Newell S W, Perchellet E M, Gao X M, Chen G, Perchellet J P
Anti-Cancer Drug Laboratory, Kansas State University, Manhattan 66506-4901, USA.
Cancer Lett. 1996 Jan 2;98(2):241-51.
The non-12-O-tetadecanoylphorbol-13-acetate (TPA)-type tumor promoters, okadaic acid (OA) and calyculin-A (CAL-A), which neither interact with the phorbol ester receptor nor directly activate protein kinase C, mimic the stimulatory effects of and thapsigargin on hydroperoxide (HPx) production in mouse epidermis in vivo. The time course and dose dependency for the stimulation of HPx production by O and TPA are similar. HPx production is maximally stimulated 16 h after two applications of 2 nmol of OA at a 48-h interval. However CAL-A is a stimulator of HPx production about 4 times more potent than OA or TPA. Combinations of TPA and OA or CAL-A have subadditive effects on HPx production. The discrepancies between the abilities of various serine/threonine protein phosphatase (PP) inhibitors to stimulate HPx production suggest that PP inhibition alone is not sufficient for this response. Cycloheximide, Ca2+ antagonists, oxypurinol, diphenyliodonium, nordihydroguaiaretic acid, bromophenacyl bromide, antiinflammatory agents, and antihistamines block or decrease OA-stimulated HPx production. Although most of these inhibitors may have more than one action, their effects suggest that protein synthesis, Ca2+, xanthine oxidase and NADPH oxidase activities, the lipoxygenase pathway of arachidonic acid metabolism, and vascular permeability may be involved in the inflammatory and HPx responses that occur after tumor promoter treatment. The increased HPx-producing activity of the epidermis, therefore, may be a common event resulting from the inflammatory and tumor-promoting actions of diverse TPA- and non-TPA-type agents.
非12 - O - 十四烷酰佛波醇 - 13 - 乙酸酯（TPA）型肿瘤促进剂冈田酸（OA）和花萼海绵诱癌素 - A（CAL - A），既不与佛波酯受体相互作用，也不直接激活蛋白激酶C，但它们在体内模拟了佛波酯和毒胡萝卜素对小鼠表皮过氧化氢（HPx）生成的刺激作用。OA和TPA刺激HPx生成的时间进程和剂量依赖性相似。以48小时间隔两次应用2 nmol的OA后16小时，HPx生成受到最大刺激。然而，CAL - A刺激HPx生成的效力约为OA或TPA的4倍。TPA与OA或CAL - A的组合对HPx生成具有亚加性效应。各种丝氨酸/苏氨酸蛋白磷酸酶（PP）抑制剂刺激HPx生成的能力之间的差异表明，仅PP抑制不足以产生这种反应。放线菌酮、钙拮抗剂、氧嘌呤醇、二苯基碘鎓、去甲二氢愈创木酸、溴苯甲酰溴、抗炎剂和抗组胺药可阻断或降低OA刺激的HPx生成。尽管这些抑制剂中的大多数可能具有多种作用，但其作用表明蛋白质合成、钙、黄嘌呤氧化酶和NADPH氧化酶活性、花生四烯酸代谢的脂氧合酶途径以及血管通透性可能参与了肿瘤促进剂处理后发生的炎症和HPx反应。因此，表皮增加的HPx生成活性可能是多种TPA和非TPA型药物的炎症和肿瘤促进作用导致的常见事件。
