5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one and Pancreatic-Neoplasms

Pancreatic ductal adenocarcinoma (PDAC) is a formidable medical challenge due to its malignancies and the absence of effective treatment. c-Myc, as an important transcription factor, plays crucial roles in cell cycle progression, apoptosis and cellular transformation. The c-Myc inhibitor, 10058-F4, has been reported act as a tumor suppressor in several different tumors. In current study, the tumor-suppressive roles of 10058-F4 was observed in human pancreatic cancer cells in vitro as demonstrated by decreased cell viability, cell cycle arrest at the G1/S transition and increased caspase3/7 activity. And tumor responses to gemcitabine were also significantly enhanced by 10058-F4 in PANC-1 and SW1990 cells. In a subcutaneous xenograft model, however, 10058-F4 showed no significant influence on pancreatic tumorigenesis. When combined with gemcitabine, tumorigenesis was drastically attenuated compared with gemcitabine group or 10058-F4 group; this synergistic effect was accompanied with decreased PCNA-positive cells and reduced TUNEL-positive cells in the combined treated group. Subsequent studies revealed that decreased glycolysis may be involved in the inhibitory effect of 10058-F4 on PDAC. Taken together, this study demonstrates the roles of 10058-F4 in PDAC and provides evidence that 10058-F4 in combination with gemcitabine showed significant clinical benefit over the usage of gemcitabine alone.

Topics: Animals; Carcinoma, Pancreatic Ductal; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Growth Inhibitors; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Proto-Oncogene Proteins c-myc; Thiazoles; Xenograft Model Antitumor Assays

Pancreatic ductal adenocarcinoma (PDA) is frequently driven by oncogenic KRAS(KRAS*) mutations. We developed a mouse model of KRAS*-induced PDA and, based on genetic results demonstrating that KRAS* tumorigenicity depends on Myc activity, we evaluated the therapeutic potential of an orally administered anti-Myc drug.. We tested the efficacy of Mycro3, a small-molecule inhibitor of Myc-Max dimerization, in the treatment of mouse PDA (n = 9) and also of xenografts of human pancreatic cancer cell lines (NOD/SCID mice, n = 3-12). Tumor responses to the drug were evaluated by PET/CT imaging, and histological, immunohistochemical, molecular and microarray analyses. The Student's t test was used for differences between groups. All statistical tests were two-sided.. Transgenic overexpression of KRAS* in the pancreas resulted in pancreatic intraepithelial neoplasia in two-week old mice, which developed invasive PDA a week later and became moribund at one month. However, this aggressive form of pancreatic tumorigenesis was effectively prevented by genetic ablation of Myc specifically in the pancreas. We then treated moribund, PDA-bearing mice daily with the Mycro3 Myc-inhibitor. The mice survived until killed at two months. PET/CT image analysis (n = 5) demonstrated marked shrinkage of PDA, while immunohistochemical analyses showed an increase in cancer cell apoptosis and reduction in cell proliferation (treated/untreated proliferation index ratio: 0.29, P < .001, n = 3, each group). Tumor growth was also drastically attenuated in Mycro3-treated NOD/SCID mice (n = 12) carrying orthotopic or heterotopic xenografts of human pancreatic cancer cells (eg, mean tumor weight ± SD of treated heterotopic xenografts vs vehicle-treated controls: 15.2±5.8 mg vs 230.2±43.9 mg, P < .001).. These results provide strong justification for eventual clinical evaluation of anti-Myc drugs as potential chemotherapeutic agents for the treatment of PDA.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Pancreatic Ductal; Cell Proliferation; Gene Expression Regulation, Neoplastic; Gene Knock-In Techniques; Immunohistochemistry; Male; Mice; Mice, Inbred NOD; Mice, SCID; Mice, Transgenic; Pancreatic Neoplasms; Positron-Emission Tomography; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Thiazoles; Tomography, X-Ray Computed; Up-Regulation; Xenograft Model Antitumor Assays

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Pancreatic Ductal; Male; Pancreatic Neoplasms; Proto-Oncogene Proteins c-myc; Proto-Oncogene Proteins p21(ras); Thiazoles