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Curcumin appears to be a safe, bioactive food compound that is a potential chemopreventive for patients at a high risk for head and neck squamous cell carcinoma (HNSCC). Identification and validation of intermediate endpoints is an important step in evaluating chemopreventive agents. AKT/MTOR pathway biomarkers are intrinsic to the carcinogenic process as well as the mechanism of intervention with curcumin. Antiproliferative effects of curcumin were assayed in 9 HNSCC and a keratinocyte cell line. Nicotine, a genotoxic alkaloid involved in tobacco addiction, forms DNA adducts and has been implicated in upper aerodigestive tract cancer promotion. The antiproliferative effects of curcumin were associated with inhibition of the AKT/MTOR pathway in presence and absence of nicotine, which also induced this pathway. Curcumin was highly effective at suppressing growth of SCC40 xenografts and its activity is associated with modulation of MTOR's downstream target pS6. Curcumin at 15 mg significantly increased survival (286 ± 37 vs. 350 days) in the 4NQO carcinogenic model survival study. A major cause of lethal progression of HNSCC is local regional migration and invasion of malignant cells, and curcumin significantly inhibited cancer cell migration and invasion in vitro and in vivo where downregulation of pS6 was associated with a significant decrease in MMP-9. This is the first study to demonstrate that curcumin inhibits the adverse effects of nicotine by blocking nicotine-induced activation of the AKT/MTOR pathway in HNSCC, which retards cell migration. These studies indicate that inhibiting the AKT/MTOR pathway with curcumin may be useful as an oral chemopreventive agent., (©2010 AACR.)

1. In confirmation of previous studies, serum obtained from cord blood demonstrated endogenous digoxin-like immunoreactivity (EDLI). Sera from pregnant women in the third trimester also demonstrated EDLI, which disappeared after delivery. 2. Cord serum inhibited the total sodium efflux rate constant of a mixed leucocyte preparation when compared with the effect of control serum. This inhibition resulted from a depression of the ouabain-sensitive (sodium pump) component of the rate constant. 3. An ultrafiltrate of the serum (mol. wt. less than 30,000) also inhibited ouabain-sensitive leucocyte sodium transport when compared with filtrate obtained from control serum. 4. DHA-S Dehydroepiandrosterone sulphate (DHA-S) and cortisone, both present in high concentration in cord serum, demonstrated EDLI but did not affect leucocyte sodium transport in the cells of normal subjects. 5. DHA-S had no effect on sodium transport or vasoconstrictor activity in human omental resistance vessels. 6. It is concluded that EDLI of cord serum is associated with sodium transport inhibitory activity. This is unlikely to be attributable to DHA-S or cortisone.