cytochrome-c-t and xanthohumol

Deregulation of glycolysis is a common phenomenon in human colorectal cancer (CRC). In the present study, we reported that Hexokinase 2 (HK2) is overexpressed in human CRC tissues and cell lines, knockout of HK2 inhibited cell proliferation, colony formation, and xenograft tumor growth. We demonstrated that the natural compound, xanthohumol, has a profound anti-tumor effect on CRC via down-regulation of HK2 and glycolysis. Xanthohumol suppressed CRC cell growth both

Topics: Animals; Apoptosis; Cell Line, Tumor; Colorectal Neoplasms; Cytochromes c; Female; Flavonoids; Glycolysis; Hexokinase; Humans; Immunohistochemistry; Mice; Mice, Nude; Propiophenones; Signal Transduction; Xenograft Model Antitumor Assays

Plant-derived polyhenols inhibit cancer cell proliferation and induce apoptosis. Recently, prenylflavonoids and alkyl-phloroacetophenones have been reported for their in vitro antitumor activity. In the present study, we examined the cytotoxic activity of prenyl (3-PAP) and geranyl (3-GAP) derivatives of phloroacetophenone, and xanthohumol (XN), a prenyl-chalcone, in human breast cancer (MCF-7) and human sarcoma (HT1080) cell lines in vitro. 3-GAP showed the strongest cytotoxicity in these cell lines with IC(50) values of less than 10 µM. In addition, we report that 3-GAP is a more potent anti-cancer agent for breast cancer than XN which is a well-known anticancer flavonoid. Moreover, 3-GAP did not induce cytotoxicity in the normal cell line, TCMK-1, whereas 3-PAP and XN significantly reduced TCMK-1 cell viability. In 3-GAP-treated MCF-7 cells, nuclear accumulation and transcriptional activity of p53 were increased. In addition, pro-apoptotic Bax but not B-cell lymphoma 2 (Bcl-2) expression was increased by 3-GAP. In accordance with the Bax increase, 3-GAP induced mitochondrial cytochrome c release and activated caspase-9, an initiator of the caspase cascade. In the MCF-7 cell line which does not express caspase-3, activation of caspase-7, a member of the caspase-3 subfamily, was increased by 3-GAP. The present results indicate that synthetic 3-GAP is a safe and effective anti-cancer agent, and the Bax-mediated mitochondrial pathway is the main apoptosis signaling pathway of 3-GAP in MCF-7 cells.

Topics: Acetophenones; Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Caspases; Cell Line; Cell Line, Tumor; Cytochromes c; Female; Flavonoids; Humans; Inhibitory Concentration 50; Mitochondria; Phytotherapy; Plant Extracts; Propiophenones; Proto-Oncogene Proteins c-bcl-2; Sarcoma; Tumor Suppressor Protein p53

The effect of the biologically active prenylated chalcone and potential anticancer agent xanthohumol (1) has been investigated on apoptosis of the T98G human malignant glioblastoma cell line. Compound 1 decreased the viability of T98G cells by induction of apoptosis in a time- and concentration-dependent manner. Apoptosis induced by 1 was associated with activation of caspase-3, caspase-9, and PARP cleavage and was mediated by the mitochondrial pathway, as exemplified by mitochondrial depolarization, cytochrome c release, and downregulation of the antiapoptotic Bcl-2 protein. Xanthohumol induced intracellular reactive oxygen species (ROS), an effect that was reduced by pretreatment with the antioxidant N-acetyl-L-cysteine (NAC). Intracellular ROS production appeared essential for the activation of the mitochondrial pathway and induction of apoptosis after exposure to 1. Oxidative stress due to treatment with 1 was associated with MAPK activation, as determined by ERK1/2 and p38 phosphorylation. Phosphorylation of ERK1/2 and p38 was attenuated using NAC to inhibit ROS production. After treatment with 1, ROS provided a specific environment that resulted in MAPK-induced cell death, with this effect reduced by the ERK1/2 specific inhibitor PD98059 and partially inhibited by the p38 inhibitor SB203580. These findings suggest that xanthohumol (1) is a potential chemotherapeutic agent for the treatment of glioblastoma multiforme.

Topics: Acetylcysteine; Antineoplastic Agents; Apoptosis; Caspase 3; Caspase 9; Cyclohexenes; Cytochromes c; Dose-Response Relationship, Drug; Flavonoids; Glioblastoma; Humans; Imidazoles; Italy; Mitogen-Activated Protein Kinases; Molecular Structure; Poly(ADP-ribose) Polymerases; Propiophenones; Pyridines; Reactive Oxygen Species; Terpenes

To study the effects of xanthohumol (XN), a flavonoid found in hops (Humulus lupulus) and honokiol (HK), a lignan isolated from Magnolia officinalis, alone and in combination, on apoptotic signaling in 3T3-L1 adipocytes.. 3T3-L1 mature adipocytes were incubated with various concentrations of XN and HK alone and in combination. Viability and apoptosis were quantified using an MTS-based cell viability assay and single-stranded DNA assay, respectively. Expression of apoptosis related proteins including cleaved poly(ADP-ribose) polymerase (PARP), cytochrome c, Bcl-2, caspase-3/7, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Akt was analyzed by western blotting.. Combinations of XN and HK significantly decreased viability and induced apoptosis in a dose-dependent manner and more than the additive responses to XN and HK alone. Western blot analysis showed an increase in cleaved PARP and cytochrome c release and decrease in expression of Bcl-2 protein by XN plus HK, whereas XN and HK individually had no effect. Furthermore, the combination of XN and HK activated PTEN and inactivated Akt by decreasing levels of phosphorylated PTEN and phosphorylated Akt.. We demonstrated that although XN and HK showed little or no effect as individual compounds, in combination (XN plus HK) they showed enhanced activity in inducing apoptosis via the cytochrome c/caspase-3/PARP and PTEN/Akt pathways in 3T3-L1 adipocytes.

Topics: 3T3-L1 Cells; Adipocytes; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Biphenyl Compounds; Caspase 3; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Drug Synergism; Flavonoids; Lignans; Mice; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases; Propiophenones; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction