Antona Annamaria, Varalda Marco, Roy Konkonika, Favero Francesco, Mazzucco Eleonora, Zuccalà Miriam, Leo Giovanni, Soggia Giulia, Bettio Valentina, Tosi Martina, Gaggianesi Miriam, Riva Beatrice, Reano Simone, Genazzani Armando, Manfredi Marcello, Stassi Giorgio, Corà Davide, D'Alfonso Sandra, Capello Daniela
Department of Translational Medicine, Centre of Excellence in Aging Sciences, University of Piemonte Orientale, 28100 Novara, Italy.
Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, 87-100 Torun, Poland.
Cancers (Basel). 2022 Feb 2;14(3):776. doi: 10.3390/cancers14030776.
Approximately 50% of colorectal cancer (CRC) patients still die from recurrence and metastatic disease, highlighting the need for novel therapeutic strategies. Drug repurposing is attracting increasing attention because, compared to traditional de novo drug discovery processes, it may reduce drug development periods and costs. Epidemiological and preclinical evidence support the antitumor activity of antipsychotic drugs. Herein, we dissect the mechanism of action of the typical antipsychotic spiperone in CRC. Spiperone can reduce the clonogenic potential of stem-like CRC cells (CRC-SCs) and induce cell cycle arrest and apoptosis, in both differentiated and CRC-SCs, at clinically relevant concentrations whose toxicity is negligible for non-neoplastic cells. Analysis of intracellular Ca kinetics upon spiperone treatment revealed a massive phospholipase C (PLC)-dependent endoplasmic reticulum (ER) Ca release, resulting in ER Ca homeostasis disruption. RNA sequencing revealed unfolded protein response (UPR) activation, ER stress, and induction of apoptosis, along with IRE1-dependent decay of mRNA (RIDD) activation. Lipidomic analysis showed a significant alteration of lipid profile and, in particular, of sphingolipids. Damage to the Golgi apparatus was also observed. Our data suggest that spiperone can represent an effective drug in the treatment of CRC, and that ER stress induction, along with lipid metabolism alteration, represents effective druggable pathways in CRC.
约50%的结直肠癌（CRC）患者仍死于复发和转移性疾病，这凸显了对新型治疗策略的需求。药物重新利用正受到越来越多的关注，因为与传统的从头药物发现过程相比，它可能会缩短药物开发周期并降低成本。流行病学和临床前证据支持抗精神病药物的抗肿瘤活性。在此，我们剖析了典型抗精神病药物螺哌隆在结直肠癌中的作用机制。螺哌隆可降低干细胞样结直肠癌细胞（CRC-SCs）的克隆形成潜力，并在分化型和CRC-SCs中诱导细胞周期停滞和凋亡，其临床相关浓度对非肿瘤细胞的毒性可忽略不计。对螺哌隆处理后的细胞内钙动力学分析显示，大量磷脂酶C（PLC）依赖的内质网（ER）钙释放，导致内质网钙稳态破坏。RNA测序显示未折叠蛋白反应（UPR）激活、内质网应激和凋亡诱导，以及IRE1依赖的mRNA降解（RIDD）激活。脂质组学分析显示脂质谱，特别是鞘脂有显著改变。还观察到高尔基体受损。我们的数据表明，螺哌隆可能是治疗结直肠癌的有效药物，内质网应激诱导以及脂质代谢改变是结直肠癌中有效的可药物作用途径。
