Disease relevance of NIGULDIPINE

• B859-35 had no effect on peripheral adenomas/adenocarcinomas, nasal cavity tumors, papillary polyps of larynx/trachea, or liver tumors induced by DEN under ambient air conditions [1].
• In the hamster model, B859-35 had no antiproliferative effect on pulmonary adenomas of Clara cell origin [2].
• The results of this study demonstrate that dexniguldipine has significant activity in the inhibition of canine osteosarcoma micrometastases [3].
• Despite the lack of dose-limiting toxicity, higher doses of dexniguldipine do not appear to be useful for clinical evaluation because of the pharmacokinetic properties of the compound: therefore, 2,500 mg/day is recommended as the daily dose for phase II trials [4].
• In this study, we have tested the hypothesis that dexniguldipine may inhibit the proliferation of lung cancer cells in response to autocrine or exogenous activation of PKC [5].

High impact information on NIGULDIPINE

• On the other hand, a selective antiproliferative effect of the dihydropyridine derivative B859-35 on neuroendocrine lung tumor cells in vivo and in vitro suggests the potential use of such agents as cancer therapeutics [6].
• The demonstrated inhibition of Ca2+/calmodulin and protein kinase C by B859-35 as reported in other in vitro systems suggests interference with such elements of signal transduction pathways as the molecular mechanism of the observed antiproliferative effects [6].
• The studies revealed that 2.5 microM B859-35, a concentration equivalent to the IC50 in cell-free extracts, significantly depresses TPA-induced c-fosCAT expression [7].
• It is demonstrated that B859-35 depresses the TPA-induced alkalinization with an IC50 of 5 microM, indicating that PKC in intact cells and the enzyme in cell-free extracts are equally sensitive to the drug [7].
• At 1 microM phosphatidylserine, half-maximal inhibition (IC50) is obtained at approximately 2.5 microM B859-35 [7].

Chemical compound and disease context of NIGULDIPINE

• We investigated BIBW22 in comparison to dexniguldipine and verapamil as modifier of MDR in blasts of de novo, relapsed or persistent acute myeloid leukemia (AML) in vitro [8].

Biological context of NIGULDIPINE

• This is close to the IC50 for the anti-PKC activity of B859-35 [7].
• B859-35 inhibited cellular proliferation of NIH3T3 cells with an IC50 of approximately 5 microM [7].
• Characterization of the dexniguldipine binding site in the multidrug resistance-related transport protein P-glycoprotein by photoaffinity labeling and mass spectrometry [9].
• The finding that an anti-tumor drug is able to reverse multi-drug resistance makes B-859-35 an interesting drug for cancer treatment [10].
• Upregulation of MDR1 mRNA to 2.7- to 3.8-fold higher levels than control mRNA in BRO/mdr1.1 xenograft tissue occurred after VCR or dexniguldipine at 4-8 h and up to 1.7-fold at 24-28 h after injection [11].

Anatomical context of NIGULDIPINE

• B859-35 was a potent antiproliferative agent in the neuroendocrine line NCI-H727 at concentrations as low as 0.001 pM, while it inhibited cell proliferation in the two other cell lines at concentrations of 100 nM and above [2].
• Studies in NIH 3T3 fibroblasts have provided evidence that dexniguldipine may also inhibit protein kinase C (PKC) [5].

Associations of NIGULDIPINE with other chemical compounds

• The resistance to ilmofosine in multidrug-resistant CCRF/VCR1000 cells cannot be reversed by the potent multidrug resistance modifier dexniguldipine-HCI (B8509-035) [12].
• Interestingly, resistance of F4-6RADR-CsA cells remained reversible for the calcium antagonists verapamil and dihydropyridine B859-35 (dexniguldipine-HCl), indicating that CsA and these compounds interfere with the P glycoprotein function by different pharmacodynamic mechanisms [13].
• Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag/Rij rats [14].
• Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rat colon carcinoma model [15].

Gene context of NIGULDIPINE

• Additionally, one daunorubicin-cytarabine-pretreated refractory AML patient was treated with the oral form of the P-gp modulator drug dexniguldipine and achieved complete remission for a duration of 7 months [16].
• Allosteric regulation of [3H]vinblastine binding to P-glycoprotein of MCF-7 ADR cells by dexniguldipine [17].

Analytical, diagnostic and therapeutic context of NIGULDIPINE

• The MS results, corroborated by MALDI-MS of peptides after one step of Edman analysis, identified the radioactive 7-kDa band as the dexniguldipine-bound, tryptic P-gp peptide, 468-527 [9].
• Dexniguldipine 40 mg/kg intraperitoneally (i.p.) given once 4 h before VCR 1 mg/kg intravenously (i.v.) resulted in increased VCR concentrations in BRO/mdr1.1 xenograft tissue [11].
• Two-dimensional high-performance liquid chromatography at low ng/ml levels of the anti-proliferative agent B859-35 in serum with automated sample clean-up, solid-phase trapping and ultraviolet detection [18].
• Amputation and dexniguldipine as treatment for canine appendicular osteosarcoma [3].

References