tNOX (ENOX2) target for chemosensitization-low-dose responses in the hormetic concentration range

An emerging concept of cancer chemotherapy is that of chemosensitization. Most often applied to the treatment of drug-resistance cancers, chemosensitization has utility when such cancers are rendered drug sensitive through treatment with the sensitizing agent. A particularly striking example of chemosensitization is that encountered with the synthetic isoflavene phenoxodiol where patients with taxane- and/or platinum-resistant ovarian carcinoma once again become sensitive to these drugs following treatment with phenoxodiol. The latter appears to be a true chemosensitization in that the phenoxodiol need not be co-administered with the taxane or platinum drugs. Sensitivity is retained many weeks after the phenoxodiol has been cleared from the system. The response appears to be mediated through the primary drug target of phenoxodiol, a cancer-specific cell surface ECTO-NOX or ENOX protein designated tNOX (ENOX2). The ENOX protein family has been previously recognized as a hormetic target. The hypothesis under investigation is that chemosensitization and low dose synergies are most obvious in the hormetic range of concentrations and that the two phenomena, hormesis and chemosensitization, may be related mechanistically. Key words: ECTO-NOX, NADH oxidase, cancer, phenoxodiol, sulforaphane, paclitaxel, cisplatin, HeLa cells, ovarian carcinoma
INTRODUCTION Hormesis is a dose-response phenomenon characterized by low-dose stimulation and a high-dose inhibition (Fig. 1) [1,2]. Hormesis is most often observed in the context of a dose-time-response framework where [...]