Reyes-Castellanos Gabriela, Abdel Hadi Nadine, Gallardo-Arriaga Scarlett, Masoud Rawand, Garcia Julie, Lac Sophie, El Kaoutari Abdessamad, Gicquel Tristan, Planque Mélanie, Fendt Sarah-Maria, Linares Laetitia Karine, Gayet Odile, Guillaumond Fabienne, Dusetti Nelson, Iovanna Juan, Carrier Alice
Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France.
Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
iScience. 2023 May 19;26(6):106899. doi: 10.1016/j.isci.2023.106899. eCollection 2023 Jun 16.
Pancreatic ductal adenocarcinoma (PDAC) remains one of the human cancers with the poorest prognosis. Interestingly, we found that mitochondrial respiration in primary human PDAC cells depends mainly on the fatty acid oxidation (FAO) to meet basic energy requirements. Therefore, we treated PDAC cells with perhexiline, a well-recognized FAO inhibitor used in cardiac diseases. Some PDAC cells respond efficiently to perhexiline, which acts synergistically with chemotherapy (gemcitabine) and in two xenografts . Importantly, perhexiline in combination with gemcitabine induces complete tumor regression in one PDAC xenograft. Mechanistically, this co-treatment causes energy and oxidative stress promoting apoptosis but does not exert inhibition of FAO. Yet, our molecular analysis indicates that the carnitine palmitoyltransferase 1C (CPT1C) isoform is a key player in the response to perhexiline and that patients with high expression have better prognosis. Our study reveals that repurposing perhexiline in combination with chemotherapy is a promising approach to treat PDAC.
胰腺导管腺癌（PDAC）仍然是预后最差的人类癌症之一。有趣的是，我们发现原发性人类PDAC细胞中的线粒体呼吸主要依赖脂肪酸氧化（FAO）来满足基本能量需求。因此，我们用哌克昔林处理PDAC细胞，哌克昔林是一种用于治疗心脏病的公认的FAO抑制剂。一些PDAC细胞对哌克昔林反应有效，它与化疗药物（吉西他滨）协同作用，并在两种异种移植模型中发挥作用。重要的是，哌克昔林与吉西他滨联合使用可使一种PDAC异种移植模型中的肿瘤完全消退。从机制上讲，这种联合治疗会导致能量和氧化应激，从而促进细胞凋亡，但不会抑制FAO。然而，我们的分子分析表明，肉碱棕榈酰转移酶1C（CPT1C）同工型是对哌克昔林反应的关键因素，高表达的患者预后较好。我们的研究表明，将哌克昔林与化疗联合重新用于治疗PDAC是一种很有前景的方法。
