Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Corneel Heymanslaan 10, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
Department for Life Quality Studies, University of Bologna, C.so d'Augusto 237, 47921 Rimini, Italy.
Biomed Pharmacother. 2022 Oct;154:113662. doi: 10.1016/j.biopha.2022.113662. Epub 2022 Sep 7.
Ferroptosis induction is an emerging strategy to treat cancer and contrast the tricky issue of chemoresistance, which can arise towards apoptosis. This work elucidates the anticancer mechanisms evoked by perillaldehyde, a monoterpenoid isolated from Ammodaucus leucotrichus Coss. & Dur. We investigated and characterized its antileukemic potential in vitro, disclosing its ability to trigger ferroptosis. Specifically, perillaldehyde induced lipid peroxidation, decreased glutathione peroxidase 4 protein expression, and depleted intracellular glutathione on HL-60 promyelocytic leukemia cells. Besides, it stimulated the active secretion of ATP, one of the most crucial events in the induction of efficient anticancer response, prompting further studies to disclose its possible nature as an immunogenic cell death inducer. To preliminarily assess the clinical relevance of perillaldehyde, we tested its ability to induce cell death on patient-derived acute myeloid leukemia biopsies, recording a similar mechanism of action and potency compared to HL-60 cells. To round the study off, we tested its selectivity towards tumor cells and disclosed lower toxicity on normal cells compared to both HL-60 and acute myeloid leukemia biopsies. Altogether, these data depict a favorable risk-benefit profile for perillaldehyde and reveal its peculiar antileukemic potential, which qualifies this natural product to proceed further through the drug development pipeline.
铁死亡诱导是一种治疗癌症的新兴策略，可以对抗细胞凋亡过程中出现的化疗耐药这一棘手问题。本研究阐明了从蒿子（Ammodaucus leucotrichus Coss. & Dur.）中分离得到的单萜化合物——香草醛的抗癌机制。我们研究并表征了其在体外的抗白血病潜力，揭示了其诱导铁死亡的能力。具体而言，香草醛可诱导脂质过氧化，降低谷胱甘肽过氧化物酶 4 蛋白表达，并耗尽 HL-60 早幼粒细胞白血病细胞内的谷胱甘肽。此外，它还刺激了 ATP 的主动分泌，这是诱导有效抗癌反应的最重要事件之一，促使进一步研究揭示其作为免疫原性细胞死亡诱导剂的可能特性。为了初步评估香草醛的临床相关性，我们测试了其在患者来源的急性髓系白血病活检上诱导细胞死亡的能力，发现其与 HL-60 细胞相比具有相似的作用机制和效力。为了完善这项研究，我们还测试了它对肿瘤细胞的选择性，并发现与 HL-60 和急性髓系白血病活检相比，它对正常细胞的毒性较低。综上所述，这些数据描绘了香草醛有利的风险效益比，并揭示了其独特的抗白血病潜力，这使该天然产物有资格进一步通过药物开发管道进行研究。
