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Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.

Woo SM, Min KJ, Seo BR, Nam JO, Choi KS, Yoo YH, Kwon TK - Cell Death Dis (2014)

Bottom Line: Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models.We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation.Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.

ABSTRACT
Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

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Tumor growth in vivo is reduced by combined treatment with cafestol and ABT-737. Nude mice were s.c. inoculated with Mcl-1-overexpressed cells. Tumor volume was monitored during the following treatments: vehicle, ABT-737 (75 mg/kg; i.p.), cafestol (75 mg/ml, i.p.), or ABT-737 plus cafestol for 14 days. (a) Tumor size shows the size of the dissected out tumors. (b) Graph shows tumor volume changes. Number of animals per group=7. Data are means±S.E. (n=7). (c) Representative images of tumor sections that were analyzed by TUNEL assay. Nuclear staining was performed with DAPI. (d) Immunohistochemical analysis of activated caspase-3
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fig3: Tumor growth in vivo is reduced by combined treatment with cafestol and ABT-737. Nude mice were s.c. inoculated with Mcl-1-overexpressed cells. Tumor volume was monitored during the following treatments: vehicle, ABT-737 (75 mg/kg; i.p.), cafestol (75 mg/ml, i.p.), or ABT-737 plus cafestol for 14 days. (a) Tumor size shows the size of the dissected out tumors. (b) Graph shows tumor volume changes. Number of animals per group=7. Data are means±S.E. (n=7). (c) Representative images of tumor sections that were analyzed by TUNEL assay. Nuclear staining was performed with DAPI. (d) Immunohistochemical analysis of activated caspase-3

Mentions: Next, we investigated the anti-cancer effect of combined treatment with cafestol and ABT-737 in vivo xenograft model. Caki/Mcl-1 cells injected subcutaneously (s.c.) into the right flank were established. Mice bearing tumor were treated with cafestol alone, ABT-737 alone, or as a combined treatment with cafestol and ABT-737. As shown in Figures 3a and b, combined treatment markedly suppressed tumor growth compared with vehicle, ABT-737 alone, and cafestol alone. Terminal deoxynucleotide transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) analysis showed that combined treatment with cafestol and ABT-737 increased cell death (Figure 3c). Moreover, immunohistochemical staining of tumor tissues showed that combined treatment increased activated caspase-3 (Figure 3d). These results suggest that combined treatment with cafestol and ABT-737 inhibits tumor growth and induces apoptosis in vivo.


Cafestol overcomes ABT-737 resistance in Mcl-1-overexpressed renal carcinoma Caki cells through downregulation of Mcl-1 expression and upregulation of Bim expression.

Woo SM, Min KJ, Seo BR, Nam JO, Choi KS, Yoo YH, Kwon TK - Cell Death Dis (2014)

Tumor growth in vivo is reduced by combined treatment with cafestol and ABT-737. Nude mice were s.c. inoculated with Mcl-1-overexpressed cells. Tumor volume was monitored during the following treatments: vehicle, ABT-737 (75 mg/kg; i.p.), cafestol (75 mg/ml, i.p.), or ABT-737 plus cafestol for 14 days. (a) Tumor size shows the size of the dissected out tumors. (b) Graph shows tumor volume changes. Number of animals per group=7. Data are means±S.E. (n=7). (c) Representative images of tumor sections that were analyzed by TUNEL assay. Nuclear staining was performed with DAPI. (d) Immunohistochemical analysis of activated caspase-3
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260730&req=5

fig3: Tumor growth in vivo is reduced by combined treatment with cafestol and ABT-737. Nude mice were s.c. inoculated with Mcl-1-overexpressed cells. Tumor volume was monitored during the following treatments: vehicle, ABT-737 (75 mg/kg; i.p.), cafestol (75 mg/ml, i.p.), or ABT-737 plus cafestol for 14 days. (a) Tumor size shows the size of the dissected out tumors. (b) Graph shows tumor volume changes. Number of animals per group=7. Data are means±S.E. (n=7). (c) Representative images of tumor sections that were analyzed by TUNEL assay. Nuclear staining was performed with DAPI. (d) Immunohistochemical analysis of activated caspase-3
Mentions: Next, we investigated the anti-cancer effect of combined treatment with cafestol and ABT-737 in vivo xenograft model. Caki/Mcl-1 cells injected subcutaneously (s.c.) into the right flank were established. Mice bearing tumor were treated with cafestol alone, ABT-737 alone, or as a combined treatment with cafestol and ABT-737. As shown in Figures 3a and b, combined treatment markedly suppressed tumor growth compared with vehicle, ABT-737 alone, and cafestol alone. Terminal deoxynucleotide transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) analysis showed that combined treatment with cafestol and ABT-737 increased cell death (Figure 3c). Moreover, immunohistochemical staining of tumor tissues showed that combined treatment increased activated caspase-3 (Figure 3d). These results suggest that combined treatment with cafestol and ABT-737 inhibits tumor growth and induces apoptosis in vivo.

Bottom Line: Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models.We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation.Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, School of Medicine, Keimyung University, 2800 Dalgubeoldaero, Dalseo-Gu, Daegu 704-701, South Korea.

ABSTRACT
Although ABT-737, a small-molecule Bcl-2/Bcl-xL inhibitor, has recently emerged as a novel cancer therapeutic agent, ABT-737-induced apoptosis is often blocked in several types of cancer cells with elevated expression of Mcl-1. Cafestol, one of the major compounds in coffee beans, has been reported to have anti-carcinogenic activity and tumor cell growth-inhibitory activity, and we examined whether cafestol could overcome resistance against ABT-737 in Mcl-1-overexpressed human renal carcinoma Caki cells. ABT-737 alone had no effect on apoptosis, but cafestol markedly enhanced ABT-737-mediated apoptosis in Mcl-1-overexpressed Caki cells, human glioma U251MG cells, and human breast carcinoma MDA-MB231 cells. By contrast, co-treatment with ABT-737 and cafestol did not induce apoptosis in normal human skin fibroblast. Furthermore, combined treatment with cafestol and ABT-737 markedly reduced tumor growth compared with either drug alone in xenograft models. We found that cafestol inhibited Mcl-1 protein expression, which is important for ABT-737 resistance, through promotion of protein degradation. Moreover, cafestol increased Bim expression, and siRNA-mediated suppression of Bim expression reduced the apoptosis induced by cafestol plus ABT-737. Taken together, cafestol may be effectively used to enhance ABT-737 sensitivity in cancer therapy via downregulation of Mcl-1 expression and upregulation of Bim expression.

Show MeSH
Related in: MedlinePlus