Okuno Keisuke, Xu Caiming, Pascual-Sabater Silvia, Tokunaga Masanori, Han Haiyong, Fillat Cristina, Kinugasa Yusuke, Goel Ajay
Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA 91016, USA.
Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.
Pharmaceuticals (Basel). 2022 Sep 28;15(10):1199. doi: 10.3390/ph15101199.
Gemcitabine (Gem)-based chemotherapy is one of the first-line treatments for pancreatic ductal adenocarcinoma (PDAC). However, its clinical effect is limited due to development of chemoresistance. Various naturally occurring compounds, including Berberine (BBR), provide an anti-cancer efficacy with time-tested safety, individually and in combination with chemotherapeutic drugs. Accordingly, we hypothesized that BBR might enhance the chemosensitivity to Gem in PDAC. In this study, cell culture studies using MIA PaCa-2 and BxPC-3 cells, followed by analysis in patient-derived organoids were performed to evaluate the anti-cancer effects of BBR in PDAC. Considering that cancer is a significant manifestation of increased chronic inflammatory stress, systems biology approaches are prudent for the identification of molecular pathways and networks responsible for phytochemical-induced anti-cancer activity, we used these approaches for BBR-mediated chemosensitization to Gem. Firstly, Gem-resistant (Gem-R) PDAC cells were established, and the combination of BBR and Gem revealed superior anti-cancer efficacy in Gem-R cells. Furthermore, the combination treatment induced cell cycle arrest and apoptosis in Gem-R PDAC cells. Transcriptomic profiling investigated the Rap1 and PI3K-Akt signaling pathway as a key regulator of Gem-resistance and was a key mediator for BBR-mediated chemosensitization in PDAC cells. All cell culture-based findings were successfully validated in patient-derived organoids. In conclusion, we demonstrate that BBR-mediated reversal of chemoresistance to Gem manifests through Rap1/PI3K-Akt signaling in PDAC.
基于吉西他滨（Gem）的化疗是胰腺导管腺癌（PDAC）的一线治疗方法之一。然而，由于化疗耐药性的产生，其临床效果有限。包括黄连素（BBR）在内的各种天然化合物，单独或与化疗药物联合使用，都具有经过时间考验的安全性的抗癌功效。因此，我们假设BBR可能会增强PDAC对Gem的化疗敏感性。在本研究中，使用MIA PaCa-2和BxPC-3细胞进行细胞培养研究，随后在患者来源的类器官中进行分析，以评估BBR在PDAC中的抗癌作用。考虑到癌症是慢性炎症应激增加的一个重要表现，系统生物学方法对于识别负责植物化学物质诱导的抗癌活性的分子途径和网络是谨慎的，我们将这些方法用于BBR介导的对Gem的化学增敏作用。首先，建立了吉西他滨耐药（Gem-R）的PDAC细胞，BBR和Gem的联合应用在Gem-R细胞中显示出优异的抗癌效果。此外，联合治疗诱导Gem-R PDAC细胞的细胞周期停滞和凋亡。转录组分析研究了Rap1和PI3K-Akt信号通路作为Gem耐药的关键调节因子，并且是BBR介导的PDAC细胞化学增敏作用的关键介质。所有基于细胞培养的研究结果均在患者来源的类器官中得到成功验证。总之，我们证明BBR介导的对Gem化疗耐药性的逆转通过PDAC中的Rap1/PI3K-Akt信号表现出来。
