zerumbone and Lung-Neoplasms

Zerumbone had been verified as a potential anti-cancer agent. Our research aimed to investigate the effect of zerumbone combined with gefitinib in lung cancer. Human pulmonary alveolar epithelial cells (HPAEpiC), A549, and H460 cell lines were used to detect the efficacy of zerumbone. BALB/c nude mice were randomly divided into five groups, including model, gefitinib (Gef, 10 mg/kg), low dose zerumbone (L-Zer, 20 mg/kg), high dose zerumbone (H-Zer, 40 mg/kg), and H-Zer + Gef groups, and the tumor growth in each group was monitored. TdT-mediated dUTP Nick-End Labeling (TUNEL) was used to detect cell apoptosis. Immunohistochemistry (IHC), immunofluorescence, and western blot were used to analyze the protein expressions in tumor tissues. Glutathione (GSH) and malondialdehyde (MAD) were detected by special kits. Zerumbone inhibited the proliferation of lung cancer cells in vitro. Tumor volume and weight were reduced after gefitinib or zerumbone treatment. Gefitinib and zerumbone treatment significantly promoted the apoptosis of tumor cells. The expression of Bcl-2, Bax, and P53 proteins confirmed cell apoptosis. IHC results indicated that zerumbone and gefitinib treatment decreased tumor angiogenesis. Consistent with this result, the expression of EGFR, VEGFR2, and Ki-67 proteins decreased, while the expression of angiostatin and endostatin proteins increased. Interestingly, zerumbone treatment increased the level of MDA while decreasing GSH. Next, the levels of glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11) decreased after zerumbone and gefitinib treatment. Our study suggested that zerumbone combined with gefitinib could effectively inhibit lung cancer for multi-model therapies, including the inhibition of tumor growth, angiogenesis, induce cell apoptosis, and ferroptosis.

Topics: Amino Acid Transport System y+; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Gefitinib; Humans; Lung Neoplasms; Mice; Mice, Nude; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor

p53 signaling plays an important role in cell death. Zerumbone, a natural cyclic sesquiterpene, has shown cytotoxic activity against many cancers. This study was done to investigate the anticancer effects of zerumbone on non-small cell lung cancer (NSCLC) cells and explored the involvement of p53 signaling. Cell viability was assessed by 3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazolium assay. Apoptosis was confirmed by annexin-V/propidium iodide staining and caspase activity assay. Mitochondrial membrane potential (Δφm) and reactive oxygen species (ROS) production were measured by flow cytometry. Depletion of p53 was achieved by transfection of specific small interfering RNA. Gene expression changes were determined by Western blot analysis. Zerumbone treatment caused a dose-dependent inhibition of A549 and H460 NSCLC cell viability. Zerumbone-induced mitochondrial apoptosis of NSCLC cells, evidenced loss of Δφm, release of mitochondrial cytochrome c, and activation of caspase-9 and -3. There was increased p53 and Bax expression and ROS production in zerumbone-treated cells. Downregulation of p53 or scavenging ROS interfered with the pro-apoptotic action of zerumbone. Combinational treatment with zerumbone and cisplatin significantly accelerated apoptosis and promoted p53 expression and ROS production in NSCLC cells, compared with each alone. These findings demonstrate that zerumbone induces mitochondrial apoptosis and enhances the susceptibility to cisplatin in NSCLC cells, which are, at least partially, mediated through activation of p53 signaling and promotion of ROS generation. This study may provide a rationale for the potential clinical application of zerumbone as a chemotherapeutic agent against NSCLC.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cisplatin; Drug Synergism; Humans; Lung Neoplasms; Membrane Potential, Mitochondrial; Oxidative Stress; Reactive Oxygen Species; Sesquiterpenes; Signal Transduction; Tumor Suppressor Protein p53

Zerumbone (ZER), present in subtropical ginger Zingiber zerumbet Smith, possesses anti-growth and anti-inflammatory properties in several human cancer cell lines. ZER also down-regulates the cyclooxygenase-2 and inducible nitric oxide synthase expression via modulation of nuclear factor (NF)-kappaB activation in cell culture systems. These findings led us to investigate whether ZER is able to inhibit carcinogenesis in the colon and lung, using 2 different preclinical mouse models. In Exp. 1, a total of 85 male ICR mice were initiated using a single intraperitoneal (i.p.) injection with azoxymethane (AOM, 10 mg/kg bw) and promoted by 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days for rapid induction of colonic neoplasms. Animals were then fed the diet containing 100, 250 or 500 ppm ZER for 17 weeks. In Exp. 2, a total of 50 female A/J mice were given a single i.p. injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (10 micromol/mouse) to induce lung proliferative lesions. They were then fed the diet mixed with 100, 250 or 500 ppm ZER for 21 weeks. At the termination of the experiments (wk 20 of Exp. 1 and wk 22 of Exp. 2), all animals were subjected to complete necropsy examination to determine the pathological lesions in both tissues. Oral administration of ZER at 100, 250 and 500 ppm significantly inhibited the multiplicity of colonic adenocarcinomas. The treatment also suppressed colonic inflammation. In the lung carcinogenesis, ZER feeding at 250 and 500 ppm significantly inhibited the multiplicity of lung adenomas in a dose-dependent manner. Feeding with ZER resulted in inhibition of proliferation, induction of apoptosis, and suppression of NFkappaB and heme oxygenase (HO)-1 expression in tumors developed in both tissues. Our findings suggest that dietary administration of ZER effectively suppresses mouse colon and lung carcinogenesis through multiple modulatory mechanisms of growth, apoptosis, inflammation and expression of NFkappaB and HO-1 that are involved in carcinogenesis in the colon and lung.

Topics: Animals; Anticarcinogenic Agents; Cell Line, Tumor; Colonic Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred ICR; NF-kappa B; Sesquiterpenes; Zingiber officinale