State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, PR China.
State Key Laboratory of Natural Medicines, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing, 210009, PR China; Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 639 Longmian Avenue, Nanjing, 211198, PR China.
Biochem Biophys Res Commun. 2023 Sep 17;673:51-58. doi: 10.1016/j.bbrc.2023.06.062. Epub 2023 Jun 19.
Pancreatic cancer is highly aggressive and lethal, and treatment options for it are limited. Gasdermin E (GSDME) is highly expressed in pancreatic cancer and can induce pyroptosis. In this type of programmed cell death, cells swell and emit large gas bubbles through their plasma membranes. Hence, GSDME induction is potentially an efficacious therapeutic approach against pancreatic cancer. In the present study, we found that the steroidal saponins polyphyllin I (PPI), collettiside III (CCRIS), and paris saponin V (PSV) significantly inhibited PANC-1, AsPC-1, and BxPC-3 cell proliferation. PPI/CCRIS/PSV altered the morphology of PANC-1 cells and induced the release of lactate dehydrogenase (LDH) from them. Therefore, these three constituents caused PANC-1 cells to undergo pyroptosis. This conclusion was confirmed by propidium iodide (PI) staining and flow cytometry assays. The present work also revealed that PPI/CCRIS/PSV induced pyroptosis via GSDME rather than gasdermin D (GSDMD). Whereas PPI/CCRIS/PSV induced caspase-3 to cleave GSDME, it had no such effect on GSDMD. We also established a PANC-1 xenograft tumor model in BALB/c nude mice and administered CCRIS to them as this compound demonstrated the most substantial pyroptotic effect in the in vitro experiments. This treatment significantly inhibited tumor growth in the mice by activating GSDME-dependent pyroptosis. This research demonstrates demonstrate that pyroptosis induction by PPI/CCRIS/PSV has important implications in basic science and clinical medicine. Future investigations should endeavor to determine the benefits and risks associated with the administration of these steroidal saponins as anti-PDAC therapy.
胰腺癌具有高度侵袭性和致命性，其治疗选择有限。Gasdermin E（GSDME）在胰腺癌中高度表达，可诱导细胞发生细胞焦亡。在这种程序性细胞死亡中，细胞通过质膜肿胀并发出大的气泡。因此，GSDME 的诱导可能是治疗胰腺癌的有效方法。在本研究中，我们发现甾体皂苷重楼苷 I（PPI）、盾叶薯蓣皂苷 III（CCRIS）和黄山药皂苷 V（PSV）显著抑制了 PANC-1、AsPC-1 和 BxPC-3 细胞的增殖。PPI/CCRIS/PSV 改变了 PANC-1 细胞的形态，并诱导其释放乳酸脱氢酶（LDH）。因此，这三种成分导致 PANC-1 细胞发生细胞焦亡。这一结论通过碘化丙啶（PI）染色和流式细胞术检测得到了证实。本研究还表明，PPI/CCRIS/PSV 通过 GSDME 而非 GSDMD 诱导细胞焦亡。虽然 PPI/CCRIS/PSV 诱导 caspase-3 切割 GSDME，但对 GSDMD 没有这种作用。我们还在 BALB/c 裸鼠中建立了 PANC-1 异种移植肿瘤模型，并给予 CCRIS 治疗，因为该化合物在体外实验中表现出最显著的细胞焦亡效应。这种治疗通过激活 GSDME 依赖性细胞焦亡显著抑制了小鼠肿瘤的生长。本研究表明，PPI/CCRIS/PSV 诱导的细胞焦亡在基础科学和临床医学中具有重要意义。未来的研究应努力确定这些甾体皂苷作为抗 PDAC 治疗的给药相关的益处和风险。
