cyclin-d1 and parthenolide

The disease caused by Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the major causes of death of individuals with acquired immunodeficiency syndrome (AIDS). Development of anti-KSHV drugs is thus crucial. In this study, we investigated the effect of parthenolide (PTL) on the proliferation and NF-κB signaling pathway of KSHV-infected cells. iSLK.219 and KSHV-infected SH-SY5Y cells (SK-RG) were treated with PTL, TaqMan real-time quantitative PCR was used to determine the number of copies of the KSHV genome, and mRNA and protein expression of KSHV genes were analyzed by real-time PCR and immunocytochemistry. A cell viability test was used to measure cell proliferation, and flow cytometry was used to examine the effect of the drug on the cell cycle. Cyclin D1, CDK6, CDK4, and NF-κB-related proteins, including IKKβ, P-p65, and P-IKB-α, were detected by Western blot. The results showed that PTL altered the morphology of the cells, reduced the KSHV copy number, and suppressed the production of ORF50, K8.1, and v-GPCR mRNA and the LANA, ORF50, and K8.1 proteins. It blocked the G1 phase in iSLK.219 cells and decreased the levels of cyclin D1, CDK6, and CDK4 as well as the levels of NF-κB signaling proteins, including IKKβ, P-p65, and P-IKB-α. Together, these results suggest that PTL is a candidate drug that can decrease KSHV pathogenicity by suppressing cell proliferation and inhibiting the NF-κB signaling pathway in KSHV-infected cells.

Topics: Cell Proliferation; Cyclin D1; Herpesvirus 8, Human; Humans; I-kappa B Kinase; Neuroblastoma; NF-kappa B; RNA, Messenger; Sarcoma, Kaposi; Signal Transduction

To investigate the effect of parthenolide (PTL), a sesquiterpene lactone medicinal compound, on the sensitivity of the gastric cancer cell line SGC7901 and the DPP- and ADR-resistant sublines SGC7901/DDP and SGC7901/ADR to cisplatin [diamminedichloroplatinum (Ⅱ), DDP] and adriamycin (ADR) in vitro.. SGC7901, SGC7901/DDP, and SGC7901/ADR were treated with various concentrations of PTL alone or in combination with DDP or ADR. The effects on cell proliferation, apoptosis, and expression/activity of several proliferation/apoptosis-related proteins [B-cell lymphoma-2 (Bcl-2), cyclin D1, nuclear factor-kappa B (NF-κB), and Caspase-8] and drug transporters (P-glycoprotein and multidrug resistance protein-1) were measured using flow cytometry, Western blotting, and in vitro activity assays.. Treatment of SGC7901 cells with PTL inhibited cell growth, increased apoptosis, and sensitized the cells to DPP. Mechanistically, PTL treatment resulted in downregulation of NF-κB activity and Bcl-2 expression, and upregulation of Caspase-8 activity. Similarly, PTL co-treatment of SGC7901/DDP and SGC7901/ADR overcame their resistance to DDP and ADR, respectively, with concomitant inhibition of NF-κB, Bcl-2, Cyclin D1, P-glycoprotein, and multidrug resistance protein-1 expression and/or activity.. PTL treatment decreases drug resistance in SGC7901, SGC7901/DDP, and SGC7901/ADR cells, as reflected by induction of apoptosis, inhibition of proliferation, downregulation of pro-survival and drug resistance pathways, and upregulation of pro-apoptotic pathways. Our results suggest that co-treatment with PTL may thus complement existing therapies for gastric cancer.

Topics: Antineoplastic Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cell Line, Tumor; Cell Proliferation; Cisplatin; Cyclin D1; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Humans; NF-kappa B; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes; Stomach Neoplasms

Tyrosine kinase inhibitors (TKI) have become a first-line treatment for chronic myeloid leuakemia (CML). TKIs efficiently target bulk CML cells; however, they are unable to eliminate the leukaemic stem cell (LSC) population that causes resistance and relapse in CML patients. In this study, we assessed the effects of parthenolide (PTL) and dimethyl amino parthenolide (DMAPT), two potent inhibitors of LSCs in acute myeloid leukaemia (AML), on CML bulk and CML primitive (CD34

Topics: Apoptosis; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclin A; Cyclin D1; Gene Expression Regulation, Neoplastic; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasm Recurrence, Local; NF-kappa B; Reactive Oxygen Species; Sesquiterpenes; Signal Transduction

FMS-like tyrosine kinase 3 (FLT3) is an independent poor prognostic marker of acute myeloid leukemia (AML), and strategies that specifically target FLT3 are therefore of substantial interest. However, previous studies with FLT3 inhibitors as single agents in patients with AML showed few clinical responses. In the present study, combined effects of FLT3 selective inhibitor (SC-203048) and NF-κB selective inhibitor (Parthenolide, PTL) on AML xenograft tumor growth in vivo were examined, and the possible antitumor mechanisms by which SC-203048 and PTL affect AML xenograft tumor growth were also detected. Results showed that the tumor growth was strongly inhibited, and increased cell apoptosis was also observed after treatments, especially in the combination group; meanwhile, the expressions of FLT3, p65, cyclin D1, and Bc1-2 decreased significantly, and the expression of nuclear Silencing mediator for retinoic acid and thyroid hormone receptors (SMRT) increased notably. All results indicate that synergism exists between FLT3 and NF-κB inhibitors, and inhibitors combination treatment may be a potential strategy for AML.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzamides; Cell Line, Tumor; Cyclin D1; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Male; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Nuclear Receptor Co-Repressor 2; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes; Thiophenes; Tumor Burden; Xenograft Model Antitumor Assays

Parthenolide, the principal component of sesquiterpene lactones present in medical plants such as feverfew (Tanacetum parthenium), has been reported to have anti-tumor activity. In this study, we evaluated the therapeutic potential of parthenolide against bladder cancer and its mechanism of action. Treatment of bladder cancer cells with parthenolide resulted in a significant decrease in cell viability. Parthenolide induced apoptosis through the modulation of Bcl-2 family proteins and poly (ADP-ribose) polymerase degradation. Treatment with parthenolide led to G1 phase cell cycle arrest in 5637 cells by modulation of cyclin D1 and phosphorylated cyclin-dependent kinase 2. Parthenolide also inhibited the invasive ability of bladder cancer cells. These findings suggest that parthenolide could be a novel therapeutic agent for treatment of bladder cancer.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Carcinoma; Cell Line, Tumor; Cell Survival; Cyclin D1; Cyclin-Dependent Kinase 2; Diffusion Chambers, Culture; Flow Cytometry; G1 Phase; Humans; Microscopy; Neoplasm Invasiveness; Phosphorylation; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Sesquiterpenes; Signal Transduction; Tanacetum parthenium; Urinary Bladder Neoplasms

The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-kappaB (NF-kappaB) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-kappaB inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either high-dose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulindac combination or high-dose sulindac alone (P < 0.05). Immunohistochemistry of BxPC-3 tumors revealed a significant decrease in Ki-67 and CD31 staining by high-dose sulindac, with no significant changes in COX-1/COX-2 levels or activity in any of the treatment groups. NF-kappaB DNA-binding activity was significantly decreased by high-dose LC-1. Cyclin D1 protein levels were reduced by the low-dose LC-1/sulindac combination or high-dose sulindac alone, correlating with BxPC-3 tumor suppression. These results suggest that LC-1 and sulindac may mediate their antitumor effects, in part, by altering cyclin D1 levels. Furthermore, this study provides preclinical evidence for the therapeutic efficacy of these agents.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Cyclin D1; Humans; Mice; Mice, Nude; NF-kappa B; Pancreatic Neoplasms; Prostaglandin-Endoperoxide Synthases; Sesquiterpenes; Sulindac