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Indospicine combined with arginine deprivation triggers cancer cell death via caspase‐dependent apoptosis
Author(s) -
Shuvayeva Galyna Y.,
Bobak Yaroslav P.,
Vovk Olena I.,
KunzSchughart Leoni A.,
Fletcher Mary T.,
Stasyk Oleh V.
Publication year - 2021
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.11321
Subject(s) - arginase , arginine , apoptosis , caspase , cancer cell , biology , protein arginine methyltransferase 5 , microbiology and biotechnology , cancer research , programmed cell death , cancer , biochemistry , amino acid , genetics , methylation , gene , methyltransferase
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.