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At least 55 records · Page 3Linked to original sources
PubMed1994

Ouabain-resistant non-small-cell lung-cancer cell line shows collateral sensitivity to cis-diamminedichloroplatinum(II) (CDDP).

We have reported that the cellular uptake of cis-diamminedichloroplatinum(II) (CDDP) was inhibited by an Na+,K(+)-adenosine triphosphatase (ATPase) inhibitor, ouabain, in a human non-small-cell lung-cancer cell line, PC-14, but not in its CDDP-resistant cell line, PC-14/CDDP. [3H]Ouabain binding of PC-14/CDDP was about 50% lower than that of PC-14. Accordingly, we speculated that a decrease in Na+,K(+)-ATPase activity in PC-14/CDDP might contribute to the decrease in cellular CDDP accumulation. To clarify the relationship between the activity or expression of Na+,K(+)-ATPase and cellular CDDP accumulation, we established an ouabain-resistant non-small-cell lung-cancer cell line (PC-14/OB300), which showed 1.9-fold resistance to the cytotoxicity of ouabain. Interestingly, this cell line was 4.2-fold more sensitive to CDDP than PC-14. The accumulation of CDDP in PC-14/OB300 was increased to 2.7-fold that in PC-14. This elevation of CDDP accumulation was not considered to be caused by increased passive diffusion, because the accumulation of CDDP in PC-14/OB300 was also inhibited by ouabain compared to PC-14. As one of the indices of Na+,K(+)-ATPase activity, we determined cellular 86Rb+ influx rates. The 86Rb+ influx rate was 1.5-fold higher in PC-14/OB300 and fell to 0.7-fold in PC-14/CDDP compared with PC-14. The mRNA expression of Na+,K(+)-ATPase was increased in PC-14/OB300 and decreased in PC-14/CDDP. There was no difference in cellular [3H]ouabain binding between PC-14/OB300 and PC-14. It is possible that Na+,K(+)-ATPase of PC-14/OB300 has a different affinity for ouabain from that of PC-14. Our results suggest that the enzyme activity or the level of expression of Na+,K(+)-ATPase may contribute to the cellular uptake of CDDP and determine the sensitivity to CDDP.

Adenocarcinoma↗
PubMed1997

Multienzyme-mediated stable and transient multidrug resistance and collateral sensitivity induced by xenobiotics.

BACKGROUND: Determinants of cellular sensitivity to anticancer drugs include enzymes that catalyze their biotransformation. Coordinated induction of some of these enzymes is known to be caused by a number of dietary constituents, environmental contaminants, pharmacological agents and other xenobiotics, e.g. 3-methylcholanthrene and catechol. Despite the potential for inducing simultaneous changes in tumor cell sensitivity to a wide range of drugs, scant attention has been paid to the impact that dietary constituents and other xenobiotics might have on the therapeutic outcome of cancer chemotherapy. PURPOSE: The aim of this investigation was to demonstrate the potential of xenobiotic-induced multienzyme-mediated stable and transient multidrug resistance/collateral sensitivity in a model system. METHODS: Human breast adenocarcinoma MCF-7/0 cells and a stably oxazaphosphorine-resistant subline thereof, MCF-7/OAP, were grown in the presence of 3-methylcholanthrene (3 microM), catechol (30 microM), or vehicle for 5 days. Spectrophotometric and spectrofluorometric assays were used to quantify catalytic activities and thus cellular levels of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferase, DT-diaphorase, UDP-glucuronosyl transferase and cytochrome P450 1A1. A colony-forming assay was used to quantify cellular sensitivities to several anticancer drugs. RESULTS: Relative to their untreated counterparts, MCF-7/0 and MCF-7/OAP cells treated with 3-methylcholanthrene or catechol transiently expressed elevated levels of cytosolic class 3 aldehyde dehydrogenase, glutathione S-transferase, DT-diaphorase and UDP-glucuronosyl transferase, and were transiently, more resistant to mafosfamide, melphalan, and mitoxantrone, and more sensitive to EO9. Further, MCF-7/0 and MCF-7/OAP cells treated with 3-methylcholanthrene, but not those treated with catechol, transiently expressed elevated levels of cytochrome P450 1A1 and were transiently more sensitive to ellipticine. Relative to MCF-7/0 cells, MCF-7/OAP cells stably overexpressed all but cytochrome P450 1A1 and were stably, more resistant to mafosfamide, melphalan and mitoxantrone, and more sensitive to EO9. Inclusion of relatively specific inhibitors of, or alternative substrates for, the enzymes of interest during drug exposure negated the influence of enzyme overexpression on cellular sensitivities to these agents. Untreated, and 3-methylcholanthrene- or catechol-treated, MCF-7/0 and MCF-7/OAP cells were equisensitive to vincristine and nearly so to doxorubicin. CONCLUSIONS: Collectively, these experiments illustrate the potential for both stable and transient xenobiotic-induced multienzyme-mediated multidrug resistance/collateral sensitivity that, although also the result of a single event, is mechanistically different from, and pertains to a largely different group of anticancer agents than does, the multidrug resistance caused by cell surface multidrug transporters.

Adenocarcinoma↗
PubMed1985

Carbamoylation of glutathione reductase and changes in cellular and chromosome morphology in a rat cell line resistant to nitrogen mustards but collaterally sensitive to nitrosoureas.

A Walker 256 rat carcinoma cell line (WR) with acquired resistance to nitrogen mustards has been found to lack cross-resistance to nitrosoureas. Although total cellular glutathione pools were similar in the parent (WS) and resistant cell lines (WS, 2.5 X 10(-6); WR, 2.0 X 10(-6) mol/mg protein), glutathione reductase activity was 3.98 in WR compared to 8.67 nmol reduced nicotinamide adenine dinucleotide phosphate oxidized per microgram protein per min in WS cells. Treatment of cells with a carbamoylating nitrosourea, N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea, produced a dose-dependent inhibition of glutathione reductase and depletion of thiols in both cell lines. The drug caused no direct DNA strand breakage, but a differential mitotic spindle-chromosome stain showed that spindle formation was inhibited in WR cells at N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea concentrations of greater than 50 microM. In WS cells, mitotic figures were still visible at 100 microM. Chromosomal damage was expressed in both cell lines at concentrations of 25 microM. The number and extent of these aberrations were greater in WR than WS. Observed karyotypic abnormalities included polyploidy, chromosome decondensation, and endoreduplication. In interphase cells, transmission electron microscopy showed that the most prevalent drug-induced lesions included (a) disappearance of plasma membrane filopodia, (b) appearance of membrane blebbing, and (c) development of irregular crescent-shaped nuclei. These morphological and cytogenetic changes correlate with cytotoxic responses of these cell lines to N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea and would be consistent with drug-induced inhibition of glutathione reductase.

Animals↗
PubMed1994

cis-Diamminedichloroplatinum(II) resistant human tumor cell lines are collaterally sensitive to PtCl4(Rh-123)2: evidence for mitochondrial involvement.

Three human tumor cell lines made resistant to cis-diamminedichloroplatinum(II) (CDDP), SCC-25/CP, MCF-7/CP, and C13, are more sensitive to rhodamine-123 [tetrachloroplatinum(II)] [(PtCl4(Rh-123)2] than are the corresponding parental cell lines. The CDDP-resistant cells have higher intracellular concentrations of PtCl4(Rh-123)2 for the same exposure than do the parent cells. Each of the CDDP-resistant cell lines has an increased level of cytochrome c oxidase activity compared with the parent cell lines, indicating that the resistant cells have greater mitochondrial mass or activity than the parent cells. In fact, there was a linear correlation between the increase in cytochrome c oxidase activity and the increased sensitivity to PtCl4(Rh-123)2 in the CDDP-resistant lines. Exposure of the cells to each of the mitochondrial effectors, chloramphenicol, FCCP, oligomycin, or antimycin prior to and during exposure to CDDP or PtCl4(Rh-123)2 had variable effects on the cytotoxicity of the platinum complexes in the parental lines. However, there was a consistent decrease in the cytotoxicity of PtCl4(Rh-123)2 in the CDDP-resistant cells in the presence of the mitochondrial effectors such that, in some cases, the CDDP-resistant lines were now less responsive to PtCl4(Rh-123)2 than were the parent cell lines. These studies indicate that mitochondrial alterations may be an important component of CDDP resistance in these cell lines and that PtCl4(Rh-123)2 may represent a prototype platinum complex useful in the treatment of CDDP resistant tumors.

Adenocarcinoma↗
PubMedDate not supplied

Collateral sensitivity to thaliblastine and/or hyperthermia exhibited by a rat ovarian tumor cell line selected for resistance to cisplatin.

Drug resistance severely limits the effectiveness of clinical cancer chemotherapy. Employment of drugs other than the selected compounds with different mechanisms of action may provide a potential way to improve the therapeutic effects. Thaliblastine (TBL), a natural compound, showed a 2-fold higher cytotoxicity in a cisplatin (DDP) resistant rat ovarian tumor cell line (0-342/DDP) than in its parental sensitive line (0-342), as determined by an antiproliferation assay with 24 h continuous exposure. This phenomenon was also observed following 2 h pulse exposure if combined with heat treatment (40 degrees C). Further escalation of the temperature to 43 degrees C alone brought about 74.7 +/- 17.0% growth inhibition in the sensitive and 97.2 +/- 1.8% in the resistant line. Under this condition, the ID50 of TBL was again only half as much in 0-342/DDP cells as in the parental cells (12 vs 24 micrograms/ml) when compared to the hyperthermic treatment alone. In a colony formation assay with 2 h pulse exposure, the hypersensitivity of the resistant cells to DDP and/or heat was further confirmed. Alkaline elution showed that 24 h continuous treatment with TBL induced DNA single-strand breaks (SSB) in a dose-dependent manner in 0-342/DDP cells, whereas there was almost no DNA-SSB production by TBL in the sensitive line, possibly in part accounting for the hypersensitivity of the DDP resistant cells to TBL. The heat treatment (40 degrees C for 2 h) induced SSB in both lines, which was further enhanced by combination with TBL. This damage was repaired in part in 0-342 but almost completely in 0-342/DDP line after cells grew in drug-free medium for 48 h following the exposure, indicating that resistant cells can more efficiently repair DNA damage by either TBL or hyperthermia. Altogether, these results suggest that TBL may have potential to be used clinically as an alternative in the treatment of cisplatin-resistant malignancies with hyperthermia.

Animals↗
PubMed1996

Novel ex vivo analysis of nonclassical, pleiotropic drug resistance and collateral sensitivity induced by therapy provides a rationale for treatment strategies in chronic lymphocytic leukemia.

Extensive research into mechanisms of cytotoxic drug resistance and subsequent clinical trials of drug resistance modifiers have produced few encouraging results. In this report, we analyze 4,400+ ex vivo Differential Staining Cytotoxicity (DiSC) assay drug response results from patients with chronic lymphocytic leukemia (CLL) to investigate the development of drug resistance during treatment. Patients were untreated (n = 216) or previously treated with various cytotoxic agents (n = 188). Data was processed to identify ex vivo resistance (or sensitivity) induced by treating patients with prednisolone, chlorambucil, cyclophosphamide, anthracycline, or fludarabine. Induced resistance was apparently not associated with any one known mechanism. Treatment with chlorambucil induced a 10-fold sensitivity to steroids; cyclophosphamide induced greater resistance to anthracyclines than alkylating agents; anthracyclines induced greatest resistance to chlorambucil, cisplatin, carboplatin, and cladribine. Patients previously treated with at least two regimens were only 2.16-fold more resistant to CLL drugs than untreated patients, but had significantly reduced survival (median survival, 7.9 months compared with 61.1 months for untreated patients). These results suggest that chlorambucil and/or an antimetabolite should be administered before cyclophosphamide or anthracyclines to delay the onset of extensive pleiotropic drug resistance. Because individual differences in drug sensitivity are considerable, specific guidance could be obtained from ex vivo assay results. Furthermore, as a model for investigating drug resistance mechanisms, fresh CLL lymphocytes represent a useful alternative to drug-resistant cell lines.

Adult↗
PubMed1978

[Transplantability, development and methotrexate sensitivity of mouse leukemia L1210 resistant to olivomycin].

A total of 52-fold passages of leukemia L-1210 were carried out for a year on mice treated intraperitoneally with olivomycin. Prolonged exposure to olivomycin resulted in decreased transplantability of the tumor cells. The tumor cells obtained under the effect of olivomycin were more sensitive (collateral sensitivity) to methotrexate as compared to the cells of the initial strain L-1210. An intramuscular route for transplantation of the tumor cells of leukemia L-1210 is recommended. The dosage intramuscular transplantation of the tumor cells provided simultaneously data on transplantability, tumor size and lifer-time of mice.

Animals↗
PubMed2026

Collateral sensitivity-harnessing microbial vulnerabilities as a solution to antimicrobial resistance.

Bacteria exhibit an evolutionary trade-off through their development of collateral sensitivity (CS) which allows them to resist one antibiotic while becoming more vulnerable to another. This vulnerability offers a compelling therapeutic opportunity by selecting against resistant isolates. Laboratory evolution studies, genome sequencing, deep mutagenesis and use of artificial intelligence and machine learning can design the bespoke strategy against multi-drug-resistant bacteria. This review discusses about recent studies that are rationally designed to harness this evolutionary trade-off for the development of alternative antimicrobial strategies. The translational barriers to the clinical implementation of CS are addressed and evidence-based design principles for optimization of CS-guided therapy are discussed.

Bacteria↗
PubMed1990

Collateral drug sensitivity induced in CPT-11 (a novel derivative of camptothecin)-resistant cell lines.

Collateral drug sensitivity was induced in CPT-11-resistant cell lines (CPT-K and T). Ten of the 19 kinds of antineoplastic agents (especially, 5 of 6 kinds of DNA topoisomerase II inhibiting agents) were effective in inducing collateral drug sensitivity. Alteration of DNA topoisomerase I seemed to be unrelated to acquisition of multidrug resistance.

Antineoplastic Agents, Phytogenic↗