Abstract
We have originally synthesized the naftopidil analogue 1-[2-(2-methoxyphenylamino)ethylamino]-3-(naphthalene-1-yloxy)propan-2-ol (HUHS 1015) as a new anticancer drug. HUHS1015 induces cell death in a wide variety of human cancer cell lines originated from malignant pleural mesothelioma, lung cancer, hepatoma, gastric cancer, colorectal cancer, bladder cancer, prostate cancer, and renal cancer. HUHS1015-induced cell death includes necrosis (necroptosis) and apoptosis, and the underlying mechanism differs depending upon cancer cell types. HUHS1015 effectively suppresses tumor growth in mice inoculated with NCI-H2052, MKN45, or CW2 cells, with a potential similar to or higher than that of currently used anticancer drugs. Here we show how HUHS1015 might offer brilliant hope for cancer therapy.
Highlights
Naftopidil, an antagonist for the α1-adrenoceptor, with high selectivity for α1A- and α1D-receptors, has been clinically used as a drug for treatment of benign prostate hyperplasia and hypertension [1].Accumulating evidence has shown that naftopidil exhibits an anticancer effect
Α1-Adrenoceptor is divided into α1A, α1B, and α1D-subtypes, and the receptor is linked to Gq/11 protein-bearing phospholipase C activation followed by protein kinase C (PKC) activation [6,7,8]
One would speculate that naftopidil should suppress PKC activation by inhibiting the α1-adrenoceptor
Summary
Naftopidil, an antagonist for the α1-adrenoceptor, with high selectivity for α1A- and α1D-receptors, has been clinically used as a drug for treatment of benign prostate hyperplasia and hypertension [1]. Accumulating evidence has shown that naftopidil exhibits an anticancer effect. Naftopidil inhibits prostate cancer cell growth by arresting them at the G1 phase of cell cycling [2,3]. Naftopidil induced cell death for bladder, prostate, renal cancer, and malignant pleural mesothelioma (MPM) cell lines [4,5]. One would speculate that naftopidil should suppress PKC activation by inhibiting the α1-adrenoceptor. The PKC inhibitor GF109203X attenuated naftopidil-induced apoptosis of MPM cells [5]. Knocking down the α1D-adrenoceptor promoted proliferation of MPM cells [5]. These data suggest that naftopidil induces MPM cell death by a mechanism independent of α1-adrenoceptor blocking. We have synthesized 21 naftopidil analogues (Figure 1) and assessed the anticancer effect of each compound
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