PI-103 is a potent cell-permeable multi-target inhibitor that primarily acts on the PI3K and mTOR signaling pathways[1]. PI-103 inhibits PI3K subtypes p110α (8nM), p110β (88nM), p110δ (48nM), and p110γ (158nM), as well as mTOR complexes mTORC1 (20nM) and mTORC2 (83nM), while simultaneously inhibiting DNA-PK activity (2nM)[2]. PI-103 can induce mitochondrial apoptosis and autophagy in cells[3]. PI-103 can restore the sensitivity of cancer cells to radiotherapy and chemotherapy[4].
In vitro, pretreatment of Dalton's lymphoma ascites (DLA) cells with PI-103 (10μM) for 24 hours, followed by stimulation with H₂O₂ (1mM) for 30 minutes, significantly inhibited the PI3K-AKT signaling pathway and induced apoptosis, while reducing the accumulation of reactive oxygen species (ROS)[5]. Pretreatment of Huh7 hepatocellular carcinoma cells with PI-103 (2μM) for 1 hour, followed by stimulation with EGF (2.5nM) for 15 minutes, significantly inhibited the phosphorylation of key proteins in the PI3K/AKT/mTOR signaling pathway and blocked EGF-stimulated cell proliferation[6].
In vivo, intraperitoneal injection of PI-103 (10mg/kg) combined with olaparib (10mg/kg) three times per week, used to treat mouse models implanted with MDA-MB-435S cells for 2 weeks followed by radiotherapy (3Gy per fraction), significantly enhanced the inhibitory effect of radiotherapy on triple-negative breast cancer xenografts[7]. Daily intraperitoneal injection of PI-103 (10mg/kg or 70mg/kg) in FVB/N mice for 8 days to several weeks significantly promoted the growth of melanoma xenografts, while inhibiting thymocyte count and inducing immunosuppression[8].
References:
[1] Park S, Chapuis N, Bardet V, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase and mTOR, has antileukemic activity in AML. Leukemia. 2008 Sep;22(9):1698-706.
[2] Raynaud FI, Eccles SA, Patel S, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther. 2009 Jul;8(7):1725-38.
[3] Djuzenova CS, Fischer T, Katzer A, et al. Opposite effects of the triple target (DNA-PK/PI3K/mTOR) inhibitor PI-103 on the radiation sensitivity of glioblastoma cell lines proficient and deficient in DNA-PKcs. BMC Cancer. 2021 Nov 11;21(1):1201.
[4] Toulany M, Iida M, Keinath S, et al. Dual targeting of PI3K and MEK enhances the radiation response of K-RAS mutated non-small cell lung cancer. Oncotarget. 2016 Jul 12;7(28):43746-43761.
[5] Maurya AK, Vinayak M. PI-103 attenuates PI3K-AKT signaling and induces apoptosis in murineT-cell lymphoma. Leuk Lymphoma. 2017 May;58(5):1153-1161.
[6] Gedaly R, Angulo P, Hundley J, et al. PI-103 and sorafenib inhibit hepatocellular carcinoma cell proliferation by blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways. Anticancer Res. 2010 Dec;30(12):4951-8.
[7] Jang NY, Kim DH, Cho BJ, et al. Radiosensitization with combined use of olaparib and PI-103 in triple-negative breast cancer. BMC Cancer. 2015 Mar 3;15:89.
[8] López-Fauqued M, Gil R, Grueso J, et al. The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells. Int J Cancer. 2010 Apr 1;126(7):1549-61.
PI-103是一种有效的细胞渗透性多靶点抑制剂，主要作用于PI3K和mTOR信号通路[1]。PI-103可抑制PI3K亚型p110α（8nM）、p110β（88nM）、p110δ（48nM）和p110γ（158nM），以及mTOR复合物mTORC1（20nM）和mTORC2（83nM），并同时抑制DNA-PK的活性（2nM）[2]。PI-103可诱导细胞线粒体凋亡和细胞自噬[3]。PI-103可恢复癌细胞的放化疗的敏感性[4]。
在体外，PI-103（10μM）预处理Dalton's淋巴瘤腹水（DLA）细胞24小时，随后以H₂O₂（1mM）刺激30分钟，PI-103显著抑制PI3K-AKT信号通路并诱导细胞凋亡，同时降低活性氧（ROS）积累[5]。PI-103（2μM）预处理Huh7肝癌细胞1小时，随后以EGF（2.5nM）刺激15分钟，PI-103显著抑制PI3K/AKT/mTOR信号通路中关键蛋白的磷酸化，同时阻断EGF刺激的细胞增殖[6]。
在体内，PI-103（10mg/kg）联合奥拉帕尼（10mg/kg）每周三次腹腔注射，用于处理植入MDA-MB-435S细胞的小鼠模型，持续2周后联合3Gy/次放疗。PI-103显著增强了放疗对三阴性乳腺癌异种移植瘤的抑制效果[7]。PI-103（10mg/kg或70mg/kg）每日腹腔注射，用于处理FVB/N小鼠，持续8天至数周。PI-103显著促进了小鼠体内黑色素瘤移植瘤的生长，同时抑制胸腺细胞数量并诱导免疫抑制[8]。