Istituto di Biomedicina e Immunologia Molecolare-Consiglio Nazionale delle Ricerche, Via Ugo La Malfa, 153, 90146, Palermo, Italy.
Fondazione Ri.MED, Palermo, Italy.
Cancer Chemother Pharmacol. 2018 Apr;81(4):705-716. doi: 10.1007/s00280-018-3538-3. Epub 2018 Feb 12.
17-oxo-DHA is an electrophilic keto-derivative of the omega-3 fatty acid docosahexaenoic acid (DHA) endogenously generated by cyclooxygenase-2 and a cellular dehydrogenase. 17-oxo-DHA displays anti-inflammatory and cytoprotective actions. DHA, alone or in combination with standard chemotherapy, displays antitumor activity. However, the effects of electrophilic keto-derivatives of DHA on cancer growth have never been evaluated. We investigated whether 17-oxo-DHA, alone or in combination with gemcitabine, displayed antitumor effects. Furthermore, we evaluated whether the enzyme 15-prostaglandin dehydrogenase (15-PGDH) was required for transducing the antitumor effects of DHA.
A panel of five histologically different human non-small cell lung cancer (NSCLC) cell lines was used. Cells were treated with 17-oxo-DHA and gemcitabine, alone or in combination, and apoptosis, proliferation, Fas and FasL expression (mRNA and protein) and active caspase-3/7 and -8 were assessed. Furthermore, an inhibitor of 15-PGDH was used to test the involvement of this enzyme in mediating the antitumor effects of DHA.
17-oxo-DHA (50 µM, 72 h) significantly reduced proliferation, increased cell apoptosis, Fas and FasL expression as well as active caspase-8 and -3/7. When 17-oxo-DHA was given in combination with gemcitabine, stronger effects were observed compared to gemcitabine alone. The enzyme 15-PGDH was required for DHA to promote its full anti-apoptotic effect suggesting that enzymatically generated keto-derivatives of DHA mediate its antitumor actions.
Data herein provided, demonstrate that 17-oxo-DHA displays antitumor effects in NSCLC cell lines. Of note, the combination of 17-oxo-DHA plus gemcitabine, resulted in stronger anticancer effects compared to gemcitabine alone.
17-氧代-DHA 是内源性生成的二十二碳六烯酸（DHA）的环氧合酶-2 和细胞脱氢酶的亲电酮衍生物。17-氧代-DHA 具有抗炎和细胞保护作用。DHA 单独或与标准化疗联合使用具有抗肿瘤活性。然而，DHA 的亲电酮衍生物对癌症生长的影响从未被评估过。我们研究了 17-氧代-DHA 单独或与吉西他滨联合使用是否具有抗肿瘤作用。此外，我们评估了酶 15-前列腺素脱氢酶（15-PGDH）是否需要转导 DHA 的抗肿瘤作用。
使用了一组五种组织学不同的人非小细胞肺癌（NSCLC）细胞系。细胞用 17-氧代-DHA 和吉西他滨单独或联合处理，并评估细胞凋亡、增殖、Fas 和 FasL 表达（mRNA 和蛋白）以及活性 caspase-3/7 和 -8。此外，使用 15-PGDH 的抑制剂来测试该酶在介导 DHA 的抗肿瘤作用中的作用。
17-氧代-DHA（50μM，72 小时）显著降低增殖，增加细胞凋亡、Fas 和 FasL 表达以及活性 caspase-8 和 -3/7。当 17-氧代-DHA 与吉西他滨联合使用时，与单独使用吉西他滨相比，观察到更强的作用。酶 15-PGDH 是 DHA 促进其完全抗凋亡作用所必需的，这表明酶促生成的酮衍生物介导 DHA 的抗肿瘤作用。
本文提供的数据表明，17-氧代-DHA 在 NSCLC 细胞系中具有抗肿瘤作用。值得注意的是，与单独使用吉西他滨相比，17-氧代-DHA 加吉西他滨联合使用可产生更强的抗癌作用。
