ABSTRACT
Multidrug resistance (MDR) caused by P-glycoprotein (P-gp, ABCB1, MDR-1) transporter over-expression in cancer cells substantially limits the effectiveness of chemotherapy. 1,4-Dihydropyridines (DHPs) derivatives possess several pharmacological activities. In this study, 18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moieties at C3 and C5 positions, respectively, as well as nitrophenyl or hetero aromatic rings at C4 were synthesized and tested for MDR reversal with the aim of establishing a structure-activity relationship (SAR) for these agents. Effect of these compounds on P-gp mediated MDR was assessed in P-gp over-expressing MES-SA/DX5 doxorubicin resistant cells by flow cytometric detection of rhodamine 123 efflux. MDR reversal was further examined as the alteration of doxorubicin׳s IC50 in MES-SA/DX5 cells in the presence of DHPs by MTT assay and was compared to nonresistant MES-SA cells. Direct anticancer effect was examined against 4 human cancer cells including HL-60, K562, MCF-7 and LS180. Calcium channel blocking (CCB) activity was also measured as a potential side effect. Most DHPs, particularly compounds bearing 3-nitrophenyl (A2B2 and A3B2) and 4-nitrophenyl (A3B1 and A4B1) moieties at C4 significantly inhibited rhodamine 123 efflux at 5-25 µM, showing that the mechanism of MDR reversal by these agents is P-gp transporter modulation. Same derivatives were also able to selectively lower the resistance of MES-SA/DX5 to doxorubicin. A2B2 bearing ethyl carboxylate at C5 had also high direct antitumoral effect (IC50 range: 3.77-15.60 µM). Our findings suggest that SAR studies of DHPs may lead to the discovery of novel MDR reversal agents.
Subject(s)
Antineoplastic Agents/pharmacology , Dihydropyridines/pharmacology , Drug Design , Drug Resistance, Multiple/drug effects , Drug Resistance, Neoplasm/drug effects , Neoplasms/drug therapy , ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors , ATP Binding Cassette Transporter, Subfamily B/metabolism , Antibiotics, Antineoplastic/metabolism , Antibiotics, Antineoplastic/pharmacology , Antineoplastic Agents/adverse effects , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Biological Transport/drug effects , Calcium Channels/chemistry , Calcium Channels/metabolism , Cell Line, Tumor , Dihydropyridines/adverse effects , Dihydropyridines/chemical synthesis , Dihydropyridines/chemistry , Doxorubicin/metabolism , Doxorubicin/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Neoplasm Proteins/antagonists & inhibitors , Neoplasm Proteins/metabolism , Neoplasms/metabolism , Stereoisomerism , Structure-Activity RelationshipABSTRACT
It has been proved that hyperhomocysteinemia has a high prevalence in patients with end-stage renal disease (ESRD), which may contribute to the high cardiovascular risk in these patients. Cardiovascular disease is the first cause of high mortality rate in ESRD patients. The aim of the present study was to assess five important factors in patients with ESRD (the amount of homocysteine, IL-6, TNF-alpha, hs-CRP, and Total Antioxidant Capacity). These factors were surveyed in ESRD patients to compare with healthy subjects. In a cross-sectional study, we enrolled 80 patients on maintenance hemodialysis and measured the inflammatory and oxidative stress indicators. The plasma samples were assayed for five above mentioned variables using standard protocols. Two-hour post hemodialysis plasma samples were also assayed for TAC. Plasma levels of inflammation markers, IL-6 and hs-CRP, homocysteine were significantly increased in ESRD group versus control group. This increase was also found in TNF-α levels as compared to the controls, but the differences were not statistically significant. Also, the post dialysis samples had significantly lower levels of TAC as compared to predialysis ones.
