Enhancing Proteotoxic Stress in Leiomyosarcoma Cells Triggers Mitochondrial Dysfunctions, Cell Death, and Antitumor Activity in vivo .

Autor:	Iuliano L; Department of Medicine, Università degli Studi di Udine, Udine, Italy., Drioli S; Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy., Pignochino Y; Department of Clinical and Biological Sciences, University of Torino, c/o San Luigi Gonzaga Hospital, Orbassano, Torino, Italy.; Sarcoma Unit, Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy., Cafiero CM; Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy., Minisini M; Department of Medicine, Università degli Studi di Udine, Udine, Italy., D'Este F; Department of Medicine, Università degli Studi di Udine, Udine, Italy., Picco R; Department of Medicine, Università degli Studi di Udine, Udine, Italy., Dalla E; Department of Medicine, Università degli Studi di Udine, Udine, Italy., Giordano G; Sarcoma Unit, Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy.; Department of Oncology, University of Torino, Torino, Italy., Grignani G; Sarcoma Unit, Division of Medical Oncology, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Torino, Italy., Di Giorgio E; Department of Medicine, Università degli Studi di Udine, Udine, Italy., Benedetti F; Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy., Felluga F; Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Trieste, Trieste, Italy., Brancolini C; Department of Medicine, Università degli Studi di Udine, Udine, Italy. claudio.brancolini@uniud.it.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2021 Jun; Vol. 20 (6), pp. 1039-1051. Date of Electronic Publication: 2021 Mar 30.
DOI:	10.1158/1535-7163.MCT-20-0521
Abstrakt:	Leiomyosarcomas are rare and aggressive tumors characterized by a complex karyotype. Surgical resection with or without radiotherapy and chemotherapy is the standard curative treatment. Unfortunately, a high percentage of leiomyosarcomas recurs and metastasizes. In these cases, doxorubicin and ifosfamide represent the standard treatment but with low response rates. Here, we evaluated the induction of proteotoxic stress as a possible strategy to kill leiomyosarcoma cells in a therapeutic perspective. We show that aggressive leiomyosarcomas coexist with high levels of proteotoxic stress. As a consequence, we hypothesized that leiomyosarcoma cells are vulnerable to further increases of proteotoxic stress. The small compound 2c is a strong inducer of proteotoxic stress. In leiomyosarcoma cells, it triggers cell death coupled to a profound reorganization of the mitochondrial network. By using stimulated emission depletion microscopy, we have unveiled the existence of DIABLO/SMAC clusters that are modulated by 2c. Finally, we have engineered a new version of 2c linked to polyethylene glycol though a short peptide, named 2cPP. This new prodrug is specifically activated by proteases present in the tumor microenvironment. 2cPP shows a strong antitumor activity in vivo against leiomyosarcomas and no toxicity against normal cells. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
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