Karna Ewa, Pałka Jerzy A
Department of Medicinal Chemistry, Medical Academy of Białystok, Kilińskiego 1, 15-230, Białystok, Poland.
Eur J Pharmacol. 2002 May 17;443(1-3):1-6. doi: 10.1016/s0014-2999(02)01557-1.
The mechanism underlying the anticancer effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is not clear. We addressed the question whether the alterations in collagen content in lung adenocarcinomas reported in previous studies result from dysregulation of gelatinolytic activity and whether the activity is altered by acetylsalicylic acid in vitro. Human lung adenocarcinomas were divided into three groups: well-differentiated (G1), moderately differentiated (G2) and poorly differentiated (G3) tumors. Each group was compared with normal lung tissue with respect to tissue collagen and collagen degradation product content (hydroxyproline assay), gelatinolytic activity (zymography) and the expression of matrix metalloproteinases, MMP-2 and MMP-9 (Western immunoblot). Moreover, in the studied tissues, the effect of acetylsalicylic acid on gelatinolytic activity was measured. The lung adenocarcinoma G1 had a similar collagen content as normal lung tissue but increased amounts of collagen degradation products and free hydroxyproline. These phenomena were accompanied by a marked increase in gelatinolytic activity (MMP-2 and MMP-9) in the G1 tumor. In adenocarcinoma G2, the free hydroxyproline content and gelatinolytic activity were increased, while the collagen and collagen degradation product contents were not markedly altered, compared to control. In contrast, adenocarcinoma G3 had an increased tissue collagen content (by about 60%), decreased percentage of collagen degradation products and similar gelatinolytic activity, compared to normal lung. Acetylsalicylic acid was found to inhibit gelatinolytic activity both in control and adenocarcinoma tissues, preferentially the active forms of gelatinases MMP-2 and MMP-9. The results suggest that human lung adenocarcinoma G1, through an elevated expression of the activated forms of both MMP-2 and MMP-9, may represent a more invasive phenotype than less differentiated tumors G2 or G3. It indicates that lung adenocarcinoma G1 should be considered as a possible target for metalloproteinase inhibitory therapy. Acetylsalicylic acid may be such a therapeutical agent in cancer prevention or early stages of tumor growth.
非甾体抗炎药（NSAIDs）抗癌作用的潜在机制尚不清楚。我们探讨了先前研究报道的肺腺癌中胶原蛋白含量的改变是否源于明胶酶活性的失调，以及体外乙酰水杨酸是否会改变该活性。人肺腺癌分为三组：高分化（G1）、中分化（G2）和低分化（G3）肿瘤。就组织胶原蛋白和胶原蛋白降解产物含量（羟脯氨酸测定）、明胶酶活性（酶谱分析）以及基质金属蛋白酶MMP - 2和MMP - 9的表达（蛋白质免疫印迹法）而言，将每组与正常肺组织进行比较。此外，在研究的组织中，测定了乙酰水杨酸对明胶酶活性的影响。肺腺癌G1的胶原蛋白含量与正常肺组织相似，但胶原蛋白降解产物和游离羟脯氨酸的量增加。这些现象伴随着G1肿瘤中明胶酶活性（MMP - 2和MMP - 9）的显著增加。与对照组相比，腺癌G2中游离羟脯氨酸含量和明胶酶活性增加，而胶原蛋白和胶原蛋白降解产物含量没有明显改变。相反，与正常肺相比，腺癌G3的组织胶原蛋白含量增加（约60%），胶原蛋白降解产物百分比降低，明胶酶活性相似。发现乙酰水杨酸在对照组织和腺癌组织中均能抑制明胶酶活性，优先抑制明胶酶MMP - 2和MMP - 9 的活性形式。结果表明，人肺腺癌G1通过MMP - 2和MMP - 9活性形式的表达升高，可能比低分化肿瘤G2或G3表现出更强的侵袭性表型。这表明肺腺癌G1应被视为金属蛋白酶抑制治疗的可能靶点。乙酰水杨酸可能是癌症预防或肿瘤生长早期阶段的此类治疗药物。
