TY - JOUR
T1 - Autophagy inhibition enhances anticancer efficacy of artepillin C, a cinnamic acid derivative in Brazilian green propolis
AU - Endo, Satoshi
AU - Hoshi, Manami
AU - Matsunaga, Toshiyuki
AU - Inoue, Takahiro
AU - Ichihara, Kenji
AU - Ikari, Akira
N1 - Funding Information:
This work was supported in part by collaborative research grant from API Co. Ltd. We are grateful to Dr. Akira Hara for helpful discussions.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/2/26
Y1 - 2018/2/26
N2 - Propolis, a resinous substance produced by honeybees, possesses various biological actions including anticancer activity towards tumor cells. Recently, the ethanol extract of Brazilian green propolis has been shown to induce autophagy, which is known to be induced in treatment of cancer cells with anticancer drugs, leading to cancer cell survival and decreased sensitivity to anticancer agents. In this study, we aimed to identify autophagy-inducing components of the propolis and elucidated the reciprocal relationship between anticancer cytotoxicity and protective autophagy in prostate cancer CWR22Rv1 cells. Among eight cinnamic acid derivatives [chlorogenic acid, p-coumaric acid, caffeic acid, 3,4-caffeoylquinic acid, artepillin C (ArtC), baccharin, drupanin and caffeic acid phenethyl ester] in propolis, only ArtC showed high autophagy-inducing activity accompanying LC3-II upregulation. ArtC was also induced apoptosis as revealed by DNA fragmentation and increases in cleaved caspase-3 and poly ADP-ribose polymerase. The apoptosis induced by ArtC was exacerbated by cotreatment with autophagy inhibitors (chloroquine, wortmannin and U0126). The cotreatment further induced necroptosis accompanying increased expression of receptor-interacting serine/threonine protein kinases 1 and 3. These data indicate that cytotoxicity of ArtC to the prostate cancer cells is dampened by induced autophagy, but is markedly augmented by inhibition of autophagy. Therefore, the combination of ArtC and autophagy inhibitors may be a novel complementary-alternative treatment for prostate cancer.
AB - Propolis, a resinous substance produced by honeybees, possesses various biological actions including anticancer activity towards tumor cells. Recently, the ethanol extract of Brazilian green propolis has been shown to induce autophagy, which is known to be induced in treatment of cancer cells with anticancer drugs, leading to cancer cell survival and decreased sensitivity to anticancer agents. In this study, we aimed to identify autophagy-inducing components of the propolis and elucidated the reciprocal relationship between anticancer cytotoxicity and protective autophagy in prostate cancer CWR22Rv1 cells. Among eight cinnamic acid derivatives [chlorogenic acid, p-coumaric acid, caffeic acid, 3,4-caffeoylquinic acid, artepillin C (ArtC), baccharin, drupanin and caffeic acid phenethyl ester] in propolis, only ArtC showed high autophagy-inducing activity accompanying LC3-II upregulation. ArtC was also induced apoptosis as revealed by DNA fragmentation and increases in cleaved caspase-3 and poly ADP-ribose polymerase. The apoptosis induced by ArtC was exacerbated by cotreatment with autophagy inhibitors (chloroquine, wortmannin and U0126). The cotreatment further induced necroptosis accompanying increased expression of receptor-interacting serine/threonine protein kinases 1 and 3. These data indicate that cytotoxicity of ArtC to the prostate cancer cells is dampened by induced autophagy, but is markedly augmented by inhibition of autophagy. Therefore, the combination of ArtC and autophagy inhibitors may be a novel complementary-alternative treatment for prostate cancer.
KW - Apoptosis
KW - Artepillin C
KW - Autophagy
KW - Necroptosis
KW - Propolis
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U2 - 10.1016/j.bbrc.2018.02.105
DO - 10.1016/j.bbrc.2018.02.105
M3 - Article
C2 - 29452093
AN - SCOPUS:85042029070
VL - 497
SP - 437
EP - 443
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -