Vacuolin-1 is an effective PIKfyve inhibitor that can protect lysosome maturation to inhibit autophagy[1]. Vacuolin-1 can also specifically regulate intracellular vesicle transport and lysosome function by inhibiting cell permeation and lysosome exocytosis[2]. Vacuolin-1 can be used to prevent viral infections, including Ebola virus and SARS-CoV-2[3]. Vacuolin-1 can protect nerve cells by reducing α-synuclein aggregation[4].
In vitro, after pre-treatment of HL-60 myeloid leukemia cells with Vacuolin-1 (0.25μM), followed by co-treatment with all-trans retinoic acid (1μM) for 24–72h, Vacuolin-1 significantly enhanced the expression of the cell differentiation marker CD11b, the production of reactive oxygen species (ROS), and G1/0 phase cell cycle arrest[5]. After pre-treatment of RBL-2H3 cells and mouse bone marrow-derived mast cells (BMMCs) with Vacuolin-1 (10μM) for 3h, Vacuolin-1 can induce the formation of a large number of vacuoles in both cell types. Vacuolin-1 significantly enhanced exocytosis and membrane repair capacity in RBL-2H3 cells, but inhibited these functions in BMMCs[6].
In vivo, Vacuolin-1 (15 or 30mg/kg) was administered orally once daily for 2 months to 1-month-old MMTV-PyMT transgenic mice. Vacuolin-1 significantly reduced the number of lung metastases, the weight of breast tumors, and the incidence of breast tumors in mice[7]. Vacuolin-1 (100mg/kg) was administered intraperitoneally once daily for 14 days to 1-month-old HA-DAT knock-in mice. Vacuolin-1 significantly blocked the Amphetamine (Amph)-induced loss of the dopamine transporter (DAT) in the striatum[8].
References:
[1] Sano O, Kazetani K, Funata M, et al. Vacuolin-1 inhibits autophagy by impairing lysosomal maturation via PIKfyve inhibition. FEBS Lett. 2016 Jun;590(11):1576-85.
[2] Pronk SD, Schooten E, Heinen J, et al. Single Domain Antibodies as Carriers for Intracellular Drug Delivery: A Proof of Principle Study. Biomolecules. 2021 Jun 22;11(7):927.
[3] Kang YL, Chou YY, Rothlauf PW, et al. Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20803-20813.
[4] Sanyal A, Scanavachi G, Somerville E, et al. Neuronal constitutive endolysosomal perforations enable α-synuclein aggregation by internalized PFFs. J Cell Biol. 2025 Feb 3;224(2):e202401136.
[5] Zhu K, Kazim N, Yue J, et al. Vacuolin-1 enhances RA-induced differentiation of human myeloblastic leukemia cells: evidence for involvement of a CD11b/FAK/LYN/SLP-76 axis subject to endosomal regulation that drives late differentiation steps. Cell Biosci. 2022 Nov 3;12(1):179.
[6] Shaik GM, Dráberová L, Heneberg P, et al. Vacuolin-1-modulated exocytosis and cell resealing in mast cells. Cell Signal. 2009 Aug;21(8):1337-45.
[7] Ye Z, Wang D, Lu Y, et al. Vacuolin-1 inhibits endosomal trafficking and metastasis via CapZβ. Oncogene. 2021 Mar;40(10):1775-1791.
[8] Bagalkot T, Sorkin A. Amphetamine Induces Sex-Dependent Loss of the Striatal Dopamine Transporter in Sensitized Mice. eNeuro. 2024 Jan 29;11(1):ENEURO.0491-23.2023.