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New Silicon Compounds As Resistance Modifiers Against Multidrug-Resistant Cancer Cells

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New Silicon Compounds As Resistance Modifiers Against Multidrug-Resistant Cancer Cells ANTICANCER RESEARCH 24: 865-872 (2004) New Silicon Compounds as Resistance Modifiers against Multidrug-resistant Cancer Cells J. MOLNAR1, I. MUCSI1, J. NACSA1, A. HEVÉR1, N. GYÉMÁNT1, K. UGOCSAI1, P. HEGYES2, ST. KIESSIG6, D. GAAL5, H. LAGE4 and A. VARGA3 1Albert Szent-Györgyi Medical Center, Faculty of Medicine, Institute of Microbiology and 2Faculty of Natural Science, Department of Organic Chemistry, University of Szeged, Hungary; 3Institute of Biology, Department of Molecular Parasitology and 4Medical Faculty, Institute of Pathology, University of Humboldt, Berlin,Germany; 5National Oncological Institute, Budapest, Department of Animal Trials, Hungary; 6Baxter (Immuno) AG, Heidelberg, Germany Abstract. The efficiency of chemotherapy is often decreased lymphoma cells was increased without down-regulation of the by the development of resistance of cancer cells to cytostatic MDR1 gene expression tested by RT-PCR assay. The drugs. This phenomenon is in most cases caused by the activity rhodamine uptake was increased in L5178/MDR1 and Colo- of the various ABC transporters, multidrug-resistance (MDR) 320/MDR1-LRP, but not drug-sensitive human breast cancer gene-encoded p-glycoproteins, that pump anticancer drugs out MCF-7 and T47D, and L5178 mouse lymphoma parent cells of the cells. The inhibition of the activities of the MDR proteins in the presence of alis-409 and alis-421. The MRP-mediated MDR1 and MRP was investigated via the administration of carboxyfluorescein accumulation in HTB-26/MRP human two new organosilicon compounds, alis-409 and alis-421. The breast cancer cells and daunorubicin accumulation in human study was focused on the inhibition of MDR by blocking the stomach cancer cells 257P/MDR were not modified by these MDR1 gene expression and through the inhibition of the alis compounds. A synergistic interaction between epirubicin pump-function of mdr-p-glycoprotein, in human breast cancer and the silicon-substituted resistance modifiers was found only cell lines expressing mrp and prostate cancer cell line (PC-3). in MDR1-mediated MDR in the case of colo-320/MDR1-LRP Apoptosis induction and the interaction between epirubicin cells and mouse lymphoma cells transfected with the human and the silicon-substituted compounds were studied in human MDR1 gene. The results indicate that the organosilyl MDR-1gene-transfected mouse lymphoma and its parent cell derivatives specifically act on MDR1 p-glycoprotein 170. The line, Colo320/MDR-LRP and sensitive subline Colo205, by alis compounds act on pgp170 in a way which is similar to means of rhodamine 123 accumulation. The activity of MRP1 verapamil isomers. p-glycoprotein was studied in human breast cancer cell lines such as HTB-26/MRP1 and two MRP-negative breast cancer The proportion of chemotherapy-resistant cases in patient cell lines, T47D and MCF7, by carboxyfluorescein populations is continuously growing. The resistance of accumulation, and on a stomach cancer cell line. The activity microbial and cancer cells to chemotherapeutics is a great of MRP in 257P/MDR and its drug-sensitive derivative were challenge in current chemotherapy. One of the most studied in human stomach cancer cells by daunorubicin important forms of resistance is related to an increased drug accumulation in a flow cytometer. The two representative efflux, mediated by an ABC transporter, a p-glycoprotein, organosilicon derivatives, alis-409 and alis-421, showed called the mdr-1 efflux pump, which reduces the antiproliferative effects without apoptosis induction. The drug effectiveness of anticancer drugs against cancer cells. Other accumulation in the human MDR1 gene-transfected mouse p-glycoprotein-mediated drug transporters such as MRP, LRP and BCRP are also related to the increased drug efflux of cancer cells. New treatment procedures frequently produce treatment-resistant cells. The activity of the mdr- Correspondence to: Prof. Joseph Molnar, Institute of Medical membrane transporter protein can be separately inhibited Microbiology, Albert Szent-Györgyi Medical Center, University of Szeged, H-6720 Szeged, Hungary. Tel/Fax: 36-62-545114 / 36-62- in eukaryotic cells by resistance modifier compounds 545113, e-mail: [email protected] independently of the effect of gene regulation. The antiproliferative activities of substituted phenothiazines Key Words: Organosilicon, multidrug resistance, reversal. on various cell lines (such as breast and colon cancer, 0250-7005/2004 $2.00+.40 865 ANTICANCER RESEARCH 24: 865-872 (2004) leukemia, melanoma, ovarian and prostate cancer cells) were EPG85-257RNOV, and the classical MDR variant EPG85- recently observed. Colon cancer exhibits the highest 257RDB have been described previously (5,6). These tumor cells sensitivity against such compounds, followed by leukemia, were grown in Leibovitz L 15 medium (Bio Whittaker, Walkersville, Maryland, USA) supplemented with 10% fetal calf melanoma, prostate, breast and ovarian cancer cells. These serum (GIBCOBRL, Grand Island, NY, USA), 1 mM L-glutamine, data suggest some type-specific antitumor action of certain 6.25 mg/1 fetuin, 80 IU/l insulin, 2.5 mg/1 transferrin, 1 g/1 glucose, compounds. 1.1 g/1 NaHCO3, minimal essential vitamins and 20000 kIU/1 To achieve the most specific mdr-reversal effects, the trasylol in a humidified atmosphere of 5% CO2 at 37ÆC. role of the stereoselectivity of various chemosensitizers was Additionally, the classical MDR line EPG85-257RDB was grown earlier systematically studied (1,2). The pharmacologically by adding 2.5 p g/ml daunorubicin (Farmitalia Carlo Erba, inactive stereoisomers of CNS drugs can be regarded as Freiburg, Germany), and the atypical MDR variant EPG85- 257RNOV was grown at a mitoxantrone (Lederle, Wolfratshausen, possible resistance modifiers for the combination treatment Germany) concentration of 0.2 pg/ml. of drug-resistant cancer without any risk of unexpected side-effects in vivo (2). However, high doses of these Assay for antiproliferative effect. The effects of increasing compounds were required for daunorubicin accumulation concentrations of the drugs alone and their combinations on cell in MDR white blood cells of leukemic patients in ex vivo growth were tested in 96-well flat-bottomed microtiter plates. The studies(3). Based on previous results we decided to compounds were diluted in a volume of 50 ÌL 4 investigate the mdr reversal of the newly synthesized Then, 1 x 10 cells in 0.1 mL medium were added to each well, with the exception of the medium control wells. The culture plates compounds alis-409 and alis-421. In the present paper we were further incubated at 37ÆC for 72 h and at the end of the report on the anticancer and MDR-reversing effects of incubation period 20 ÌL MTT solution (from a 5 mg/mL stock) was these patented organosilicon compounds on mdr mouse added to each well. After incubation at 37ÆC for 4 h, 100 ÌL SDS lymphoma cells transfected with the human MDR1 gene, solution (10%) was measured into each well and the plates were colon cancer cells expressing MDR1-LRP and breast further incubated at 37ÆC overnight. The inhibition of the cell cancer cell lines. growth was determined by measuring the optical density at 550 nm (ref. 630 nm) with a Dynatech MRX vertical beam ELISA reader. Materials and Methods The percentage inhibition of cell growth was determined according to the formula: Chemicals. Compounds alis-409 (1,3-dimethyl-1,3-p-fluorophenyl- 1,3(3-morfolinopropyl)-1,3 disiloxan dihydrochlorid) and alis-421 OD sample - OD medium control 100 - ––––––––––––––––––––––––––––––––––––– x 100 (1,3-dimethyl-1,3-(4-fluorophenyl)-1,3-[3(4-buthyl)-(1piperazinyl)- [ OD cell control – OD medium control ] propyl]-1,3-disiloxan-tetrahydrochlorid). The compounds were originally synthesized by Hegyes et al. (4). The silicion substituted A checkerboard micro-plate method was applied to study the alis compounds and 12H-benzo(a)phenothiazine were dissolved in effects of drug interactions between resistance modifiers and DMSO by preparing stock solutions at a concentration 1.0 mg/ml. doxorubicin on cancer cells. Verapamil (Sigma, St. Louis MO, USA) was dissolved in water The effects of an anticancer drug such as doxorubicin and the (5.0 mg/ml). Annexin-V (human recombinant-FITC) (Alexis resistance modifiers alis-409 and alis-421 in combination were Biochemicals, ALEXIS DEUTCHLAND Gmbh, Grünberg, studied on various cancer cell lines. The dilutions of anticancer Germany) and epirubicin (Pharmacia and Upjohn, Milan, Italy) drug A were made in horizontal direction and the dilutions of were dissolved in deionized water. 3- [4,5-Dimethylthiazol-2-yl] resistance modifiers B vertically in the microtiter plate in 100Ìl 1-2,5-diphenyltetrazolium bromide (MTT) and sodium volume. The cell suspension in tissue culture medium was dodecylsulfate (SDS) were purchased from Sigma. The silyl- distributed to each well in 100 ÌL containing 5x104 cells. The plates compounds are patented in Germany: Patent no. 199 23 801. were incubated for 48 h at 37ÆC in a CO2 incubator. The cell growth rate was determined after MTT staining and the intensity Cell cultures. L5178 (parent) mouse T-cell lymphoma cells and the of the blue color was measured on a micro ELISA reader. Drug human MDR-1-transfected subline were cultured in McCoy's 5A interaction was evaluated according to the following system: medium supplemented with 10% heat-inactivated horse serum L- glutamine and antibiotics. Human cancer cell lines MCF-7, T47-D, FIC = ID / ID Colo 205 parent, Colo 320/MDR-LRP and PC-3 prostate cancer A 50A in combination 50A alone FIC = ID / ID cells were cultured in RPMI supplemented with 10% heat- B 50B in combination 50B alone inactivated fetal bovine serum, and HTB-26 breast cancer cells where FIC=fractional inhibitory concentration were cultured in Leibovitz L-15 medium supplemented with 10% heat-inactivated fetal bovine serum with 2 mM L-glutamine. Most FIX = FICA+FICB of these cell lines were maintained in a humified atmosphere of 5% FIX = 0.51-1 ADDITIVE EFFECT CO2 (except HTB-26, which do not need extra CO2) at 37ÆC.
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