NKH 477は新型の水溶性ホルスコリン誘導体である[1]。NKH 477はアデニル酸シクラーゼを活性化することでcAMPを上方制御する。アデニル酸シクラーゼは、心筋収縮の増強と血管の拡張に使われる[2]。NKH 477はよく、心不全などの心血管疾患の研究と治療によく使われる[3-4]。
MCF7, HT29, A431, WiDr, RKO, A375, H630, Du145, SW480とSW620細胞で、NKH 477 (100μM；48時間)は癌細胞株の増殖を阻害する[5]。内皮細胞で、NKH477 (0.1-1.0μM；1時間)は濃度依存的にcAMPを増やす[2]。CellSensorTM CRE-bla CHO-K1細胞で、NKH 477 (30nM；5時間)はCRE結合のβ-ラクタマーゼの活性を濃度依存的に誘発する[6]。内皮細胞で、NKH477 (0.01-0.3μM；1時間)は、濃度依存的に、10μMのノルアドレナリンによって誘発される[Ca2+]iと力の相動性と持続性の増加を弱めた[7]。
無特定病原体のLewisラットとbrown-norwayラットで、NKH 477 (1, 2, 3mg/kg；経口；10日間)は同種移植生存率を著しく延ばし、組織組織病理学的拒絶反応を用量依存的に減らした[8]。sprague-dawleyラットで、ラットへの急性または慢性のNKH 477 (1.5mg/kg、腹腔内、9日間)の投与は、その移動と直立行動を減らした[9]。
References:
[1]. Hosono M, Takahira T, Fujita A, et al. Cardiovascular and adenylate cyclase stimulant properties of NKH477, a novel water-soluble forskolin derivative. Journal of cardiovascular pharmacology. 1992 Apr 1; 19(4): 625-634.
[2]. Shafiq J, Suzuki S, Itoh T, Kuriyama H. Mechanisms of vasodilation induced by NKH477, a water-soluble forskolin derivative, in smooth muscle of the porcine coronary artery. Circulation research. 1992 Jul; 71(1): 70-81.
[3]. Fujita A, Takahira T, Hosono M, et al. Improvement of drug-induced cardiac failure by NKH477, a novel forskolin derivative, in the dog heart-lung preparation. The Japanese Journal of Pharmacology. 1992;58(4):375-381.
[4]. Hosoda S, Motomiya T, Katagiri T, et al. Acute Effect of NKH477, a Novel Forskolin Derivative, in Patients with Acute Heart Failure A Multicenter Placebo-Controlled Double-Blind Trial. Rinsho yakuri/Japanese Journal of Clinical Pharmacology and Therapeutics. 1997 Jun 30; 28(2): 583-602.
[5]. Faris Q. Alenzi, Mohamed L. Salem, Waleed G, et al. NKH477 inhibits proliferation and induces apoptosis in a panel of cancer cell lines. Journal of Personalized Medicine. 2010; 24(03): 182-187.
[6]. Xia M, Guo V, Huang R, et al. A cell-based β-lactamase reporter gene assay for the CREB signaling pathway. Current chemical genomics. 2009 Mar 17; 3: 7.
[7]. Ito S, Suzuki S, Itoh T. Effects of a water‐soluble forskolin derivative (NKH477) and a membrane‐permeable cyclic AMP analogue on noradrenaline‐induced Ca2+ mobilization in smooth muscle of rabbit mesenteric artery. British journal of pharmacology. 1993 Nov; 110(3): 1117-1125.
[8]. Nakashima S, Morikawa M, Komatsu K, et al. Antiproliferative effects of NKH477, a forskolin derivative, on cytokine profile in rat lung allografts. The Journal of heart and lung transplantation. 2005 Apr 1; 24(4): 462-469.
[9]. Kofman O, Bersudsky Y. Behavioural effects of NKH-477, a forskolin analogue, on locomotion and rearing in rats. International Journal of Neuropsychopharmacology. 2000 Mar 1; 3(1): 27-33.