Azuine Magnus A, Tokuda Harukuni, Takayasu Junko, Enjyo Fumio, Mukainaka Teruo, Konoshima Takao, Nishino Hoyoku, Kapadia Govind J
Laboratory of Natural Drug Products, Department of Pharmaceutical Sciences, School of Pharmacy, Howard University, 2300 4th Street, NW, Washington, DC 20059, USA.
Pharmacol Res. 2004 Feb;49(2):161-9. doi: 10.1016/j.phrs.2003.07.014.
In continuation of our search for novel agents, we have investigated 29 phenothiazines and related tri-heterocyclic compounds as potential cancer chemopreventive agents in a short-term in vitro assay of Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Among the evaluated compounds, chlorpromazine, phenoxazine, ethylpropazine, 9-oxo-9H-thioxanthene-3-carbonitrile-10,10-dioxide, thiothixene and phenothiazine showed profound inhibition of EBV-EA in the in vitro assay. This activity was influenced by a modification of the phenothiazine ring. Replacement of nitrogen in the phenothiazine ring with sulfur atoms decreased the anti-tumor activity. Overall analysis showed that the simple tri-cyclic compound phenoxazine was the most active anti-tumor promoting compound in the test system. Therefore, we assessed the anti-tumor promoting effect of phenoxazine in vivo in two different chemical carcinogen-induced-promotion experimental models in mice namely the 7,12-dimethylbenz(a)anthracene (DMBA) initiated and TPA-promoted ICR mouse skin two-stage carcinogenesis protocol and the peroxynitrite (PN)-induced and TPA-promoted skin carcinogenesis in HOS:HR-1 mouse. Following tumor initiation with DMBA, topical application of 0.0025% phenoxazine to the dorsal initiated mouse skin resulted in a highly significant inhibition of TPA tumor promotion. The compound exhibited remarkable inhibitory effects on the mouse skin tumor promotion in terms of a reduction in tumor multiplicity (>50%) and incidence, accompanied by an extension of the tumor latency. In the PN-induced and TPA-promoted two-stage mouse skin carcinogenesis, oral administration of phenoxazine (0.0025%) for 2 weeks showed profound decrease in both the tumor incidence and burden by more than 20 and 80%, respectively, at 10 weeks of treatment. This was also accompanied by a 20% delay in the tumor latency period. In all the treatment groups, there was no toxicity due to phenoxazine in the treatment groups as compared to the control animals. These significant anti-tumor potentials of phenoxazine either via topical or oral administration might be due to the inherent cytotoxicity of these classes of compounds, which can be utilized in the prevention of development of overt tumors, immunopotentiation, induction of differentiation and apoptosis. In addition, since phenoxazine derivatives and other related phenothiazine compounds in use, as anti-psychotic agents without any reported adverse effect are known to pass the blood-brain barrier, they represent a new class of cancer chemopreventive agents with greater implication in the prevention of brain cancers.
在继续寻找新型药物的过程中，我们研究了29种吩噻嗪类及相关三杂环化合物，作为潜在的癌症化学预防剂，采用肿瘤启动剂十四烷酰佛波醇-13-乙酸酯（TPA）诱导爱泼斯坦-巴尔病毒早期抗原（EBV-EA）激活的短期体外试验。在所评估的化合物中，氯丙嗪、吩恶嗪、乙丙嗪、9-氧代-9H-噻吨-3-甲腈-10,10-二氧化物、硫利达嗪和吩噻嗪在体外试验中对EBV-EA有显著抑制作用。这种活性受吩噻嗪环修饰的影响。用硫原子取代吩噻嗪环中的氮原子会降低抗肿瘤活性。总体分析表明，简单的三环化合物吩恶嗪是测试系统中最具活性的抗肿瘤促进化合物。因此，我们在两种不同的化学致癌物诱导促进的小鼠实验模型中评估了吩恶嗪的体内抗肿瘤促进作用，即7,12-二甲基苯并(a)蒽（DMBA）启动和TPA促进的ICR小鼠皮肤两阶段致癌方案，以及过氧亚硝酸盐（PN）诱导和TPA促进的HOS:HR-1小鼠皮肤致癌。用DMBA启动肿瘤后，将0.0025%的吩恶嗪局部应用于背部已启动的小鼠皮肤，对TPA肿瘤促进有高度显著的抑制作用。该化合物在降低肿瘤多发性（＞50%）和发病率方面对小鼠皮肤肿瘤促进表现出显著的抑制作用，并伴有肿瘤潜伏期的延长。在PN诱导和TPA促进的两阶段小鼠皮肤致癌中，口服吩恶嗪（0.0025%）2周，在治疗10周时，肿瘤发病率和负担分别显著降低超过20%和80%。这也伴有肿瘤潜伏期延迟20%。与对照动物相比，所有治疗组中吩恶嗪均无毒性。吩恶嗪通过局部或口服给药的这些显著抗肿瘤潜力可能归因于这类化合物固有的细胞毒性，可用于预防明显肿瘤的发生、免疫增强、诱导分化和凋亡。此外，由于已知用作抗精神病药物且无任何不良反应报道的吩恶嗪衍生物和其他相关吩噻嗪化合物可通过血脑屏障，它们代表了一类新的癌症化学预防剂，对预防脑癌具有更大的意义。
