Curcumin inhibits carcinogen and nicotine-induced mammalian target of rapamycin pathway activation in head and neck squamous cell carcinoma
Cancer Prev Res. 2010;3(12):1586-95
Despite of decrease in the prevalence of cigarette smoking, in the USA, 30% of cancer deaths are due to cigarette smoking and 90-95% of diagnosed head and neck squamous cell carcinoma (HNSCC) are tobacco-related with ~40,000 new cases, 13,000 U.S. deaths and 500,000 new cases worldwide. It has been found that cigarette smokers are 3 times more likely to develop smoking-related second primary tumors than non-smokers. Hence, there is urgent need for chemopreventive agents.
Tobacco use at HNSCC diagnosis is a recognized risk factor for second primary tumors (SPTs), and current smokers are 3 times more likely than never-smokers to develop smoking-related SPT (6), indicating a need for chemopreventive agents among tobacco users.
One promising agent is Curcumin, which has been implicated as a powerful therapeutic agent in several human cancers, as it has the ability to block tumor initiation and progression in several types of cancers.
To examine the effects of Curcumin on HNSCC growth in a variety of HNSCC cell lines, xenograft model and in a carcinogen-induced survival study.
- Three HNSCC cell lines, FaDu, SCC25 and OKF6 were evaluated for influence of Curcumin on cell proliferation and cell motility
- In the xenograft model, Balb/c nu/nu mice (4-6 weeks old) were injected SCC40 cells
- Once tumors reached 40 mm3, treatment was initiated with Curcumin (0, 5, 10 or 15 mg) (considered as day 0)
- Similarly, 10 Balb/c nu/nu mice per group were pretreated for 4 days with Curcumin (0, 10 or 15 mg) and injected with SCC40 cells, to determine the chemopreventive effects of Curcumin prior to grafting
- Mice continued to receive curcumin for the remainder of the study and the control group received vehicle only
- Tumor volumes were compared on day 24, the last day when all control mice were still alive
- In oral carcinogen-induced model, 24 CBA/CaJ mice (4-6 weeks old) were painted in their oral cavity with 5 mg/mL (3 times per week) tobacco-derivative 4-nitroquinoline 1-oxide (4NQO), to mimic tobacco-induced carcinogenesis in humans for 20 weeks and followed up to 50 weeks
- Simultaneously, mice were also painted with 0, 5, 10 or 15 mg Curcumin (5 times per week) to determine its anticarcinogenic activity
Results and Discussion:
- Cell proliferation assay demonstrated that HNSCC cells were more sensitive to Curcumin compared to normal cells after 72 h
- In xenograft model, a significant reduction in tumor volume was observed with 15 mg of Curcumin at day 5 and day 8, compared to control
- In oral carcinogen-induced model, Curcumin inhibited oral tumor growth compared with control with no visible tumors formed in the highest curcumin dose (15 mg) group
- Curcumin inhibited gene products modulated by the mTOR pathway induced by nicotine both in vitro and in vivo
Curcumin effectively inhibited the adverse effects of nicotine by blocking nicotine-induced activation of the AKT/MTOR pathway in HNSCC, in turn retarding cell migration, suggesting that Curcumin may be useful as an oral chemopreventive agent.