Indospicine combined with arginine deprivation triggers cancer cell death via caspase‐dependent apoptosis

Arginine‐deprivation therapy is a rapidly developing metabolic anticancer approach. To overcome the resistance of some cancer cells to this monotherapy, rationally designed combination modalities are needed. In this report, we evaluated for the first time indospicine, an arginine analogue of Indigof...

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Bibliographic Details
Published in:Cell biology international 2021-03, Vol.45 (3), p.518-527
Main Authors: Shuvayeva, Galyna Y., Bobak, Yaroslav P., Vovk, Olena I., Kunz‐Schughart, Leoni A., Fletcher, Mary T., Stasyk, Oleh V.
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
AKT protein
Apoptosis
Arginase
Arginine
arginine deprivation
Cancer
Caspase
Cell death
Colorectal carcinoma
Endoplasmic reticulum
indospicine
MAP kinase
metabolic anticancer therapy
Metabolism
Rapamycin
TOR protein
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Summary:Arginine‐deprivation therapy is a rapidly developing metabolic anticancer approach. To overcome the resistance of some cancer cells to this monotherapy, rationally designed combination modalities are needed. In this report, we evaluated for the first time indospicine, an arginine analogue of Indigofera plant genus origin, as potential enhancer compound for the metabolic therapy that utilizes recombinant human arginase I. We demonstrate that indospicine at low micromolar concentrations is selectively toxic for human colorectal cancer cells only in the absence of arginine. In arginine‐deprived cancer cells indospicine deregulates some prosurvival pathways (PI3K‐Akt and MAPK) and activates mammalian target of rapamycin, exacerbates endoplasmic reticulum stress and triggers caspase‐dependent apoptosis, which is reversed by the exposure to translation inhibitors. Simultaneously, indospicine is not degraded by recombinant human arginase I and does not inhibit this arginine‐degrading enzyme at its effective dose. The obtained results emphasize the potential of arginine structural analogues as efficient components for combinatorial metabolic targeting of malignant cells.
ISSN:1065-6995
1095-8355
DOI:10.1002/cbin.11321