Retinoids that regulate cell growth, differentiation, and apoptosis have shown promising results in preclinical studies and in a few clinical trials of
cancer chemoprevention and
therapy. However, the clinical use of
retinoids is limited by resistance of certain malignant cells to their antitumor effects and by side effects. To identify more potent
retinoids, we examined the effects of heteroarotinoids (Hets), new synthetic
retinoids with reduced toxicity, on the growth of human
head and neck squamous cell carcinoma (
HNSCC) lines. Six Hets with different
retinoic acid receptor activation potentials were found to exhibit distinct efficacies. The most potent among the Hets examined,
SHetA2, [[(4-nitrophenyl)amino][2,2,4,4-tetramethyl thiochroman-6-yl)amino] methane-1-
thione], was more effective than either all-trans- or 9-cis-RA. The growth of UMSCC38, the most sensitive among the eight
HNSCC cell lines examined, was suppressed by
ShetA2 in a dose- and time-dependent fashion.
SHetA2-induced apoptosis in UMSCC38 cells was comparable with N-(4-hydroxyphenyl)
retinamide (4HPR).
Reactive oxygen species (ROS) generation in the UMSCC38 cells was increased by
SHetA2, and this effect was suppressed by the
antioxidant butylated hydroxyanisol, which also suppressed
SHetA2-induced apoptosis.
SHetA2 suppressed mitochondrial permeability transition and enhanced
cytochrome c release from mitochondria. Both of these effects were prevented by
cyclosporin A, which also decreased
SHetA2-induced apoptosis.
SHetA2 increased
caspase-3-like activity, and a
caspase-3 inhibitor diminished
SHetA2-induced apoptosis. Several
retinoid receptor antagonists failed to prevent apoptosis induction by
SHetA2. These results demonstrate that
SHetA2 is a potent, receptor-independent, apoptosis inducer that acts on the mitochondria in
HNSCC cells. Further investigation of the potential of
SHetA2 in prevention and
therapy of
HNSCC is warranted also because of much lower toxicities compared with receptor active
retinoids.