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4‐Deoxyraputindole C induces cell death and cell cycle arrest in tumor cell lines
Author(s) -
Vital Wagner D.,
Torquato Heron F. V.,
Jesus Larissa de Oliveira Passos,
Judice Wagner Alves de Souza,
Silva Maria Fátima das G. F. da,
Rodrigues Tiago,
Justo Giselle Zenker,
Veiga Thiago A. M.,
ParedesGamero Edgar J.
Publication year - 2019
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/jcb.28238
Subject(s) - programmed cell death , cathepsin b , microbiology and biotechnology , cell cycle checkpoint , chemistry , cell cycle , apoptosis , cell culture , biochemistry , cell growth , biology , enzyme , genetics
Several molecules extracted from natural products exhibit different biological activities, such as ion channel modulation, activation of signaling pathways, and anti‐inflammatory or antitumor activity. In this study, we tested the antitumor ability of natural compounds extracted from the Raputia praetermissa plant. Among the compounds tested, an alkaloid, here called compound S4 (4‐Deoxyraputindole C), showed antitumor effects against human tumor lineages. Compound S4 was the most active against Raji, a lymphoma lineage, promoting cell death with characteristics that including membrane permeabilization, dissipation of the mitochondrial potential, increased superoxide production, and lysosomal membrane permeabilization. The use of cell death inhibitors such as Z‐VAD‐FMK (caspase inhibitor), necrostatin‐1 (receptor‐interacting serine/threonine‐protein kinase 1 inhibitor), E‐64 (cysteine peptidases inhibitor), and N ‐acetyl‐ L ‐cysteine (antioxidant) did not decrease compound S4‐dependent cell death. Additionally, we tested the effect of cellular activity on adherent human tumor cells. The highest reduction of cellular activity was observed in A549 cells, a lung carcinoma lineage. In this lineage, the effect on the reduction of the cellular activity was due to cell cycle arrest, without plasma membrane permeabilization, loss of the mitochondrial potential or lysosomal membrane permeabilization. Compound S4 was able to inhibit cathepsin B and L by a nonlinear competitive (negative co‐operativity) and simple‐linear competitive inhibitions, respectively. The potency of inhibition was higher against cathepsin L. Compound S4 promoted cell cycle arrest at G 0 and G 2 phase, and increase the expression of p16 and p21 proteins. In conclusion, compound S4 is an interesting molecule against cancer, promoting cell death in the human lymphoma lineage Raji and cell cycle arrest in the human lung carcinoma lineage A549.