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PubMed1989

Differential effect of collaterally sensitive antimetabolites on P388 murine leukemia sensitive and resistant to adriamycin in vitro.

Experiments were carried out in vitro using DNA polymerase and ribonucleotide reductase inhibitors to investigate their cytotoxicity to P388 murine leukemia sensitive (P388/S) and resistant (P388/R) to adriamycin (ADR). DNA polymerase inhibitors such as cytosine arabinoside (ara-C) and aphidicolin elicited comparative inhibition of DNA biosynthesis in both parental and ADR-resistant tumor cells. However, ribonucleotide reductase inhibitors such as hydroxyurea (HU) and caracemide were collaterally more sensitive to P388/R cells. Inosine diglycolaldehyde (Inox) was ineffective in showing such a response. Pretreatment with HU significantly increased intracellular ADR levels and inhibition of RNA biosynthesis by ADR in P388/R cells while, in P388/S cells, sequential or concurrent treatment with HU did not enhance intracellular ADR levels. Mechanisms underlying such an effect, implications due to reduced intracellular ATP levels in drug-resistant cells, and the possible utility of using ribonucleotide reductase as a target in drug-resistant tumors for the therapeutic benefit are discussed.

Animals↗
PubMed1996

Cross-resistance and collateral sensitivity to natural product drugs in cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cells.

The cytotoxicity of mitotic spindle poisons, vinca alkaloids and the anthracycline, adriamycin, against cisplatin-sensitive and -resistant rat lymphoma and human ovarian carcinoma cell lines was investigated. Interestingly, it was found that all cell lines were more sensitive to the mitotic spindle poisons, vincristine and vinblastine. Adriamycin was the least effective and taxol had intermediate activity. The Walker rat lymphoma cell line resistant to cisplatin (WR) exhibited the multiple drug resistance phenotype since it showed collateral resistance to all drugs (ranging from twofold to taxol, colcemid and colchicine and sixfold to the vinca alkaloids). Verapamil potentiated the cytotoxic activity of adriamycin and vincristine in a striking fashion with the Walker cells. P-glycoprotein was found to be present in the plasma membranes of the Walker cells with approximately a 2.5-fold increase in the WR as compared to the sensitive (WS) cells. Glutathione levels were elevated in all of the cisplatin-resistant cell lines when compared to the cisplatin-sensitive parental cell lines. A profound effect of buthionine sulfoximine pretreatment on adriamycin cytotoxicity was observed. Glutathione S-transferase (pi) was present in all the human cell lines but the WS cells had markedly lower levels (almost negligible) when compared to the WR cells. These observations imply that cisplatin-resistant cells may be more sensitive to mitotic spindle poisons and vinca alkaloids, irrespective of the mechanism of platinum resistance, and that the cytotoxicity of vinca alkaloids could be further modulated by verapamil, irrespective of the presence or absence of P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
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↗
PubMed2001

Steroids affect collateral sensitivity to gemcitabine of multidrug-resistant human lung cancer cells.

Gemcitabine is phosphorylated by deoxycytidine kinase and thymidine kinase 2 and during S-phase incorporated into DNA. The steroids cortisol and dexamethasone, which regulate cell proliferation and gene expression, are pumped out of the cell by the membrane efflux pumps P-glycoprotein and multidrug resistance-associated protein (MRP), which are blocked by verapamil. In parental non-small cell lung cancer (NSCLC) cells (SW1573), 5 microM cortisol and 100 nM dexamethasone decreased sensitivity to gemcitabine. However, both cortisol and dexamethasone only decreased sensitivity with verapamil in MRP (2R120) and P-glycoprotein (2R160) overexpressing variants. Cortisol decreased deoxycytidine kinase activity in SW1573 cells and cortisol with verapamil in 2R120 and 2R160 cells. Dexamethasone with verapamil decreased deoxycytidine kinase activity in 2R160. Cortisol decreased thymidine kinase 2 activity in 2R120 and 2R160 cells. Dexamethasone decreased thymidine kinase 2 activity in SW1573, 2R120 and 2R160 cells. In conclusion, since dexamethasone is frequently used to treat side effects of oncolytic therapy, a decrease of sensitivity to gemcitabine by steroids might be clinically relevant.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line: collateral sensitivity to azidothymidine.

Cisplatin (CDDP) resistance is one of the major impediments in cancer chemotherapy. In an attempt to define this complex mechanism(s) of resistance, we have identified 7 cDNA fragments which are overexpressed in CDDP resistant small cell lung cancer cell line (SR-2) using PCR selected cDNA subtraction. One of these fragments was identical with nucleotide 3657-4042 of MRP4. The other fragments share sequence homology with elongation factor alpha, human placenta villi cDNA, heat shock protein (Hsp70), ribosomal RNA, BNP1 brain specific Na-dependent inorganic phosphate cotransporter and telomeric catalytic subunit. Examination of other MRP members (MRP1, 2, 3, 5, 6) did not show discernable differences in their expression between the parental (SCLC1) and the CDDP-resistant variant (SR-2). Full length MRP4 cDNA was obtained from SCLC1 and SR-2. Both cell lines carry a point mutation at nucleotide 3532 while SR-2 carries two additional mutations at 3228 and 3246. Since MRP4 is known to transport azidiothymidine (AZT) and overexpression of MRP4 confers AZT resistance, we have studied growth inhibitory effects of AZT and [3H]-AZT accumulation. Interestingly, SR-2 is more sensitive to AZT while accumulating lesser amounts of [3H]-AZT. The thymidine kinase activity is similar in both cell lines. Thus, the increased sensitivity to AZT in SR-2 could not be solely due to mutation of MRP4. These findings are most likely due to the inhibitory effects of telomere catalytic subunit by AZT. Thus, certain biochemical changes induced by CDDP can be explored for future treatment to overcome this form of resistance.

Blotting, Northern↗
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↗