IITZ-01, a novel potent lysosomotropic autophagy inhibitor, has single-agent antitumor efficacy in triple-negative breast cancer in vitro and in vivo

Oncogene
Lalita GuntukuNaidu G M Vegi

Abstract

Autophagy is a homeostatic process that recycles damaged organelles and long-lived proteins by delivering them in double-membrane vesicles to lysosomes for degradation. Autophagy has a prominent role in survival, proliferation, and resistance of tumors in metabolic and chemotherapeutic stress conditions. Clinical trials with chloroquine-a known autophagy inhibitor-were unable to achieve complete autophagy inhibition in vivo, warranting the search for more potent autophagy inhibitors. In a process of exploring the mechanism of action of previously identified cytotoxic s-triazine analogs, we discovered that both IITZ-01 and IITZ-02 act as potent autophagy inhibitors. Treatment with these compounds resulted in the vacuolated appearance of cells due to their specific accumulation in lysosomes. In addition, these basic compounds also deacidify lysosomes as evidenced by the decrease in lysotracker red staining and inhibit maturation of lysosomal enzymes leading to lysosomal dysfunction. IITZ-01 and IITZ-02 enhance autophagosome accumulation but inhibit autophagosomal degradation by impairing lysosomal function, finally resulting in the inhibition of autophagy. Interestingly, compound IITZ-01 exhibited more than 10-fold potent autopha...Continue Reading

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Citations

Apr 26, 2019·Journal of Cellular Biochemistry·Ziv Radisavljevic
Aug 1, 2020·Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences·Maryam Amini PouyaKayvan Mirnia
Mar 12, 2020·Current Topics in Medicinal Chemistry·Hua Guo, Quan-Ping Diao
Jun 21, 2020·Anti-cancer Agents in Medicinal Chemistry·Milad AshrafizadehAmirhossein Sahebkar

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Datasets Mentioned

BETA
MDA-MB-453

Methods Mentioned

BETA
transmission electron microscopy
xenografts
fluorescence imaging
protein assay
flow cytometry
density gradient centrifugation
xenograft

Software Mentioned

MarvinSketch
Select Screen
GraphPad Prism

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