No abstract

No abstract

A tylophorine analogue, DCB-3503, has been shown to have potent activity against tumor growth in vitro and in vivo, as well as activity in an autoimmune disease model in vivo. This study focuses on investigating the mechanisms responsible for antitumor activity of DCB-3503. The concentrations for inhibiting 50% growth/colony formation ability are 50/162 and 40/149 nmol/L for PANC-1 and HPAC cells, respectively. The growth inhibition effects are associated with DCB-3503-induced reprogramming of tumor cells. DCB-3503 could interfere with cell cycle progression. Several cell cycle regulatory proteins, including cyclin D 1 , are down-regulated by DCB-3503. Using several different transcription elements coupled with a reporter gene, it was found that the nuclear factor-KB (NF-KB) signaling pathway is the most sensitive pathway mediator affected by DCB-3503. The inhibition of NF-KB activity is dependent on the down-regulation of nuclear phosphorylated p65, a component of the active form of the NF-KB complex. Such a decrease in nuclear phosphorylated p65 can be reversed by a proteosome inhibitor. Furthermore, the activity and protein expression of nuclear IKB kinase A, which is responsible for p65 phosphorylation, is suppressed and down-regulated in cells treated with DCB-3503. In summary, DCB-3503 could affect cell cycle regulatory proteins and is a potent modulator of NF-KB function. It is a potentially useful compound in the management of cancers in which cyclin D1 overexpression and high NF-KB activity play a pivotal role. [Mol Cancer Ther 2006;5(10):2484-93]

Small cell lung cancer (SCLC) represents one of the most aggressive malignancies among cancer types. Not only tumor sample availability is limited, but also the ability for tumor cells to rapidly acquire drug resistance are the rate-limiting bottlenecks for overall survival in current clinical settings. A liquid biopsy capable of capturing and enriching circulating tumor cells (CTCs), together with the possibility of drug screening, is a promising solution. Here, we illustrate the development of a highly efficient ex vivo CTC expansion system based on binary colloidal crystals substrate. Clinical samples were enrolled from 22 patients with SCLC in the study. The CTCs were enriched and expanded from the collected peripheral blood samples. Expanded cells were analyzed for protein expression and observed for drug sensitivity with the use of immunofluorescence and ATP titer evaluation, respectively. Successful CTC spheroid proliferation was established after 4 weeks within 82% of all the collected peripheral blood samples from enrolled patients. Upon immunofluorescence analysis, the enriched cells showed positive markers for EpCAM, TTF-1, synaptophysin and negative for CD45. Additionally, the expanded CTCs demonstrated marked heterogeneity in the expression of E-cadherin and N-cadherin. In a preliminary case series, the drug sensitivity of patient-derived CTC to cisplatin and etoposide was studied to see the correlation with the corresponding therapeutic outcome. In conclusion, our study demonstrates that it is possible to efficiently expand CTCs from SCLC within a clinically relevant time frame; the biomarker information generated from enriched CTCs can assist the selection of effective drugs and improve disease outcome.