Enhanced anti-tumor activity by the combination of the natural compounds (-)-epigallocatechin-3-gallate and luteolin: potential role of p53.
Natural dietary agents have drawn a great deal of attention toward cancer prevention because of their wide safety margin. However, single agent intervention has failed to bring the expected outcome in clinical trials; therefore, combinations of chemopreventive agents are gaining increasingly popularity. In the present study, we investigated a combinatorial approach using two natural dietary polyphenols, luteolin and EGCG, and found that their combination at low doses (at which single agents induce minimal apoptosis) synergistically increased apoptosis (3-5-fold more than the additive level of apoptosis) in both head and neck and lung cancer cell lines. This combination also significantly inhibited growth of xenografted tumors in nude mice. The in vivo findings also were supported by significant inhibition of Ki-67 expression and increase in TUNEL-positive cells in xenografted tissues. Mechanistic studies revealed that the combination induced mitochondria-dependent apoptosis in some cell lines and mitochondria-independent apoptosis in others. Moreover, we found more efficient stabilization and ATM-dependent Ser(15) phosphorylation of p53 due to DNA damage by the combination, and ablation of p53 using shRNA strongly inhibited apoptosis as evidenced by decreased poly(ADP-ribose) polymerase and caspase-3 cleavage. In addition, we observed mitochondrial translocation of p53 after treatment with luteolin or the combination of EGCG and luteolin. Taken together, our results for the first time suggest that the combination of luteolin and EGCG has synergistic/additive growth inhibitory effects and provides an important rationale for future chemoprevention trials of head and neck and lung cancers.
Amin
A R M Ruhul
AR
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322, USA.
Wang
Dongsheng
D
Zhang
Hongzheng
H
Peng
Shifang
S
Shin
Hyung Ju C
HJ
Brandes
Johann C
JC
Tighiouart
Mourad
M
Khuri
Fadlo R
FR
Chen
Zhuo Georgia
ZG
Shin
Dong M
DM
D000818:Animals; D016588:Anticarcinogenic Agents / Q000819:agonists / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D064007:Ataxia Telangiectasia Mutated Proteins; D053148:Caspase 3 / Q000378:metabolism; D002392:Catechin / Q000819:agonists / Q000031:analogs & derivatives* / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000494:pharmacology; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000494:pharmacology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000517:prevention & control*; D006801:Humans; D019394:Ki-67 Antigen / Q000096:biosynthesis; D047311:Luteolin / Q000819:agonists / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D055550:Protein Stability / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D016588:Anticarcinogenic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002392:Catechin; C045651:epigallocatechin gallate; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D047311:Luteolin
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