Background

Epidemiological studies indicate that aspirin consumption reduces the risk of tumors, which is especially relevant for colonic adenoma and carcinoma. Similar observations were made for glial brain tumors and breast cancers, yet the results are inconsistent. Gentisic acid (GA) is a minor catabolite of aspirin; yet humans carrying CYP2C9-variants incapable to catabolize aspirin to GA do not benefit from aspirin in prevention against colonic adenoma. GA blocks binding of Fibroblastic Growth Factor to its receptor and its sulphonate metabolite dobesilic acid blocks growth of C6 glioblastoma in vivo. GA is also an endogenously produced siderophore in mammalians for the transport of iron, a trace element which stimulates tumor growth and enhances anthracycline cardiotoxicity.

Materials and Methods

In this study, we assessed whether GA exerts direct antitumor activity on C6 glioma cells in vitro (cytotoxicity, colony growth, 3H-thymidine labeling analysis of DNA synthesis); and whether it can modify growth of Ehrlich breast ascites carcinoma (EAC) and solid tumors (EST) in vivo. GA and antitumoral trace element selenium block 12-lipoxygenase activity and aspirin's paradoxical inflammatory effects are seen in selenium-deficient humans; thus, we also investigated antitumor interactions between GA and sodium selenite. Lastly, we evaluated whether GA could protect against doxorubicin cardiotoxicity due to its function to chelate iron.

Results

Clinically achievable doses of GA blocked growth, colony formation and DNA synthesis of C6 glioma in vitro with high significance. GA enhanced the survival of EAC-bearing mice at a dosage of 0.4 mg/mice/day, in which 33% of the treated animals survived more than 3-weeks, when all untreated mice succumbed to their tumors. Selenium decreased EST volumes initially, yet increased tumor volumes at later stages in surviving mice. GA alone reduced solid tumor growth and did not modify selenite antineoplasticity initially, but blocked the late tumor-stimulating effects of selenite. Lastly, doxorubicin-induced cardiac myofibrillary and endothelial damage and hyalinization necrosis were attenuated with GA treatment.

Conclusions

GA highly merits to be studied in further animal models as an anticancer and chemoprotective drug.

中文翻译：

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从流行病学到治疗：阿司匹林对脑癌和乳腺癌的预防以及心脏保护作用可能与其代谢产物龙胆酸有关

背景

流行病学研究表明，服用阿司匹林可降低患肿瘤的风险，这与结肠腺瘤和癌特别相关。对于神经胶质脑肿瘤和乳腺癌也进行了类似的观察，但结果不一致。龙胆酸（GA）是阿司匹林的次要分解代谢产物。然而，携带不能将阿司匹林分解代谢为GA的CYP2C9变体的人在预防结肠腺瘤中并未受益于阿司匹林。GA阻断了成纤维细胞生长因子与其受体的结合，磺酸代谢物dobesilic acid阻断了C6胶质母细胞瘤在体内的生长。GA在哺乳动物中也是内源性产生的铁载体，用于铁的运输，铁是一种微量元素，可刺激肿瘤生长并增强蒽环类药物的心脏毒性。

材料和方法

在这项研究中，我们评估了GA是否在体外对C6胶质瘤细胞具有直接的抗肿瘤活性（细胞毒性，菌落生长，DNA合成的3H-胸苷标记分析）；以及它是否可以在体内改变Ehrlich乳腺癌腹水癌（EAC）和实体瘤（EST）的生长。在缺乏硒的人中发现了GA和抗肿瘤微量元素硒会阻断12-脂氧合酶的活性，并导致阿司匹林的矛盾性炎症作用。因此，我们还研究了GA与亚硒酸钠之间的抗肿瘤相互作用。最后，我们评估了GA是否具有螯合铁的功能，因此可以预防阿霉素的心脏毒性。

结果

临床上可达到的剂量的GA可以在体外阻断C6胶质瘤的生长，集落形成和DNA合成，具有重要意义。GA以0.4 mg /小鼠/天的剂量提高了带有EAC的小鼠的存活率，其中，当所有未治疗的小鼠都死于其肿瘤时，其中33％的治疗过的动物存活超过3周。硒最初降低了EST的体积，但在存活小鼠的后期却增加了肿瘤的体积。单独的GA降低了实体瘤的生长，最初并未改变亚硒酸盐的抗肿瘤能力，但阻止了亚硒酸盐的晚期肿瘤刺激作用。最后，用GA治疗减弱了阿霉素引起的心肌纤维和内皮损伤以及透明质化坏死。

结论

GA高度值得作为抗癌和化学保护药物在其他动物模型中进行研究。