Luteolin inhibits Cr(VI)-induced malignant cell transformation of human lung epithelial cells by targeting ROS mediated multiple cell signaling pathways

Abstract

Hexavalent chromium [Cr(VI)] is a well-known human carcinogen associated with the incidence of lung cancer. Inhibition of metal induced carcinogenesis by a dietary antioxidant is a novel approach. Luteolin, a natural dietary flavonoid found in fruits and vegetables, possesses potent antioxidant and anti-inflammatory activity. We found that short term exposure of human bronchial epithelial cells (BEAS-2B) to Cr(VI) (5 μM) showed a drastic increase in ROS generation, NADPH oxidase (NOX) activation, lipid peroxidation, and glutathione depletion, which were significantly inhibited by the treatment with luteolin in a dose dependent manner. Treatment with luteolin decreased AP-1, HIF-1α, COX-2, and iNOS promoter activity induced by Cr(VI) in BEAS-2B cells. In addition, luteolin protected BEAS-2B cells from malignant transformation induced by chronic Cr(VI) exposure. Moreover, luteolin also inhibited the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) and VEGF in chronic Cr(VI) exposed BEAS-2B cells. Western blot analysis showed that luteolin inhibited multiple gene products linked to survival (Akt, Fak, Bcl-2, Bcl-xL), inflammation (MAPK, NF-κB, COX-2, STAT-3, iNOS, TNF-α) and angiogenesis (HIF-1α, VEGF, MMP-9) in chronic Cr(VI) exposed BEAS-2B cells. Nude mice injected with BEAS-2B cells chronically exposed to Cr(VI) in the presence of luteolin showed reduced tumor incidence compared to Cr(VI) alone treated group. Overexpression of catalase (CAT) or SOD2, eliminated Cr(VI)-induced malignant transformation. Overall, our results indicate that luteolin protects BEAS-2B cells from Cr(VI)-induced carcinogenesis by scavenging ROS and modulating multiple cell signaling mechanisms that are linked to ROS. Luteolin, therefore, serves as a potential chemopreventive agent against Cr(VI)-induced carcinogenesis.

Platycodin D attenuates acute lung injury by suppressing apoptosis and inflammation in vivo and in vitro

“…c o m / l o c a t e / i n t i m p that increased epithelial/endothelial cell apoptosis contributed to the endothelial and epithelial injury which was the key feature of ALI/ARDS in humans. Previous studies showed that apoptosis inhibitors increased survival rates in rodent models of ALI [8].…”

Regulation of Sirt1/Nrf2/TNF-α signaling pathway by luteolin is critical to attenuate acute mercuric chloride exposure induced hepatotoxicity

“…This molecule has received extensive attention because of its antiinflammatory17, antioxidative18, and anticarcinogenic19 activities. Increasing evidence has indicated that luteolin might modulate the homeostasis between oxidants and antioxidants, and reduce reactive oxygen species (ROS) production and apoptosis18.…”

Isorhamnetin Inhibits Reactive Oxygen Species-Dependent Hypoxia Inducible Factor (HIF)-1α Accumulation

“…[9][10][11] Although studies on isorhamnetin have reported its anti-cancer efficacy, direct effects on HIF-1α regulation have not been identified. In this study, we observed that isorhamnetin inhibited HIF-1α following induction of HIF-1α accumulation in HCT116 and HT29 cells using hypoxia or CoCl 2 (Fig.…”

“…9) Luteolin can inhibit free radicals in the bronchial epithelial cells, which decreases HIF-1α. 10) In addition, quercetin can suppress HIF-1α-dependent transcriptional activity in hypoxic colon cancer cells.…”