Structural rationale for the cross-resistance of tumor cells bearing the A399V variant of elongation factor eEF1A1 to the structurally unrelated didemnin B, ternatin, nannocystin A and ansatrienin B

Abstract The cytotoxic effect of anticancer drugs has been shown to involve induction of apoptosis. We report here that tumor cells resistant to CD95 (APO-1/Fas) -mediated apoptosis were cross-resistant to apoptosis-induced by anticancer drugs. Apoptosis induced in tumor cells by cytarabine, doxorubicin, and methotrexate required the activation of ICE/Ced-3 proteases (caspases), similarly to the CD95 system. After drug treatment, a strong increase of caspase activity was found that preceded cell death. Drug-induced activation of caspases was also found in ex vivo-derived T-cell leukemia cells. Resistance to cell death was conferred by a peptide caspase inhibitor and CrmA, a poxvirus-derived serpin. The peptide inhibitor was effective even if added several hours after drug treatment, indicating a direct involvement of caspases in the execution and not in the trigger phase of drug action. Drug-induced apoptosis was also strongly inhibited by antisense approaches targeting caspase-1 and -3, indicating that several members of this protease family were involved. CD95-resistant cell lines that failed to activate caspases upon CD95 triggering were cross-resistant to drug-mediated apoptosis. Our data strongly support the concept that sensitivity for drug-induced cell death depends on intact apoptosis pathways leading to activation of caspases. The identification of defects in caspase activation may provide molecular targets to overcome drug resistance in tumor cells.

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The 'cross-resistance' in four-terminal resistance measurements on anisotropic bars

Journal of Physics D Applied Physics ◽

10.1088/0022-3727/13/11/019 ◽

1980 ◽

Vol 13 (11) ◽

pp. 2095-2099 ◽

Cited By ~ 2

Author(s):

R G Chambers

Keyword(s):

Cross Resistance ◽

The Cross

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SDX-105 (Treanda™), Active in Non-Hodgkin’s Lymphoma Cells, Induces the Mitotic Catastrophe Death Pathway.

Blood ◽

10.1182/blood.v104.11.4593.4593 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4593-4593 ◽

Cited By ~ 1

Author(s):

Lorenzo M. Leoni ◽

Christina Niemeyer ◽

Heather Bendall ◽

Jack Reifert ◽

Brandi Bailey

Keyword(s):

Tumor Cells ◽

Mechanism Of Action ◽

Chromatin Condensation ◽

Alkylating Agents ◽

Mitotic Catastrophe ◽

Cross Resistance ◽

Pcr Analysis ◽

Dna Damaging Agents ◽

Anti Tumor Activity ◽

In Cells

Abstract SDX-105 (Treanda™) is an alkylating agent with a distinct mechanism of action that has been shown to be active in clinical trials in NHL and CLL patients refractory to traditional DNA-damaging agents. SDX-105 induces unique changes in gene expression in NHL cells and displays a lack of cross resistance with other 2-chloroethylamine alkylating agents. Quantitative PCR analysis confirmed that the G2/M checkpoint regulators Polo-like kinase 1 (PLK-1) and Aurora A kinase (AurkA) are down-regulated in the NHL cell line SU-DHL-1 after 8 hours of exposure to clinically relevant concentrations of SDX-105. No changes in these same genes were observed when cells were exposed to equi-toxic doses of chlorambucil or an active metabolite of cyclophosphamide. Because our previous studies demonstrated that SDX-105 treatment can activate apoptotic cell death pathways, we examined the ability of SDX-105 to induce cytotoxicity in cells unable to undergo ‘classical’ caspase-mediated apoptosis. Multi-drug resistant MCF-7/ADR cells and p53 deficient RKO-E6 colon adenocarcinoma cells were exposed for two or three days to either 50 μM SDX-105 alone or 50 μM SDX-105 and 20 μM pan-caspase inhibitor zVAD-fmk. Although zVAD-fmk was able to inhibit SDX-105 induced increases in Annexin-V-positive cells, microscopic analysis of nuclear morphology using the DNA stain DAPI in cells treated with either SDX-105 alone or in combination with zVAD-fmk showed increased incidence of micronucleation. Multi/micro-nucleation and abnormal chromatin condensation are both hallmarks of mitotic catastrophe and have been observed in tumor cells exposed to microtubule-binding drugs such as the vinca alkaloids and taxanes. Activation of mitotic catastrophe may amplify the cytotoxicity of SDX-105 and its activity in tumor cells where classical apoptotic pathways are inhibited. This may explain, at least in part, the potent anti-tumor activity of SDX-105 in tumor cells refractory to conventional 2-chloroethylamine DNA-damaging agents. Additional studies are ongoing to further elaborate the role of mitotic catastrophe in SDX-105’s mechanism of action. The capacity to induce mitotic catastrophe may explain the anti-tumor activity of SDX-105 in chemotherapy relapsed and resistant patients.

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Cross-Resistance of Pink Bollworm (Pectinophora gossypiella) to Bacillus thuringiensis Toxins

Applied and Environmental Microbiology ◽

10.1128/aem.66.10.4582-4584.2000 ◽

2000 ◽

Vol 66 (10) ◽

pp. 4582-4584 ◽

Cited By ~ 48

Author(s):

Bruce E. Tabashnik ◽

Yong-Biao Liu ◽

Ruud A. de Maagd ◽

Timothy J. Dennehy

Keyword(s):

Bacillus Thuringiensis ◽

Pink Bollworm ◽

Pectinophora Gossypiella ◽

Cross Resistance ◽

Mechanism Of Resistance ◽

Narrow Spectrum ◽

Target Sites ◽

The Cross

ABSTRACT Two strains of pink bollworm (Pectinophora gossypiella) selected in the laboratory for resistance to Bacillus thuringiensis toxin Cry1Ac had substantial cross-resistance to Cry1Aa and Cry1Ab but not to Cry1Bb, Cry1Ca, Cry1Da, Cry1Ea, Cry1Ja, Cry2Aa, Cry9Ca, H04, or H205. The narrow spectrum of resistance and the cross-resistance to activated toxin Cry1Ab suggest that reduced binding of toxin to midgut target sites could be an important mechanism of resistance.

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Elongation Factor 1 from Ascites Tumor Cells: Interaction with Ribosomes and Elongation Factor 2

European Journal of Biochemistry ◽

10.1111/j.1432-1033.1974.tb03789.x ◽

1974 ◽

Vol 48 (2) ◽

pp. 485-493 ◽

Cited By ~ 16

Author(s):

Hans GRASMUK ◽

Robert D. NOLAN ◽

Jurgen DREWS

Keyword(s):

Tumor Cells ◽

Elongation Factor ◽

Ascites Tumor ◽

Elongation Factor 2 ◽

Elongation Factor 1

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PPO2 Mutations in Amaranthus palmeri: Implications on Cross-Resistance

Agriculture ◽

10.3390/agriculture11080760 ◽

2021 ◽

Vol 11 (8) ◽

pp. 760

Author(s):

Pâmela Carvalho-Moore ◽

Gulab Rangani ◽

James Heiser ◽

Douglas Findley ◽

Steven J. Bowe ◽

...

Keyword(s):

Dose Response ◽

High Frequency ◽

High Potential ◽

Target Site ◽

Cross Resistance ◽

Amaranthus Palmeri ◽

Mutation Profile ◽

The Cross

In Arkansas, resistance to protoporphyrinogen IX oxidase (PPO)-inhibiting herbicides in Amaranthus palmeri S. Wats. is mainly due to target site mutations. Although A. palmeri PPO-mutations are well investigated, the cross-resistance that each ppo mutant endows to weed populations is not yet well understood. We aimed to evaluate the response of PPO-resistant A. palmeri accessions, harboring the ppo2 mutations ΔG210 and G399A, to multiple PPO-inhibiting herbicides. Six resistant and one susceptible field accessions were subjected to a dose–response assay with fomesafen, and selected survivors from different fomesafen doses were genotyped to characterize the mutation profile. The level of resistance to fomesafen was determined and a cross-resistance assay was conducted with 1 and 2 times the labeled doses of selected PPO herbicides. The accession with higher predicted dose to control 50% of the population (ED50) had a higher frequency of ΔG210-homozygous survivors. Survivors harboring both mutations, and those that were ΔG210-homozygous, incurred less injury at the highest fomesafen rate tested (1120 g ai ha−1). The populations with a high frequency of ΔG210-homozygous survivors, and those with individuals harboring ΔG210 + G399A mutations, exhibited high potential for cross-resistance to other PPO herbicides. The new PPO–herbicide chemistries (saflufenacil, trifludimoxazin) generally controlled the PPO-resistant populations.

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