Modulation by d,l-buthionine-S,R-sulphoximine of etoposide cytotoxicity on human non-small cell lung, ovarian and breast carcinoma cell lines

Mans, Dennis R.A.; Schuurhuis, Gerrit Jan; Treskes, M.; Lafleur, M.V.M.; Retèl, J.; Pinedo, H.M.; Lankelma, J.

doi:10.1016/0959-8049(92)90541-9

Cited by 24 publications

(8 citation statements)

References 21 publications

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“…The effect of cellular GSH depletion on the DATS-induced cell cycle arrest was studied. BSO depletes cellular GSH by inhibiting the activity of γ-glutamylcysteine synthetase, and at the same time, it enhances the cytotoxic effects of DNA topoisomerase inhibitor or alkylating agents ( 20 – 24 ). The cells were incubated with or without 500 μM BSO for 24 h and then treated with 10 μM DATS or DPTS.…”

Section: Resultsmentioning

confidence: 99%

Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells

Hosono

Hosono-Fukao

Inada³

et al. 2008

Carcinogenesis

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Alk(en)yl trisulfides (R-SSS-R′) are organosulfur compounds produced by crushed garlic and other Allium vegetables. We found that these compounds exhibit potent anticancer effects through the reaction with microtubules, causing cell cycle arrest. Nine alk(en)yl trisulfides including dimethyl trisulfide, diethyl trisulfide, dipropyl trisulfide (DPTS), dibutyl trisulfide, dipentyl trisulfide, diallyl trisulfide (DATS), dibutenyl trisulfide, dipentenyl trisulfide and allyl methyl trisulfide were synthesized and added to cultures of HT-29 human colon cancer cells at a concentration of 10 μM. The trisulfides with alkenyl groups such as DATS, but not those with alkyl groups, induced rapid microtubule disassembly at 30–60 min as well as cell cycle arrest during the mitotic phase approximately at 4 h after the treatment. Both DATS-induced microtubule disassembly and the cell cycle arrest were cancelled by the simultaneous treatment of the cancer cells with 2 mM L-cysteine, glutathione (GSH) or N-acetyl-L-cysteine. Reciprocally, L-buthionine-(S,R)-sulfoximine (500 μM), an inhibitor of GSH synthesis, enhanced the power of DATS in inducing the cell cycle arrest. These results indicate that alk(en)yl trisulfide react with sulfhydryl groups in cysteine residues of cellular proteins such as microtubule proteins. Thus, the present study provides evidence that trisulfides with alkenyl groups have potent anticancer activities, at least in part, directed toward microtubules. These findings suggest that alkenyl trisulfides and their structurally related compounds may provide novel and effective anticancer agents.

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Section: Resultsmentioning

confidence: 99%

Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells

Hosono

Hosono-Fukao

Inada³

et al. 2008

Carcinogenesis

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“…As a control, we used S1 cells transfected with an MDR1 cDNA construct. S1 cells contain a low amount of MDR1 mRNA (24) (28). In clonogenic assays, the fraction of surviving colonies was decreased by 15%, indicating that BSO had little toxic effect.…”

Section: Resultsmentioning

confidence: 99%

Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein.

Zaman

Lankelma

Tellingen

et al. 1995

Proc. Natl. Acad. Sci. U.S.A.

436

298

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Multidrug-resistance-associated protein [6][7][8] and is able to decrease cellular drug levels against a concentration gradient (4, 6). However, recent work has also indicated interesting differences between MRP and Pgp. Increased cellular MRP levels are associated with increased reduced glutathione (GSH) S-conjugate carrier (GS-X pump) activity in isolated plasma membrane vesicles (9-11). This suggests that MRP is a GS-X pump (12) present in many, if not all, mammalian cells (9-13). These pumps transport substrates containing a large hydrophobic moiety and at least two negative charges (12, 13), as present in drug GSH Sconjugates. Moreover, recent studies indicate that GS-X pumps are also involved in the export of cisplatin (14-16) and arsenite (11). Indeed, some cell lines overexpressing MRP are moderately resistant to arsenite (4, 11). These results link MRP to older experiments in which resistance to anthracyclines was found to correlate with increased levels of cellular GSH, GSH synthesis, or GSH Stransferases (17)(18)(19). This link is supported by the strong decrease in drug resistance in two MDR lung carcinoma cell lines that overexpress MRP by DL-buthionine (S,R)-sulfoximine (BSO) (20)(21)(22), an inhibitor of y-glutamylcysteine synthetase, the enzyme that catalyzes the first step in GSH synthesis (23). The interpretation of these inhibitor experiments is not unambiguous, however. In both cell lines, other resistance mechanisms (e.g., alterations in topoisomerase II) contribute to resistance, and it is not clear whether the GSH depletion in these cells does not result in membrane damagee.g., by lipid peroxidation. Damage of the plasma membrane could increase drug influx and, hence, decrease resistance. To test whether GSH is specifically required for MDR caused by MRP but not by Pgp, we have analyzed the effects of BSO treatment on lung cancer cells transfected with an expression vector containing either MRP cDNA or MDR1 cDNA. MATERIALS AND METHODSCell Lines. S1(MRP) was obtained after transfection of non-small cell lung cancer SW-1573/S1 cells with an expression vector containing MRP cDNA and a neomycin-resistance marker gene (pRc/RSV-MRP), followed by selection with geneticin (G418) (6). Sl(MDR1) was previously named S1(1.1) (24) and was obtained after transfection of S1 cells with the expression vector pJ3fl (25) containing MDR1 cDNA, followed by selection with 10 nM vincristine. GLC4/ADR is a MRP-overexpressing subline of the non-small cell lung cancer cell line GLC4 and was obtained by selection with doxorubicin (20,21).Clonogenic Survival Assay. In six-well dishes, 400 cells per well were seeded and incubated in medium with or without 25 ,uM BSO for 24 hr prior to incubation with increasing concentrations of drug. After 1 hr, drug was removed, the wells were rinsed with phosphate-buffered saline, and drug-free medium without BSO was added. Seven days after the start of the experiment, the percentage of cells that were able to produce a colony of >50 cells was used as a measure of cell sur...

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“…The GS-X conjugates of etoposide are pumped out of the cell by GS-X pumps encoded by ABCC1, ABCC2, ABCC3 etc (49). Depletion of GSH levels by D,L-buthionine-S,R-sulfoximine treatment enhanced the cytotoxicity of etoposide (50). Thus it appears that total cellular GSH content plus phase-II and phase-III drug detoxification enzymes may be a determinant for etoposide toxicity.…”

Section: Discussionmentioning

confidence: 99%

RNAi-Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy

et al. 2008

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Nuclear factor erythroid-2 related factor-2 (Nrf2) is a redox-sensitive transcription factor that regulates the expression of electrophile and xenobiotic detoxification enzymes and efflux proteins, which confer cytoprotection against oxidative stress and apoptosis in normal cells. Loss of function mutations in the Nrf2 inhibitor, Kelch-like ECH-associated protein (Keap1), results in constitutive activation of Nrf2 function in non-small-cell lung cancer (NSCLC). In this study, we demonstrate that constitutive activation of Nrf2 in lung cancer cells promotes tumorigenicity and contributes to chemoresistance by upregulation of glutathione, thioredoxin and the drug efflux pathways involved in detoxification of electrophiles and broad spectrum of drugs. RNAi-mediated reduction of Nrf2 expression in lung cancer cells induces generation of reactive oxygen species, suppresses tumor growth and results in increased sensitivity to chemotherapeutic drug induced cell death in vitro and in vivo. Inhibiting Nrf2 expression using naked siRNA duplexes in combination with carboplatin significantly inhibits tumor growth in a subcutaneous model of lung cancer. Thus, targeting Nrf2 activity in lung cancers, particularly those with Keap1 mutations, could be a promising strategy to inhibit tumor growth and circumvent chemoresistance.

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Modulation by d,l-buthionine-S,R-sulphoximine of etoposide cytotoxicity on human non-small cell lung, ovarian and breast carcinoma cell lines

Cited by 24 publications

References 21 publications

Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells

Alkenyl group is responsible for the disruption of microtubule network formation in human colon cancer cell line HT-29 cells

Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein.

RNAi-Mediated Silencing of Nuclear Factor Erythroid-2–Related Factor 2 Gene Expression in Non–Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy

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