Kogami Mariko, Abe Shinji, Nakamura Hiroyuki, Aoshiba Kazutetsu
Department of Respiratory Medicine, Tokyo Medical University Ibaraki Medical Center, Ami, Ibaraki 300-0395, Japan.
Department of Respiratory Medicine, Tokyo Medical University, Tokyo 160-0023, Japan.
Oncol Lett. 2023 Jun 6;26(1):313. doi: 10.3892/ol.2023.13899. eCollection 2023 Jul.
Fenofibrate (FF) is a peroxisome proliferator- activated receptor (PPAR)-α agonist that is widely used for the treatment of hyperlipidemia. It has been shown to have pleiotropic actions beyond its hypolipidemic effect. FF has been shown to exert a cytotoxic effect on some cancer cells when used at higher than clinically relevant concentrations; on the other hand, its cytoprotective effect on normal cells has also been reported. The present study assessed the effect of FF on cisplatin (CDDP) cytotoxicity to lung cancer cells The results demonstrated that the effect of FF on lung cancer cells depends on its concentration. FF at ≤50 µM, which is a clinically achievable blood concentration, attenuated CDDP cytotoxicity to lung cancer cells, whereas FF at ≥100 µM, albeit clinically unachievable, had an anticancer effect. The mechanism of FF attenuation of CDDP cytotoxicity involved PPAR-α-dependent aryl hydrocarbon receptor (AhR) expression, which in turn stimulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and antioxidant production, resulting in lung cancer cell protection from CDDP-evoked oxidative damage. In conclusion, the present study revealed that FF, at clinically relevant concentrations, attenuated CDDP cytotoxicity to lung cancer cells by enhancing the antioxidant defense system through activation of a pathway that involves the PPAR-α-PPAR response element-AhR xenobiotic response element-Nrf2-antioxidant response element. These findings suggested that concomitant use of FF with CDDP may compromise the efficacy of chemotherapy. Although the anticancer property of FF has recently attracted much attention, concentrations that exceed clinically relevant concentrations are required.
非诺贝特（FF）是一种过氧化物酶体增殖物激活受体（PPAR）-α激动剂，广泛用于治疗高脂血症。已证明它除了具有降血脂作用外，还有多效性作用。当使用高于临床相关浓度时，FF已显示对某些癌细胞具有细胞毒性作用；另一方面，也有报道称其对正常细胞具有细胞保护作用。本研究评估了FF对顺铂（CDDP）对肺癌细胞细胞毒性的影响。结果表明，FF对肺癌细胞的影响取决于其浓度。≤50μM的FF（这是临床上可达到的血药浓度）可减弱CDDP对肺癌细胞的细胞毒性，而≥100μM的FF（尽管临床上无法达到）则具有抗癌作用。FF减弱CDDP细胞毒性的机制涉及PPAR-α依赖性芳烃受体（AhR）的表达，这反过来又刺激了核因子红细胞2相关因子2（Nrf2）的表达和抗氧化剂的产生，从而保护肺癌细胞免受CDDP引起的氧化损伤。总之，本研究表明，在临床相关浓度下，FF通过激活一条涉及PPAR-α-PPAR反应元件-AhR外源性反应元件-Nrf2-抗氧化反应元件的途径来增强抗氧化防御系统，从而减弱CDDP对肺癌细胞的细胞毒性。这些发现表明，FF与CDDP联合使用可能会降低化疗效果。尽管FF的抗癌特性最近备受关注，但需要超过临床相关浓度。
