1. Ritterostatin GN 1N , a Cephalostatin-Ritterazine Bis-steroidal Pyrazine Hybrid, Selectively Targets GRP78.
- Author
-
Ambrose, Andrew, Santos, Evelyne, Jimenez, Paula, Rocha, Danilo, Wilke, Diego, Beuzer, Paolo, Axelrod, Josh, Kumar Kanduluru, Ananda, Fuchs, Philip, Cang, Hu, Costa-Lotufo, Letícia, Chapman, Eli, and La Clair, James
- Subjects
GRP78 ,cephalostatin ,drug discovery ,natural products ,ritterazine ,Cell Line ,Tumor ,Cell Proliferation ,Cell Survival ,Cells ,Cultured ,Coumarins ,Drug Delivery Systems ,Endoplasmic Reticulum Chaperone BiP ,Heat-Shock Proteins ,Humans ,Molecular Probes ,Molecular Structure ,Phenazines ,Protein Binding ,Pyrazines ,Steroids - Abstract
Natural products discovered by using agnostic approaches, unlike rationally designed leads or those obtained through high-throughput screening, offer the ability to reveal new biological pathways and, hence, serve as an important vehicle to unveil new avenues in drug discovery. The ritterazine-cephalostatin family of natural products displays robust and potent antitumor activities, with sub-nanomolar growth inhibition against multiple cell lines and potent activity in xenograft models. Herein, we used comparative cellular and molecular biological methods to uncover the ritterazine-cephalostatin cytotoxic mode of action (MOA) in human tumor cells. Our findings indicated that, whereas ritterostatin GN 1N , a cephalostatin-ritterazine hybrid, binds to multiple HSP70s, its cellular trafficking confines activity to the endoplasmic reticulum (ER)-based HSP70 isoform, GRP78. This targeting results in activation of the unfolding protein response (UPR) and subsequent apoptotic cell death.
- Published
- 2017