<br>脂肪酸合酶抑制剂 C75 通过阻断前列腺癌细胞的脂肪酸摄取来增强细胞毒性和放射增敏活性,Advances in Radiation Oncology

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脂肪酸合酶抑制剂 C75 通过阻断前列腺癌细胞的脂肪酸摄取来增强细胞毒性和放射增敏活性
Advances in Radiation Oncology Pub Date : 2020-09-01 , DOI: 10.1016/j.adro.2020.06.022
Colin Rae ₁ , Georgios I Fragkoulis ₁ , Anthony J Chalmers ₁

Affiliation

与许多其他类型的癌症一样，前列腺癌表达的脂肪酸合酶 (FASN) 水平升高，可以产生更多的脂肪酸，而脂肪酸是能量、信号传导和增殖所需的。由于 FASN 的抑制已被证明可使肿瘤对化疗和放疗敏感，因此我们研究了 C75（一种放射增敏 FASN 抑制剂）的作用，并将其单药和在 2 种前列腺癌细胞系 PC3 和 LNCaP 中的放射增敏活性与替代 FASN 抑制剂进行了比较已进入临床试验阶段。我们还研究了补充血清和脂肪酸对 FASN 抑制剂反应的影响，探讨了与 FASN 抑制、辐射和血清脂质浓度反应中脂肪酸摄取相关的关键蛋白的表达，以及如何调节这些蛋白以提高 FASN 抑制剂的效力。 C75。我们证明 C75 是唯一使细胞对电离辐射敏感的 FASN 抑制剂； FASN 抑制剂 TVB-3166 或奥利司他没有明显的致敏作用。前列腺癌细胞系能够从培养基中吸收脂肪酸，并且脂肪酸的可用性影响这些细胞对 C75 的敏感性，但不影响测试的其他 FASN 抑制剂。 C75 还增加了脂肪酸转运蛋白 FATP1 和 CD36 的表达。此外，用抗体阻断CD36增加了细胞对C75的敏感性。我们认为 C75 的效力受到脂肪酸可用性的影响，并且 FASN 抑制剂与电离辐射组合的有效性可以通过调节脂肪酸的摄取来进一步增强。

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The cytotoxicity and radiosensitizing activity of the fatty acid synthase inhibitor C75 is enhanced by blocking fatty acid uptake in prostate cancer cells

Prostate cancers, like many other types of cancer, express elevated levels of fatty acid synthase (FASN) to make more fatty acids, which are required for energy, signaling, and proliferation. Because inhibition of FASN has been shown to sensitize tumors to chemotherapy and radiation, we studied the effect of C75, a radiosensitizing FASN inhibitor, and compared its single agent and radiosensitizing activities in 2 prostate cancer cell lines, PC3 and LNCaP, with alternative FASN inhibitors that have progressed into clinical trials. We also investigated the effect of serum and fatty acid supplementation on responses to FASN inhibitors, probing expression of key proteins related to fatty acid uptake in response to FASN inhibition, irradiation, and serum lipid concentration and how this may be modulated to increase the potency of C75. We demonstrated that C75 was the only FASN inhibitor to sensitize cells to ionizing radiation; no sensitization was apparent with FASN inhibitors TVB-3166 or Orlistat. The prostate cancer cell lines were able to take up fatty acids from the culture medium, and the availability of fatty acids affected sensitivity of these cells to C75 but not the other FASN inhibitors tested. C75 also increased expression of fatty acid transporter proteins FATP1 and CD36. Furthermore, blocking CD36 with antibody increased the sensitivity of cells to C75. We suggest that the potency of C75 is affected by fatty acid availability and that the effectiveness of FASN inhibitors in combination with ionizing radiation can be further enhanced by regulating fatty acid uptake.

更新日期：2020-09-01

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