Anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cell line

Abstract

To investigate the anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer, gastric cancer AGS cells were treated with luteolin and/or other chemotherapeutic agents. Cell growth was assessed by MTT assay, cell cycle and apoptosis were assessed by flow-cytometric analysis, and the expression of major proteins regulating cell cycle and apoptosis was also detected. The results showed that luteolin inhibited the growth of gastric cancer cells in a dose- and time-dependent manner. Flow cytometry revealed that the percentage of cells at G2/M phase increased dose-dependently. The protein levels of Cdc2, Cyclin B1 and Cdc25C were reduced and p21/cip1 was up-regulated after the treatment with luteolin. Furthermore, luteolin induced apoptosis in gastric cancer AGS cells. Western blotting showed that luteolin treatment significantly increased the levels of pro-apoptotic proteins, including Caspase-3, 6, 9, Bax, and p53, and decreased the levels of anti-apoptotic protein Bcl-2, thus shifting the Bax/Bcl ratio in favor of apoptosis. It was also demonstrated that a combinational treatment of cisplatin and luteolin induced more effectively cell growth inhibition, compared to cisplatin treatment alone. These findings indicate the anti-proliferative and chemosensitizing effects of luteolin on human gastric cancer AGS cells and luteolin may be a promising candidate agent used in the treatment of gastric cancer.

Anticancer potential of selected Fallopia Adans species

“…Apigenin, baicalein, luteolin, nobiletin and tangeretin have been shown to be the most effective flavonoids against carcinomas of the stomach, whereas luteolin has been shown to be a promising candidate for the treatment of skin cancer (9,10). Hesperidin has been shown to inhibit human pancreatic cancer cell growth and its use has been suggested for the prevention of pancreatic cancer (11).…”

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

“…Além disso, é um composto altamente potente contra alguns tipos de câncer (Tuorkey, 2015) e é capaz de reverter a resistência de alguns tipos de tumores (Tu et al, 2013). 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).…”

“…Os efeitos pró-apoptóticos da luteolin têm sido alvo de diversas investigações (Wu et al, 2008). Este fármaco pode desencadear a morte celular programada tanto através da via extrínseca quanto da via intrínseca da apoptose.…”

“…Luteolin parece mediar a estabilização e acúmulo do p53 através da ativação do JNK e outras moléculas (Shi et al, 2007), o que induz a apoptose e previne a proliferação de diversos tipos de células neoplásicas, incluindo de mama (Momtazi-Borojeni et al, 2013), estômago (Wu et al, 2008), pulmão (Amin et al, 2010) e de cabeça de pescoço (Amin et al, 2010). Inclusive, a ativação do JNK pela luteolin estabiliza o p53 por fosforilação, levando a uma redução da sua ubiquitinação e da sua degradação (Seelinger et al, 2008).…”

“…O composto interrompe o ciclo celular através da diminuição da expressão do Akt, PLK1, ciclina B1, ciclina A, ciclina D1, c-myc, CDK2, CDK4, CDK6, Bcl-2, Bcl-xL, Cdc2, Cdc25C, Rb1 e/ou survivin bem como do aumento da expressão do Bax, caspase-3 e/ou p21 em câncer de nasofaringe, pele, esôfago, intestino, mama, próstata e estômago (Lim Do et al, 2007;Wu et al, 2008;Zhang et al, 2009;Ong et al, 2010;Shoulars et al, 2010;Lee et al, 2012;Verschooten et al, 2012;Wang, T. T. et al, 2012;Pandurangan et al, 2013). Os dados prévios indicam que a luteolin é capaz de interromper o ciclo celular em diversas fases, atuando nas fases G1, S e G2 (Park et al, 2014).…”