cytochrome-c-t and parthenolide

Parthenolide, a naturally occurring sesquiterpene lactone derived from feverfew (Tanacetum parthenium), exhibits exceptional anti-cancer and anti-inflammatory properties, making it a prominent candidate for further studies and drug development. In this review, we briefly investigate molecular events and cell-specific activities of this chemical in relation to cytochrome c, nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), signal transduction and activation of transcription (STAT), reactive oxygen species (ROS), TCP, HDACs, microtubules, and inflammasomes. This paper reports that parthenolide shows strong NF-κB- and STAT-inhibition-mediated transcriptional suppression of pro-apoptotic genes. This compound acts both at the transcriptional level and by direct inhibition of associated kinases (IKK-β). Similarly, this review discusses parthenolide-induced ROS-mediated apoptosis of tumor cells via the intrinsic apoptotic signaling pathway. The unique ability of this compound to not harm normal cells but at the same time induce sensitization to extrinsic as well as intrinsic apoptosis signaling in cancer cells provides an important, novel therapeutic strategy for treatment of cancer and inflammation-related disorders.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Agents; Apoptosis; Cytochromes c; Humans; I-kappa B Kinase; Inflammation; Neoplasms; NF-kappa B; Plant Extracts; Reactive Oxygen Species; Sesquiterpenes; Signal Transduction; STAT Transcription Factors; Tanacetum parthenium; Transcription, Genetic

Parthenolide (PT), a NF-κB inhibitor, has recently been demonstrated as a promising anticancer agent that promotes apoptosis of cancer cells. 5-fluorouracil (5-FU) has been a drug of choice for treatment of colorectal cancer (CRC). Unfortunately, many of the therapies that use 5-FU alone or in combination with other agents are likely to become ineffective due to drug resistance. In the present study, we investigated the antitumor effect of PT combined with 5-FU on a human CRC cell line, SW620. The results demonstrated that combination of PT and 5-FU induced apoptosis which was determined using MTT, cell cycle analysis, annexin-V assay, and Hoechst 33258 staining. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, cytochrome C release, and activation of caspase 3 and 9. Moreover, intra-peritoneal injection of PT and 5-FU showed significant inhibition of tumor growth in the xenograft model. These results demonstrate that PT exhibits anticancer activity in human colorectal cancer in vitro and in vivo. These findings provide an efficacious strategy to overcome 5-FU resistance in certain CRC.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antimetabolites, Antineoplastic; Apoptosis; Caspase 3; Caspase 9; Cell Cycle; Cell Line, Tumor; Colorectal Neoplasms; Cytochromes c; Drug Combinations; Drug Resistance, Neoplasm; Drug Synergism; Fluorouracil; Humans; Mice; Mice, Nude; Mitochondria; Neoplasm Transplantation; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes; Xenograft Model Antitumor Assays

Hsp90 inhibitor geldanamycin and parthenolide have been shown to induce apoptosis in cancer cells. However, the combined effect of geldanamycin and parthenolide on epithelial ovarian cancer cells has not been studied. In respect of cell death process, we investigated the promoting effect of parthenolide on geldanamycin-induced apoptosis in the human epithelial ovarian carcinoma cell lines OVCAR-3 and SK-OV-3. Geldanamycin induced a decrease in Bid, Bcl-2, Bcl-xL and survivin protein levels; an increase in Bax and tumour suppressor p53 levels; loss of the mitochondrial transmembrane potential; cytochrome c release; activation of caspases (-8, -9 and -3); cleavage of PARP-1; and increase in the reactive oxygen species formation. Parthenolide enhanced geldanamycin-induced changes in the apoptosis-related protein levels, reactive oxygen species formation, nuclear damage and cell death. The combined effect was inhibited by the addition of oxidant scavengers. The results suggest that parthenolide may potentiate the apoptotic effect of geldanamycin on ovarian carcinoma cell lines by the activation of the caspase-8- and Bid-dependent pathway and the mitochondria-mediated apoptotic pathway. The apoptosis-promoting effect seems to be mediated by the stimulatory effect on the formation of reactive oxygen species.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-2-Associated X Protein; Benzoquinones; Blotting, Western; Carcinoma, Ovarian Epithelial; Caspase 3; Caspase 8; Caspase 9; Cell Line, Tumor; Cell Survival; Cytochromes c; Female; HSP90 Heat-Shock Proteins; Humans; Lactams, Macrocyclic; Mitochondria; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Reactive Oxygen Species; Sesquiterpenes; Tumor Suppressor Protein p53

Parthenolide (PT), a principal active component in medicinal plants, has been used conventionally to treat migraine and inflammation. This component has recently been reported to induce apoptosis in cancer cells, through mitochondrial dysfunction. In the present study, we investigated PT-mediated cell death signaling pathway by focusing on the involvement of Bcl-2 family members in human colorectal cancer cells. We also investigated the inhibitory effect of PT on tumor growth in xenografts. Using the human colorectal cancer cell lines HT-29, SW620 and LS174T, we demonstrated that treatment of these cancer cells with PT induces apoptosis using MTT, Annexin V assay and Hoechst 33258 staining. Apoptosis through the mitochondrial pathway was confirmed by detecting regulation of Bcl-2 family members, cytochrome c release and caspase activation. Moreover, intraperitoneal injection of PT showed significant inhibition of tumor growth, angiogenesis in the xenograft model. These results demonstrate that PT exhibits anti-cancer activity in human colorectal cancer in vitro and in vivo. These findings may also provide a novel approach for the treatment of colorectal cancer.

Topics: Apoptosis; Carcinogenesis; Colorectal Neoplasms; Cytochromes c; Genes, bcl-2; HT29 Cells; Humans; Mitochondria; Neovascularization, Pathologic; Sesquiterpenes; Signal Transduction; Xenograft Model Antitumor Assays

In this study, we have examined the molecular events induced by parthenolide, a sesquiterpene lactone, and explored possible mechanisms of resistance and sensitization of tumor cells to Taxol. We showed that parthenolide could antagonize Taxol-mediated nuclear factor-kappaB (NF-kappaB) nuclear translocation and activation and Bcl-xl up-regulation by selectively targeting I-kappaB kinase activity. In A549 cells, inhibition of nuclear factor-kappaB by parthenolide resulted in activation of the mitochondrial death pathway to promote cytochrome c release and caspase 3 and 9 activation. In contrast, Taxol alone induced apoptosis via a pathway independent of mitochondria cytochrome c cascade. In addition, depletion of Bcl-xl rescued the apoptotic response to Taxol. Moreover, treatment with parthenolide increased the efficacy of the Taxol-induced inhibition of A549 tumor xenografts in mice. This study elucidated the cellular responses induced by parthenolide that decrease the threshold of mitochondria-dependent apoptosis in the treatment of non-small cell lung cancer cells.

Topics: Analysis of Variance; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Carcinoma, Non-Small-Cell Lung; Caspases; Cell Line, Tumor; Cell Survival; Cytochromes c; Drug Synergism; Histocytochemistry; I-kappa B Kinase; Kaplan-Meier Estimate; Lung Neoplasms; Mice; Mitochondrial Membranes; NF-kappa B; Paclitaxel; Sesquiterpenes; Xenograft Model Antitumor Assays

To investigate the effect of parthenolide (PAR) on proliferation and apoptosis in gastric cancer cell line SGC7901.. Human gastric cancer cell line SGC7901 cells were incubated with various concentration of PAR. After various periods of incubation, the proliferation of SGC7901 cells was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide methyl thiazolyl tetrazolium (MTT) assay. Apoptosis was measured by the annexin V-fluorescein isothiocyanate fluoresceine isothiocyanate (FITC)/propidium iodide (PI) double labeled staining method and the morphology of the cell was observed under a fluorescent microscope. Mitochondrial potential was measured by flow cytometry after Rhodamine 123 staining. The expressions of cytochrome C and the Bcl-2 family of proteins, including Bcl-2, Bax, Bid and tBid were measured by Western blot. Caspase 3 and 8 activities were measured by enzyme-linked immunosorbent assay.. Treatment with PAR induced apoptosis as confirmed by annexin V-FITC/PI assay. PAR-induced apoptosis was associated with intracellular events including the decline of mitochondrial potential, increased release of cytochrome C from the mitochondria, decreased expression of Bcl-2, increased expression of Bax, Bid and tBid and activation of caspase 3 and 8.. These results suggest that possibly via activation of the mitochondrial pathway, PAR causes mitochondrial damage leading to the release of cytochrome C and by regulating the expression of the Bcl-2 family of proteins and activating caspases which leads to results in apoptotic cell death in SGC7901 cells. Our results might be helpful in formulating new therapeutic approaches using Chinese herbal medicine.

Topics: Apoptosis; Cell Line, Tumor; Cell Proliferation; Cytochromes c; Humans; NF-kappa B; Sesquiterpenes; Stomach Neoplasms

Cholangiocarcinomas are intrahepatic bile duct carcinomas that are known to have a poor prognosis. Sesquiterpene lactone parthenolide, which is the principal active component in medicinal plants, has been used to treat tumors. Parthenolide effectively induced apoptosis in all four cholangiocarcinoma cell lines in a dose-dependent manner. However, the sarcomatous SCK cells were more sensitive to parthenolide than the other adenomatous cholangiocarcinoma cells. Therefore, this study investigated whether or not the expression of p53, the Fas/Fas ligand (FasL), Bcl-2/Bcl-X(L) determines the enhanced drug susceptibility of SCK cells. The results showed that Bcl-2 family molecules, such as Bid, Bak, and Bax, are involved in the parthenolide-induced apoptosis and that the defective expression of Bcl-X(L) might contribute to the higher parthenolide sensitivity in the SCK cells than in the other adenomatous cholangiocarcinoma cells. SCK cells, which stably express Bcl-X(L), were resistant to parthenolide, whereas Bcl-X(L)-positive Choi-CK cells transfected with the antisense Bcl-X(L) showed a higher parthenolide sensitivity than the vector control cells. Molecular dissection revealed that Bcl-X(L) inhibited the translocation of Bax to the mitochondria, decreased the generation of intracellular reactive oxygen species, reduced the mitochondrial transmembrane potential (deltapsi(m)), decreased the release of cytochrome c, decreased the cleavage of poly(ADP-ribose) polymerase, and eventually inhibited apoptotic cell death. These results suggest that parthenolide effectively induces oxidative stress-mediated apoptosis, and that the susceptibility to parthenolide in cholangiocarcinoma cells might be modulated by Bcl-X(L) expression in association with Bax translocation to the mitochondria.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; bcl-X Protein; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cholangiocarcinoma; Cytochromes c; Drug Resistance, Neoplasm; Fas Ligand Protein; fas Receptor; Humans; Membrane Glycoproteins; Membrane Potentials; Mitochondria; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Sesquiterpenes; Tumor Suppressor Protein p53