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.
Highlights
ABT-737 has been developed as a small-molecule BH3 mimetic
Bcl-2 family is classified as two groups, which is characterized by the presence of Bcl-2 homology (BH) domains: (1) anti-apoptotic proteins, containing the BH1–4 domains (Bcl-2, Bcl-XL, Bcl-w, and Mcl-1), and (2) pro-apoptotic proteins, containing the BH1–3 domains (Bax, Bak, and Bok), and BH3-only proteins, containing only BH3 domain (B-cell lymphoma 2 interacting mediator of cell death (Bim), p53 upregulated modulator of apoptosis (PUMA), and NOXA).[1,2]
ABT-737 directly binds to Bcl-2, Bcl-xL, and Bcl-w with very high affinity, and antagonizes sequestration of Bax and Bak, which results in induction of apoptosis in cancer cells.[6,7]
Summary
ABT-737 directly binds to Bcl-2, Bcl-xL, and Bcl-w with very high affinity, and antagonizes sequestration of Bax and Bak, which results in induction of apoptosis in cancer cells.[6,7] ABT-737 has very low affinity for Mcl-1, so cancer cells with high levels of Mcl-1 are resistant to ABT-737.8,9 To increase sensitivity to ABT-737, a large number of studies have developed strategies using multiple drugs, which modulate the expression and activity of Mcl-1.10–15. Received 13.6.14; revised 04.9.14; accepted 05.9.14; Edited by A Stephanou induce apoptosis.[21] we recently showed that cafestol increased apoptosis in several types of cancer cells through through downregulation of anti-apoptotic proteins (Bcl-2 and Mcl-1) and inhibition of Akt phosphorylation.[22] As downregulation of Mcl-1 expression has been known to increase the sensitivity to ABT-737 in multiple cancer cells,[10,12,23] treatment with cafestol may be a promising agent, which can overcome resistance of cancer cells to ABT-737. We aimed to investigate whether induction of cafestol plus ABT-737 mediated apoptosis and to identify molecular mechanisms of cafestol to overcome resistance against ABT-737 in Mcl-1-overexpressed Caki cells
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