Kikuyama Fumihiro, Suzuki Sayo, Jibiki Aya, Yokoyama Yuta, Kawazoe Hitoshi, Kitanaka Susumu, Nakamura Tomonori
Division of Pharmaceutical Care Sciences, Keio University Graduate School of Pharmaceutical Sciences, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan.
Center for Social Pharmacy and Pharmaceutical Care Sciences Division of Pharmaceutical Care Sciences, Keio University Faculty of Pharmacy, 1-5-30 Shibakoen, Minato-Ku, Tokyo, 105-8512, Japan.
J Nat Med. 2023 Mar;77(2):343-351. doi: 10.1007/s11418-023-01682-1. Epub 2023 Jan 24.
Pancreatic cancer is associated with a poor prognosis; thus, there is an urgent need to develop new and effective treatments. Ingenol mebutate (IM), which is isolated from the latex of Euphorbia peplus, was recently shown to be effective against pancreatic cancer cell lines; however, its mechanism of action has not been fully elucidated. In this study, we focused on the less drug-sensitive pancreatic cancer cell line Panc-1 and compared IM to commercially available anticancer drugs using cell survival assays. In addition, we aimed to identify novel biomolecules that may be involved in the mechanism of action of IM using RNA sequencing, western blotting, and inhibition assays. The IC values after 72 h of exposure to IM and SN-38, drugs to which the Panc-1 cells are most sensitive among the tested anticancer agents, were 43.1 ± 16.8 nM and 165 ± 37 nM, respectively. IM showed a cytostatic effect equal to or greater than that of the clinically used pancreatic cancer therapeutic drugs. RNA sequencing and protein expression analysis revealed that expression of stimulator of interferon genes (STING) increased at low IM concentration, whereas cell viability decreased. Co-exposure of IM and STING inhibitor, H-151, to Panc-1 or MIA PaCa-2 cell lines canceled the growth-inhibitory effects of IM alone. In conclusion, IM may have an efficacy comparable to that of existing pancreatic cancer therapeutic agents on the less drug-sensitive Panc-1 cell line and the immune-related molecule STING plays a role in the mechanism of action of IM.
胰腺癌的预后较差，因此迫切需要开发新的有效治疗方法。从泽漆乳汁中分离出的 ingenol mebutate（IM）最近被证明对胰腺癌细胞系有效；然而，其作用机制尚未完全阐明。在本研究中，我们聚焦于对药物敏感性较低的胰腺癌细胞系 Panc-1，并通过细胞存活试验将 IM 与市售抗癌药物进行比较。此外，我们旨在通过 RNA 测序、蛋白质印迹和抑制试验，鉴定可能参与 IM 作用机制的新型生物分子。在测试的抗癌药物中，Panc-1 细胞对 IM 和 SN-38 最为敏感，暴露于这两种药物 72 小时后的 IC 值分别为 43.1±16.8 nM 和 165±37 nM。IM 显示出与临床使用的胰腺癌治疗药物相当或更强的细胞生长抑制作用。RNA 测序和蛋白质表达分析表明，在低 IM 浓度下，干扰素基因刺激物（STING）的表达增加，而细胞活力下降。将 IM 和 STING 抑制剂 H-151 共同作用于 Panc-1 或 MIA PaCa-2 细胞系，可消除 IM 单独作用时的生长抑制作用。总之，IM 对药物敏感性较低的 Panc-1 细胞系可能具有与现有胰腺癌治疗药物相当的疗效，免疫相关分子 STING 在 IM 的作用机制中发挥作用。
