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Augmentation of the Anticancer Effect of Proteasome Inhibitors by Butyrate in Human Colorectal Carcinoma
Author(s) -
Abaza Mohamed Salah I.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.925.14
Subject(s) - mg132 , proteasome , sodium butyrate , proteasome inhibitor , apoptosis , butyrate , cell cycle , chemistry , cell growth , cancer research , bortezomib , cancer cell , biology , pharmacology , cancer , biochemistry , immunology , multiple myeloma , genetics , fermentation , gene
The ubiquitin‐proteasome pathway plays a critical role in the degradation of cellular proteins and cell cycle control. Dysregulating the degradation of such proteins should have profound effects on tumor growth and causes cells to undergo apoptosis. This study deals with the apoptotic effect of both proteasome inhibitors; MG115, MG132, proteasome inibitor‐1 (PSI‐1), proteasome inhibitor‐2 (PSI‐2) and epoxomicin; and sodium butyrate (NaB), their synergistic interaction and whether NaB , a natural product capable of inducing apoptosis in a number of tumor cells and exhibit a low degree of clinical toxicity, can enhance the anticancer effect of the proteasome inhibitors in colorectal cancer. The results showed that proteasome inhibitors and NaB inhibited the proliferation cancer cells in a dose and time dependent manner. The combinations of MG115, MG132, PSI‐1, PSI‐2 or epoxomicin and NaB produced prominent, additive and/or synergistic dose and time dependent growth inhibitory effects as well as a marked induction of apoptosis compared to single treatment with proteasome inhibitors or NaB. Cancer cells treated with NaB, proteasome inhibitors and their combinations were growth arrested at G 1 , G 2 ‐M/S and G 1 or S/G 2 ‐M phases of cell cycle, respectively. p53, p21 Waf1 , p27 Kip1 and Bax were over‐expressed. Meanwhile, Bcl2 was down‐regulated after treatment with proteasome inhibitors and their combinations with NaB. Taken together, these results indicated a synergistic interaction between proteasome inhibitors and sodium butyrate that could represent a new tool in tumor therapy. This study was supported by Kuwait University, Research Grant No. SL04‐02