Original ContributionT63, a new 4-arylidene curcumin analogue, induces cell cycle arrest and apoptosis through activation of the reactive oxygen species–FOXO3a pathway in lung cancer cells
Highlights
► T63, a curcumin analogue, induced G0/G1 arrest and apoptosis in lung cancer cells. ► T63 treatment rapidly increased reactive oxygen species levels. ► Activation of FOXO3a is essential for T63-induced cell cycle arrest and apoptosis. ► T63 significantly suppressed the growth of A549 lung cancer xenograft tumors. ► T63 treatment showed no notable organ-related toxicity in vivo.
Section snippets
Materials
T63 and curcumin were synthesized at our laboratory, dissolved in dimethyl sulfoxide (DMSO) to prepare a 10 mM stock solution, and stored at −20 °C. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), propidium iodide, 3,3′-diaminobenzidine, SB203580, LY294002, diphenylene iodonium (DPI), rotenone, allopurinol, PEG–catalase (PEG-CAT), PEG–superoxide dismutase (PEG-SOD), and N-acetylcysteine (NAC) were obtained from Sigma (Poole, UK). 4,6-Diamidino-2-phenylindole (DAPI), the
Effects of T63 on cell viability
We first determined the effects of T63 (Fig. 1A) on cell proliferation of lung cancer cells. A549 and H460 cells were treated with T63 or curcumin (0.01 to 10 μM) for 24 h, and then the viability was determined by MTT assay. As shown in Fig. 1B, T63 significantly suppresses proliferation of A549 and H460 cells within a 24-h treatment period. More important, the inhibitory effects were observed at a dose of 1 μM, whereas curcumin showed no significant inhibitory effect upon A549 or H460 cell
Discussion
The ability of cancer cells to avoid apoptosis has been identified as one of the major mechanisms for development of cancers [36]. Induction of cell cycle arrest and cell apoptosis in cancer cells is a critical feature of chemotherapeutic agents. Curcumin has been shown to inhibit proliferation of various human tumor cells, including lung, colon, breast, myeloma, leukemia, and prostate carcinoma [21], [37]. The chemotherapeutic action of curcumin might be due to its ability to induce apoptosis
Acknowledgments
This work was supported by grant from the MOST of China (863 Program 2008AA02Z304), the National Natural Science Foundation of China (Grants 30973619, 31101071, 81071712, 30873032, and 81172931), and the National Basic Research Program of China (973 Program 2011CB9358003).
References (66)
- et al.
Targeted therapies for non-small cell lung cancer
Lung Cancer
(2010) - et al.
Mitochondrial manganese-superoxide dismutase expression in ovarian cancer: role in cell proliferation and response to oxidative stress
J. Biol. Chem.
(2005) - et al.
FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines
J. Biol. Chem.
(2003) - et al.
Integration of Smad and forkhead pathways in the control of neuroepithelial and glioblastoma cell proliferation
Cell
(2004) - et al.
FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis
Cell
(2007) - et al.
Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor
Cell
(1999) - et al.
IkappaB kinase promotes tumorigenesis through inhibition of forkhead FOXO3a
Cell
(2004) - et al.
Multiple biological activities of curcumin: a short review
Life Sci.
(2006) - et al.
Measuring reactive oxygen and nitrogen species with fluorescent probes: challenges and limitations
Free Radic. Biol. Med.
(2012) - et al.
Rapid reactive oxygen species (ROS) generation induced by curcumin leads to caspase-dependent and -independent apoptosis in L929 cells
Free Radic. Biol. Med.
(2008)
Inhibition of the EGF receptor blocks autocrine growth and increases the cytotoxic effects of doxorubicin in rat hepatoma cells: role of reactive oxygen species production and glutathione depletion
Biochem. Pharmacol
Hallmarks of cancer: the next generation
Cell
Induction of apoptosis in human lung cancer cells by curcumin
Cancer Lett.
Reactive oxygen species in cancer cells: live by the sword, die by the sword
Cancer Cell
Selective killing of oncogenically transformed cells through a ROS-mediated mechanism by beta-phenylethyl isothiocyanate
Cancer Cell
Cholesterol secoaldehyde induces apoptosis in H9c2 cardiomyoblasts through reactive oxygen species involving mitochondrial and death receptor pathways
Free Radic. Biol. Med.
Redox control of cell fate by MAP kinase: physiological roles of ASK1–MAP kinase pathway in stress signaling
Biochim. Biophys. Acta
Nrf2:INrf2 (Keap1) signaling in oxidative stress
Free Radic. Biol. Med.
Apigenin-induced prostate cancer cell death is initiated by reactive oxygen species and p53 activation
Free Radic. Biol. Med
Forkhead transcription factor FOXO subfamily is essential for reactive oxygen species-induced apoptosis
Mol. Cell. Endocrinol.
Tumor suppressor genes and ROS: complex networks of interactions
Free Radic. Biol. Med.
Phosphorylation of FOXO3a on Ser-7 by p38 promotes its nuclear localization in response to doxorubicin
J. Biol. Chem.
Vanadate-induced expression of hypoxia-inducible factor 1 alpha and vascular endothelial growth factor through phosphatidylinositol 3-kinase/Akt pathway and reactive oxygen species
J. Biol. Chem.
Hydrogen peroxide-induced Akt phosphorylation regulates Bax activation
Biochimie
ROS-driven Akt dephosphorylation at Ser-473 is involved in 4-HPR-mediated apoptosis in NB4 cells
Free Radic. Biol. Med.
Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: a potential new treatment for hepatocellular carcinoma
Free Radic. Biol. Med
Thymoquinone suppresses growth and induces apoptosis via generation of reactive oxygen species in primary effusion lymphoma
Free Radic. Biol. Med.
Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths
CA Cancer J. Clin
Mechanisms of resistance to therapy and tumor cell survival
Curr. Opin. Hematol.
Tumor intracellular redox status and drug resistance—serendipity or a causal relationship?
Curr. Pharm. Des
Sense and sensitivity: FOXO and ROS in cancer development and treatment
Antioxid. Redox Signaling
Targeting cancer cells by ROS-mediated mechanisms: a radical therapeutic approach?
Nat. Rev. Drug Discovery
FOXO3a mediates the androgen-dependent regulation of FLIP and contributes to TRAIL-induced apoptosis of LNCaP cells
Oncogene
Cited by (46)
Cytosolic and mitochondrial ROS production resulted in apoptosis induction in breast cancer cells treated with Crocin: The role of FOXO3a, PTEN and AKT signaling
2020, Biochemical PharmacologyCitation Excerpt :FOXO3a protein is an important downstream target of the growth factor-induced PI3K/Akt pathway. It can serve as a therapeutic target in various cancers by mediating the cytostatic and cytotoxic effects of various chemotherapeutic drugs such as paclitaxel [6], T63 [64], berberine [65] and triciribine [66]. These compounds can activate FOXO3a by reducing AKT activity.
Activation of FOXO3a reverses 5-Fluorouracil resistance in human breast cancer cells
2018, Experimental and Molecular Pathology