Sulfinosine enhances doxorubicin efficacy through synergism and by reversing multidrug resistance in the human non-small cell lung carcinoma cell line (NCI-H460/R)
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A resistant non-small cell lung carcinoma cell line—NSCLC (NCI-H460/R) was established in order to investigate the potential of sulfinosine (SF) to overcome multidrug resistance (MDR). The cytotoxicity of doxorubicin (DOX) in NCI-H460/R cells was enhanced by interaction with SF. SF improved the sensitivity of resistant cells to DOX when NCI-H460/R cells were pretreated with SF. Synergism was accompanied by the accumulation of cells in S and G2/M phases. Pretreatment with SF was more potent in improving the sensitivity to DOX than verapamil (VER). The decrease of mdr1 and topo II α expression (assessed by RT-PCR), was consistent with the DOX accumulation assay and cell cycle analysis. Also, SF significantly decreased intracellular glutathione (GSH) concentration. These results point to SF as a potential agent of MDR reversal and a valuable drug for improving chemotherapy of NSCLC.
KeywordsNSCLC Multidrug Resistance, Sulfinosine Doxorubicin Drug Combination, Glutathione
This study was supported by grant #143009B from the Ministry of Science, Republic of Serbia.
- 22.Willis RC, Fujitaki JM, Matsumoto SS (1989) In vitro antitumor activity of sulfinosine, 2-amino-9-(β-D-ribofuranosyl) purine-6-sulfinamide and other related nucleosides. Proc Am Assoc Cancer Res 30:597Google Scholar
- 23.Fujitaki JM, Nord LD, Willis RC (1989) Cellular metabolism of the antitumor nucleoside, sulfinosine, 2-amino-9-(β-D-ribofuranosyl)purine-6-sulfinamide. Proc Am Assoc Cancer Res 30:596Google Scholar
- 25.Riley TA, Finch RA, Vasquez KM (1989) Isolation, identification, synthesis and therapeutic evaluation of selected metabolites of sulfinosine, a novel purine nucleoside analog active against thiopurine refractory experimental leukemia. Proc Am Assoc Cancer Res 30:599Google Scholar
- 26.Crabtree GW, Finch RA, Vasquez KM (1989) Cysteine and glutathione competition for adduct formation with 2-amino-9-(β-D-ribofuranosyl)purine-6-sulfinamide (sulfinosine, fin) modulates therapeutic efficacy. Proc Am Assoc Cancer Res 30:597Google Scholar
- 27.Chou J, Chou TC (1987) (eds) Dose-effect analysis with microcomputers: Quantification of ED50, LD50, synergism, antagonism, low-dose risk, receptor-ligand binding and enzyme kinetics. In Manual and software for IBM-PC. Biosoft, Cambrige, EnglandGoogle Scholar
- 28.Chou TC, Talalay P (1987) (eds) Applications of median-effect principle for the assessment of low-dose risk of carcinogenesis and for the quantification of synergism and antagonism of chemotherapeutic agents. In New Avenues in Development Cancer Chemotherapy, Bristol-Myers Series, New YorkGoogle Scholar
- 33.NicAmhlaoibh R, Heenan M, Cleary I, Touhey S, O’Loughlin C, Daly C et al (1999) Altered expression of mRNAs for apoptosis-modulating proteins in a low level multidrug resistant variant of a human lung carcinoma cell line that also expresses mdr1 mRNA. Int J Cancer 82:368–376PubMedCrossRefGoogle Scholar
- 36.Seminara P, Pastore C, Iascone C, Cicconetti F, Nigita G, Ielapi T, Franchi F (2007) Mitomycin C and etoposide in advanced colorectal carcinoma. A clinical and in vitro experience that focuses the problem of schedule dependence in combination therapy. Chemotherapy 53:218–225PubMedCrossRefGoogle Scholar
- 37.O’Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace AJ, Kohn KW (1997) Characterization of the p53 tumor suppressor pathway in cell lines of the national cancer institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Res 57:4285–4300PubMedGoogle Scholar
- 46.Hasinoff BB, Wu X, Krokhin OV, Ens W, Standing KG, Nitiss JL et al (2005) Biochemical and proteomics approaches to characterize topoisomerase IIalpha cysteines and DNA as targets responsible for cisplatin-induced inhibition of topoisomerase IIalpha. Mol Pharmacol 67:937–947PubMedCrossRefGoogle Scholar