Tang Hu, Chen Fangquan, Gao Wanli, Cai Xiutao, Lin Zhi, Kang Rui, Tang Daolin, Liu Jiao
DAMP Laboratory, The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510150, China.
Department of Pediatrics, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China.
iScience. 2024 Jul 26;27(8):110598. doi: 10.1016/j.isci.2024.110598. eCollection 2024 Aug 16.
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive solid malignancy with low 5-year survival and limited treatment options. We conducted an unbiased screening using FDA-approved drug and demonstrated that cetylpyridinium chloride (CPC), a component commonly found in mouthwash and known for its robust bactericidal and antifungal attributes, exhibits anticancer activity against human PDAC cells. CPC inhibited PDAC cell growth and proliferation by inducing paraptosis, rather than apoptosis. Mechanistically, CPC induced paraptosis through the initiation of endoplasmic reticulum stress, leading to the accumulation of misfolded proteins. Subsequently, the endoplasmic reticulum stress to nucleus signaling 1 (ERN1)-mitogen-activated protein kinase kinase kinase 5 (MAP3K5)-p38 mitogen-activated protein kinase (MAPK) signaling pathway was activated, ultimately culminating in the induction of paraptosis. experiments, including those involving patient-derived xenografts, orthotopic models, and genetically engineered mouse models of PDAC, provided further evidence of CPC's effectiveness in suppressing the growth of pancreatic tumors.
胰腺导管腺癌（PDAC）是一种侵袭性很强的实体恶性肿瘤，5年生存率低，治疗选择有限。我们使用美国食品药品监督管理局（FDA）批准的药物进行了一项无偏差筛选，结果表明，十六烷基氯化吡啶（CPC）是一种常见于漱口水的成分，以其强大的杀菌和抗真菌特性而闻名，对人PDAC细胞具有抗癌活性。CPC通过诱导类凋亡而非凋亡来抑制PDAC细胞的生长和增殖。从机制上讲，CPC通过引发内质网应激诱导类凋亡，导致错误折叠蛋白的积累。随后，内质网应激到细胞核信号转导1（ERN1）-丝裂原活化蛋白激酶激酶激酶5（MAP3K5）-p38丝裂原活化蛋白激酶（MAPK）信号通路被激活，最终导致类凋亡的诱导。包括涉及患者来源异种移植、原位模型和PDAC基因工程小鼠模型在内的实验，进一步证明了CPC在抑制胰腺肿瘤生长方面的有效性。
