TRAM-34 is a selective and potent inhibitor of the intermediate-conductance Ca2+-activated K+ channel (IKCa1, KCa3.1) with Kd of 20 nM. Unlike clotrimazole, TRAM-34 dose not inhibit mammalian cytochrome P450 enzyme (CYP3A4). TRAM-34 displays >200-fold selectivity for IKCa1 over Kv, BKCa, SKCa, Na, CRAC, and chloride channels. TRAM-34 does not exhibit toxicity against a variety of cell lines in vitro or cause obvious deleterious changes in a limited short-term acute toxicity study in rodents. TRAM-34 significantly inhibits the reactivation process of human lymphocytes by mitogenic stimuli, and when in combination with cyclosporin A suppresses T-cell mitogenesis more potently than either compound alone. TRAM-34 significantly inhibits EGF-induced IKCa1 up-regulation, and EGF-stimulated proliferation of A7r5 cells. TRAM-34 treatment at 120 mg/kg/day significantly reduces intimal hyperplasia in rat model of balloon catheter injury (BCI). TRAM-34 inhibits human endometrial cancer (EC) cell proliferation, arrests its cell cycle at G0/G1 phase, and suppresses the development of EC tumors in nude mice. By specifically targeting IKCa1, TRAM-34 treatment inhibits the prostate cancer (PCa) cell proliferation in a dose-dependent manner, involving growth arrest and an accumulation of p21Cip1.
|Cell lines||Human T lymphocytes, Jurkat E6-1, MEL, C2F3, CHO, COS-7, L929, NGP, NLF, and RBL-2H3|
|Preparation method||Exposing cells to TRAM-34 for 48 hours. 48 hours later , cells are harvested by suction (suspension cells) or by trypsinization (adherent cell lines), centrifuged, resuspended in 0.5 mL PBS containing 1 μg/mL propidium iodide (PI), and measured red fluorescence on a FACScan flow cytometer. The percentage of dead cells is determined by their PI uptake, 104 cells of every sample being analyzed.|
|Concentrations||Dissolved in DMSO, final concentration ~10 μM|
|Incubation time||48 hours|
|Animal models||Sprague-Dawley rats subjected to BCI of the left CA by use of a 2F Fogarty embolectomy catheter|
|Formulation||Formulated in peanut oil|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
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