Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Institute for Food Toxicology and Analytical Chemistry, University of Veterinary Medicine Hannover, Hannover, Germany.
Int J Cancer. 2020 Mar 15;146(6):1618-1630. doi: 10.1002/ijc.32567. Epub 2019 Jul 25.
MALT1 is a key mediator of NF-κB signaling and a main driver of B-cell lymphomas. Remarkably, MALT1 is expressed in the majority of pancreatic ductal adenocarcinomas (PDACs) as well, but absent from normal exocrine pancreatic tissue. Following, MALT1 shows off to be a specific target in cancer cells of PDAC without affecting regular pancreatic cells. Therefore, we studied the impact of pharmacological MALT1 inhibition in pancreatic cancer and showed promising effects on tumor progression. Mepazine (Mep), a phenothiazine derivative, is a known potent MALT1 inhibitor. Newly, we described that biperiden (Bip) is a potent MALT1 inhibitor with even less pharmacological side effects. Thus, Bip is a promising drug leading to reduced proliferation and increased apoptosis in PDAC cells in vitro and in vivo. By compromising MALT1 activity, nuclear translocation of c-Rel is prevented. c-Rel is critical for NF-κB-dependent inhibition of apoptosis. Hence, off-label use of Bip or Mep represents a promising new therapeutic approach to PDAC treatment. Regularly, the Anticholinergicum Bip is used to treat neurological side effects of Phenothiazines, like extrapyramidal symptoms.
MALT1 是 NF-κB 信号转导的关键介质，也是 B 细胞淋巴瘤的主要驱动因素。值得注意的是，MALT1 也在大多数胰腺导管腺癌 (PDAC) 中表达，但在正常外分泌胰腺组织中不存在。随后，MALT1 被证明是 PDAC 癌细胞中的一个特异性靶点，而不会影响正常的胰腺细胞。因此，我们研究了药理 MALT1 抑制对胰腺癌的影响，并显示出对肿瘤进展的有希望的效果。吩噻嗪衍生物美普嗪 (Mep) 是一种已知的强效 MALT1 抑制剂。最近，我们描述了比哌立登 (Bip) 是一种强效的 MALT1 抑制剂，具有更少的药理副作用。因此，Bip 是一种很有前途的药物，可导致 PDAC 细胞在体外和体内增殖减少和凋亡增加。通过损害 MALT1 活性，可以防止 c-Rel 的核易位。c-Rel 对于 NF-κB 依赖性凋亡抑制至关重要。因此，Bip 或 Mep 的非适应证使用代表了 PDAC 治疗的一种有前途的新治疗方法。通常，Bip 被用来治疗吩噻嗪类药物的神经副作用，如锥体外系症状。
