR-E. coli) and antibiotic resistance genes (ARGs) in aquatic environments pose a serious threat to public health. However, their presence in river water in South Asian countries is not well established. The present study investigated AR-E. coli and ARGs from culturable bacteria in drinking water sources from 14 drinking water treatment plants situated along the Upper Mahaweli River, a tropical central hill-country river system in Sri Lanka. A total of 167 E. coli isolates were tested against ten antibiotics using the Kirby-Bauer method, and genomic DNA from culturable bacteria in 45 water samples were screened for 11 ARGs using PCR. Overall, 60.48% E. coli isolates exhibited resistance to at least one antibiotic and multidrug resistance was detected in 27.54%. Highest resistance was for amoxicillin (47.31%), tetracycline (26.95%), and co-trimoxazole (24.55%) and four antibiotics showed seasonal variation. ARGs, dominated by blaTEM (80.0%), tetA (66.67%), and tetM and qnrS (62.22%) were detected in 42.42% PCR assays (n = 210). Multiple antibiotic resistance index varied from 0.00 to 0.80, with 44.91% exceeding the 0.2 threshold value, and the antibiotic resistance index varied from 0.00 to 0.32, with eight above the threshold (≥ 0.2). Hierarchical cluster analysis grouped majority of drinking water sources into the intermediate category while few were categorized under low (Kotagala and Thalawakelle-Galkanda) and high (Haragama, Paradeka, and Nawalapitiya), reflecting the variability of anthropogenic interference. Results highlight the risk associated with AR-E. coli and ARGs from culturable bacteria in one of Sri Lanka's key drinking water sources. Proactive interventions ensuring long-term safety of drinking water sources are urgently needed to safeguard public health.

Sri Lanka↗

PubMed1994

Emergence of high-level mupirocin resistance in methicillin-resistant Staphylococcus aureus in Western Australia.

Six mupirocin-resistant Staphylococcus aureus were isolated from patients living in the northern part of Western Australia (WA). They were all resistant to methicillin, tetracycline, trimethoprim and cadmium and harboured similar 41.4 kb plasmids. Transfer and curing experiments with one of the isolates, WBG7569, demonstrated that the 41.4 kb plasmid encoded resistance to mupirocin, tetracycline, trimethoprim and cadmium. The isolates were compared by pulsed-field gel electrophoresis with methicillin-resistant S. aureus (MRSA) previously isolated from the Kimberley region in the northern-most part of WA (WA MRSA). The mupirocin-resistant isolates were found to be closely related to WA MRSA suggesting that they were WA MRSA which had acquired a new multiple-resistance plasmid encoding high-level mupirocin resistance.

Cadmium↗

PubMed2005

Molecular characterisation and mechanisms of resistance of multidrug-resistant human Salmonella enterica serovar Typhimurium isolated in Amiens (France).

Antimicrobial resistance patterns of Salmonella enterica serovar Typhimurium isolates obtained during the study period were examined. The molecular epidemiology and the mechanisms of resistance to ampicillin, chloramphenicol and tetracycline were investigated. Resistance to ampicillin increased from 59% between 1996 and 1999 to 62.5% in 2000 and to 66.6% in 2001. Of 51 S. Typhimurium isolates studied, 100% were resistant to ampicillin (minimum inhibitory concentration (MIC)>256 mg/L) and sulphonamide (MIC range, 128 to >256 mg/L). Ninety-eight percent of isolates were resistant to streptomycin (MIC range, 48-256 mg/L), 92.2% to tetracycline (MIC range, 32 to >256 mg/L), 88.2% to chloramphenicol (MIC>256 mg/L), 21.5% to sulphamethoxazole/trimethoprim (MIC>32 mg/L), 5.8% to amoxicillin/clavulanic acid (MIC, 32 mg/L) and 1.9% to cefalothin (MIC, 64mg/L). Six resistance phenotypes were found (a-f), with phenotypes a (47%) and b (27.5%) being predominant. Twenty-five (49%) of 51 isolates produced a single beta-lactamase, among which 48% produced PSE-1, 44% produced TEM-1 and 8% produced OXA-1. Among 26 of the 51 isolates, 10 produced PSE-1+OXA-1, 7 produced TEM-1+PSE-1+OXA-1, 6 produced TEM-1+PSE-1, and 3 produced TEM-1+OXA-1. Forty-eight (94.1%) of the 51 isolates had the plasmid-mediated resistance gene flo(ST) to chloramphenicol and tetracycline. Combining enterobacterial repetitive intergenic consensus polymerase chain reaction (ERIC-PCR) and pulsed-field gel electrophoresis (PFGE), 16 distinct patterns were identified, among which patterns IA (35.3%) and IF (27.4%) were considered as epidemic patterns. The dendrogram obtained from S. Typhimurium pulsotypes allowed five clones (S1-S5) to be identified, with two prevalent clones comprising 47.8% (S2) and 27.3% (S4) of the isolates.

Ampicillin Resistance↗

PubMed1996

Schedule-dependent reversion of acquired cisplatin resistance by 5-fluorouracil in a newly established cisplatin-resistant HST-1 human squamous carcinoma cell line.

In vitro continuous stepwise exposure of HST-1 human squamous carcinoma cell line to cisplatin (CDDP) for 12 months resulted in a 3.5-fold stably resistant subline designated HST-1/CP0.2. Compared with parental cells, this cell line showed a 1.8-fold increase in cellular glutathione (GSH) and a 50% reduction in initial numbers of DNA interstrand cross-links (ICLs), despite similar levels of intracellular platinum accumulation. Evaluation of the kinetics of DNA ICL removal at nearly equivalent levels of DNA ICL formation indicated that HST-1/CP0.2 cells appeared to remove DNA ICLs more rapidly than do HST-1 parental cells. Thus, both elevated cellular GSH and increased DNA repair capacity would be the major factors contributing to CDDP resistance. Pretreatment of HST-1/CP0.2 cells with 5-FU, with drug-free intervals of 24 to 48 hr before exposure to CDDP, completely reversed CDDP resistance, or even increased the sensitivity to a level greater than that of parental cells, whereas the opposite sequence had no effect on resistance. In parallel with augmentation of the cytotoxicity, the levels of cellular GSH were significantly reduced over 48 hr by 5-FU pretreatment. However, depletion of cellular GSH using buthionine sulfoximine resulted in partial reversal of CDDP resistance, indicating that reduction of cellular GSH alone is not sufficient for complete reversal of CDDP resistance. Our data, together with evidence that 5-FU modulates the repair of platinum-DNA cross-links, suggest that schedule-dependent, complete reversal of CDDP resistance by 5-FU might be attributed to its inhibitory effects on both GSH levels and the repair of platinum-DNA adducts. Thus, optimization for the drug administration schedule is important when aiming at therapeutic synergy and circumvention of acquired CDDP resistance.

Antineoplastic Agents↗

PubMed1997

Mechanism of resistance to cisplatin in a human ovarian-carcinoma cell line selected for resistance to doxorubicin: possible role of p53.

A possible novel mechanism of cross-resistance to cisplatin (CDDP) in the doxorubicin-resistant ovarian-cancer cell line A2780-DX3, which displays atypical multidrug resistance, is presented. A2780-DX3 is found to be more resistant than the parental line A2780 in terms of CDDP-induced cytotoxicity and apoptosis. Resistance is not related to the amount of cross-links. Topoisomerase-II (topII) protein levels were similar in both cell lines, with lower cleavage activity in A2780-DX3 cells. The parental and the doxorubicin-resistant cells expressed the same level of c-erb2, which could be implicated in CDDP resistance. bcl2 was almost undetectable in both cell lines. At the same time, we found strong induction of p53, waf-1 and bax protein levels after CDDP treatment in the A2780, but not in the A2780-DX3, cell line. Treatment of both cell lines with mitomycin C (MMC), which acts with a mechanism different from CDDP, caused equal accumulation of p53 and induction of bax. We found that A2780-DX3 cells exhibit altered cellular localization of p53 protein in comparison with A2780. A significant proportion of p53 in A2780-DX3 cells was found in the cytoplasmic compartment, and CDDP treatment induced a functional p53 protein in the nucleus of A2780 much more strongly than in A2780-DX3, which coincides with an increase of transcriptional activity of p53 in treated A2780 cells. We propose that the cross-resistance to CDDP in the A2780-DX3 cell line may be due to inactivation of a CDDP-dependent p53-accumulation pathway.

Cisplatin↗