Chun Kyung-Hee, Benbrook Doris M, Berlin K Darrell, Hong Waun Ki, Lotan Reuben
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer Res. 2003 Jul 1;63(13):3826-32.
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.
维甲酸可调节细胞生长、分化和凋亡，在临床前研究以及癌症化学预防和治疗的一些临床试验中已显示出有前景的结果。然而，维甲酸的临床应用受到某些恶性细胞对其抗肿瘤作用的抗性以及副作用的限制。为了鉴定更有效的维甲酸，我们研究了杂芳维甲酸（Hets），即毒性降低的新型合成维甲酸，对人头颈部鳞状细胞癌（HNSCC）细胞系生长的影响。发现六种具有不同视黄酸受体激活潜能的Hets表现出不同的功效。在所研究的Hets中，最有效的SHetA2，[[(4-硝基苯基)氨基][2,2,4,4-四甲基硫代色满-6-基)氨基]甲烷-1-硫酮]，比全反式或9-顺式视黄酸更有效。在所检测的八种HNSCC细胞系中最敏感的UMSCC38细胞的生长，被SHetA2以剂量和时间依赖性方式抑制。SHetA2诱导UMSCC38细胞凋亡的作用与N-(4-羟基苯基)视黄酰胺（4HPR）相当。SHetA2增加了UMSCC38细胞中活性氧（ROS）的产生，而抗氧化剂丁基羟基茴香醚抑制了这种作用，该抗氧化剂也抑制了SHetA2诱导的凋亡。SHetA2抑制线粒体通透性转换并增强细胞色素c从线粒体的释放。这两种作用都被环孢素A阻止，环孢素A也减少了SHetA2诱导的凋亡。SHetA2增加了半胱天冬酶-3样活性，并且半胱天冬酶-3抑制剂减少了SHetA2诱导的凋亡。几种维甲酸受体拮抗剂未能阻止SHetA2诱导的凋亡。这些结果表明，SHetA2是一种有效的、不依赖受体的凋亡诱导剂，作用于HNSCC细胞中的线粒体。鉴于与受体活性维甲酸相比毒性低得多，因此有必要进一步研究SHetA2在HNSCC预防和治疗中的潜力。
