Enhanced Anti-tumor Activity by the Combination of the Natural Compounds (−)-Epigallocatechin-3-gallate and Luteolin

Abstract

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.

Epigallocatechin gallate promotes p53 accumulation and activity via the inhibition of MDM2-mediated p53 ubiquitination in human lung cancer cells

“…Although several reports have shown that EGCG exerts its anticancer activity by targeting specific cell signaling pathways, the underlying mechanism is not yet fully understood. Previous reports revealed that EGCG treatment induces lung cancer cell apoptosis or cell cycle arrest (18,35). Other groups also found that the tumor suppressor gene p53 may be involved in the antitumor activity of EGCG since cancer cells expressing wild-type p53 are more sensitive to EGCG treatment compared with p53-null or p53 knock down cancer cells (36,40).…”

“…Previous studies have demonstrated that EGCG treatment increases the expression levels of p53 in various human cancer (35)(36)(37)(38). Previous reports found that cells expressing wildtype p53 are more sensitive than p53-null or p53 knock down cells to EGCG-induced growth inhibition and apoptosis (36,39,40).…”

Inhibition of hypoxia-induced epithelial mesenchymal transition by luteolin in non-small cell lung cancer cells

“…As an anticancer agent, luteolin inhibits cancer cell proliferation by suppressing protein kinases and inducing apoptosis by inhibiting cell survival pathways (12). The activity of this compound regulates the redox state, causing DNA damage (13). Luteolin also inhibits metastasis and angiogenesis (14,15).…”

Reposicionamento de fármacos no câncer de boca: Identificação de possíveis agentes

“…A luteolin participa da modulação da apoptose, regulação de ciclo celular, angiogênese e até da regulação epigenética, auxiliando a impedir a invasão e metástase de tumores do fígado (Shi et al, 2007), estômago (Wu et al, 2008), pulmão (Hong et al, 2014) e mama (Lee et al, 2012). Em relação ao câncer de boca, ainda há escassez de informações a respeito do mecanismo de ação deste fármaco (O'prey et al, 2003;Yang et al, 2008;Amin et al, 2010;Verschooten et al, 2012;Majumdar et al, 2014). Foi demonstrado que a luteolin é capaz de induzir a interrupção do ciclo celular e a apoptose de células de câncer de cabeça e pescoço in vitro (Yang et al, 2008;Amin et al, 2010;Verschooten et al, 2012;Majumdar et al, 2014).…”

“…Em relação ao câncer de boca, ainda há escassez de informações a respeito do mecanismo de ação deste fármaco (O'prey et al, 2003;Yang et al, 2008;Amin et al, 2010;Verschooten et al, 2012;Majumdar et al, 2014). Foi demonstrado que a luteolin é capaz de induzir a interrupção do ciclo celular e a apoptose de células de câncer de cabeça e pescoço in vitro (Yang et al, 2008;Amin et al, 2010;Verschooten et al, 2012;Majumdar et al, 2014).…”