dihydropyridines and Leukemia-L5178

Multidrug resistance, the principal mechanism by which cancer cells develop resistance to chemotherapy drugs, is a major factor in the failure of many forms of chemotherapies.. The aim of the study was to investigate the effect of K-2-11 on the reversal of multidrug resistance.. The effects of amphiphilic dihydropyridine derivative K-2-11 were tested on MDR1-expressing mouse lymphoma cells and their parental control. The effects of K-2-11 with and without doxorubicin were studied by determination of cell viability, cell proliferation and production of reactive oxygen species.. K-2-11 caused complete reversal of multidrug resistance of the MDR cells, being much more efficient than the positive control verapamil. Accordingly, the cytotoxic effects of doxorubicin were enhanced by K-2-11, both in the MDR and in parental cell line, while K-2-11 alone did not affect cell viability. K-2-11 also acted as an antioxidant, reducing the cellular generation of reactive oxygen species.. Our results indicate the high potential of K-2-11 as a novel antioxidant with potent MDR-blocking ability that should be studied further for development in adjuvant anticancer treatments.

Topics: Animals; Antioxidants; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Dihydropyridines; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Drug Synergism; Humans; Leukemia L5178; Lymphoma, T-Cell; Mice; Reactive Oxygen Species; Transfection

The aim of this study was to investigate the effects of 3,5-diacetyl- (DP1-DP5) and 3,5-dibenzoyl-1,4-dihydropyridines (DP6-DP11) on vascular functions in vitro, by comparing their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, and to quantify their multidrug resistance (MDR)-reversing activity in L5178 Y mouse T-lymphoma cells transfected with MDR1 gene. In rat aorta, the 11 compounds tested, but 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7), 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP9), 3,5-dibenzoyl-4-(4-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP10) and 3,5-dibenzoyl-4-phenyl-1,4-dihydro-2,6-dimethylpyridine (DP11), antagonized 60 mm K+ (K60)-induced contraction in a concentration-dependent manner, with IC50 (m) values ranging between 5.65 x 10(-7) and 2.23 x 10(-5). The 11 dihydropyridines tested, but DP7, inhibited L-type Ca2+ current recorded in artery myocytes in a concentration-dependent manner, with IC50 (M) values ranging between 1.12 x 10(-6) and 6.90 x 10(-5). The K+ -channel opener cromakalim inhibited the Ca2+ -induced contraction in K30 but not that evoked in K60. On the contrary, DP7 was ineffective in both experimental conditions. When the rings were preincubated with 1 mm Ni2+ plus 1 microm nifedipine, the response to phenylephrine was significantly reduced by 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ), a well-known endoplasmic reticulum Ca2+ -ATPase inhibitor. DP7 had no effects on this model system. In L5178 MDR cell line, the 11 dihydropyridines tested, but 3,5-diacetyl-4-(2-nitrophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP1), 3,5-diacetyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP2) and 3,5-diacetyl-4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP4), exhibited an MDR-reversing activity, with IC50 values ranging between 3.02 x 10(-7) and 4.27 x 10(-5), DP7 being the most potent. In conclusion, DP7 may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of vascular effects. British Journal of Pharmacology (2004) 141, 415-422. doi:10.1038/sj.bjp.0705635

Topics: Animals; Aorta, Thoracic; Cell Line, Tumor; Dihydropyridines; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Leukemia L5178; Mice; Muscle, Smooth, Vascular; Rats; Vasoconstriction