M R Sam1, S Ghoreishi1. 1. Department of Cellular and Molecular Biotechnology, Institute of Biotechnology, Urmia University, Urmia, Iran.
Abstract
AIMS: Matrix metalloproteinase-9 (MMP-9) and survivin are involved in several steps of carcinogenesis in acute lymphoblastic leukaemia (ALL). Yet, no MMP-9 and survivin-modulating drugs with low toxicity on normal cells but high efficacy against high MMP-9- and survivin-expressing leukaemia cells have been approved for clinical application in ALL. Prodigiosin, a secondary metabolite of Serratia marcescens, induces apoptosis in different kinds of cancer cells with low toxicity on normal cells. However, little is known about the effects of this compound on the high MMP-9- and survivin-expressing leukaemia cells. METHODS AND RESULTS: CCRF-CEM cells as a model for high MMP-9- and survivin-expressing ALL cells were treated with 100, 200 and 400 nmol l-1 prodigiosin after which cell number, proliferation rate, MMP-9 and survivin expression, caspase-3 activation and apoptosis were evaluated. After 24-, 48-, and 72-h treatments with 100, 200 and 400 nmol l-1 prodigiosin, proliferation rates were measured to be 92·3-76·7%, 82-63% and 63·7-46·6% respectively. Treatment with prodigiosin for 48 h decreased MMP-9 mRNA levels followed by decreases in secreted (S) and intracellular (I) MMP-9 protein levels by 20-22% and 69-72% for 100-400 nmol l-1 prodigiosin respectively. Prodigiosin decreased survivin protein levels from 40 to 26% followed by 3·7-5·6-fold increases in caspase-3 activation for the aforementioned prodigiosin concentration ranges. Treatment with 100-400 nmol l-1 prodigiosin increased the caspase-3/survivin, caspase-3/I-MMP-9 and caspase-3/S-MMP-9 ratios by 6-7·3-, 11·5-19·1- and 4·9-6·8-fold increases respectively. A dramatic increase in the number of apoptotic cells was also observed with increasing prodigiosin concentrations. CONCLUSION: The inhibitory effects of prodigiosin on MMP-9 and survivin expression, as well as its pro-apoptotic capacity, represent a novel therapeutic avenue against ALL cells. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings provide an important and interesting basis to develop a new therapeutic compound with high potential against ALL cells.
AIMS: Matrix metalloproteinase-9 (MMP-9) and survivin are involved in several steps of carcinogenesis in acute lymphoblastic leukaemia (ALL). Yet, no MMP-9 and survivin-modulating drugs with low toxicity on normal cells but high efficacy against high MMP-9- and survivin-expressing leukaemia cells have been approved for clinical application in ALL. Prodigiosin, a secondary metabolite of Serratia marcescens, induces apoptosis in different kinds of cancer cells with low toxicity on normal cells. However, little is known about the effects of this compound on the high MMP-9- and survivin-expressing leukaemia cells. METHODS AND RESULTS: CCRF-CEM cells as a model for high MMP-9- and survivin-expressing ALL cells were treated with 100, 200 and 400 nmol l-1 prodigiosin after which cell number, proliferation rate, MMP-9 and survivin expression, caspase-3 activation and apoptosis were evaluated. After 24-, 48-, and 72-h treatments with 100, 200 and 400 nmol l-1 prodigiosin, proliferation rates were measured to be 92·3-76·7%, 82-63% and 63·7-46·6% respectively. Treatment with prodigiosin for 48 h decreased MMP-9 mRNA levels followed by decreases in secreted (S) and intracellular (I) MMP-9 protein levels by 20-22% and 69-72% for 100-400 nmol l-1 prodigiosin respectively. Prodigiosin decreased survivin protein levels from 40 to 26% followed by 3·7-5·6-fold increases in caspase-3 activation for the aforementioned prodigiosin concentration ranges. Treatment with 100-400 nmol l-1 prodigiosin increased the caspase-3/survivin, caspase-3/I-MMP-9 and caspase-3/S-MMP-9 ratios by 6-7·3-, 11·5-19·1- and 4·9-6·8-fold increases respectively. A dramatic increase in the number of apoptotic cells was also observed with increasing prodigiosin concentrations. CONCLUSION: The inhibitory effects of prodigiosin on MMP-9 and survivin expression, as well as its pro-apoptotic capacity, represent a novel therapeutic avenue against ALL cells. SIGNIFICANCE AND IMPACT OF THE STUDY: These findings provide an important and interesting basis to develop a new therapeutic compound with high potential against ALL cells.
Authors: Andrew J Ambrose; Nhan T Pham; Jared Sivinski; Larissa Guimarães; Niloufar Mollasalehi; Paula Jimenez; Maria A Abad; A Arockia Jeyaprakash; Steven Shave; Letícia V Costa-Lotufo; James J La Clair; Manfred Auer; Eli Chapman Journal: RSC Chem Biol Date: 2020-11-27
Authors: Lena Berning; David Schlütermann; Annabelle Friedrich; Niklas Berleth; Yadong Sun; Wenxian Wu; María José Mendiburo; Jana Deitersen; Hannah U C Brass; Margaretha A Skowron; Michèle J Hoffmann; Günter Niegisch; Jörg Pietruszka; Björn Stork Journal: Molecules Date: 2021-02-27 Impact factor: 4.411