pregna-4-17-diene-3-16-dione and Pancreatic-Neoplasms

Biliary cancer and pancreatic cancer are considered to be difficult diseases to cure. Although complete resection provides the only means of curing these cancers, the rate of resectability is not high. Therefore, chemotherapy is often selected in patients with advanced unresectable biliary-pancreatic cancer. Many combination chemotherapy regimens have been applied in clinical trials. However, the survival time is not satisfactory. On the other hand, most chemotherapeutic agents induce anti-apoptotic transcriptional factor nuclear factor kappa b (NF-κB) activation, and agent-induced NF-κB activation is deeply involved in the onset of chemoresistance. Recently, novel approaches to potentiating chemosensitivity in cases of biliary-pancreatic cancer using NF-κB inhibitors with cytotoxic agents have been reported, most of which comprise translational research, although some clinical trials have also been conducted. Nevertheless, to date, there is no breakthrough chemotherapy regimen for these diseases. As some reports show promising data, combination chemotherapy consisting of a NF-κB inhibitor with chemotherapeutic agents seems to improve chemosensitivity and prolong the survival time of biliary-pancreatic cancer patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamidines; Biliary Tract Neoplasms; Bortezomib; Camptothecin; Curcumin; Deoxycytidine; Ditiocarb; Drug Resistance, Neoplasm; Gemcitabine; Guanidines; Humans; Irinotecan; Molecular Targeted Therapy; NF-kappa B; Paclitaxel; Pancreatic Neoplasms; Pregnenediones; Treatment Outcome

Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pancreatic Neoplasms; Pregnenediones; Proto-Oncogene Proteins c-akt; Signal Transduction; Structure-Activity Relationship; TOR Serine-Threonine Kinases; Tumor Cells, Cultured

E- and Z-guggulsterones and nine guggulsterone derivatives (GSDs) were synthesized and evaluated for their preferential cytotoxicity against human PANC-1 cell in nutrient deprived medium utilizing antiausterity strategy. Among the synthesized compounds, GSD-1 and GSD-7 showed potent cytotoxicity against PANC-1 cells under nutrient-deprived conditions in a concentration dependent manner, with a PC

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Survival; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Pancreatic Neoplasms; Pregnenediones; Structure-Activity Relationship

Inadequate efficacy, high toxicity and drug resistance associated with existing chemotherapeutic agents mandate a need for novel therapeutic strategies for highly aggressive Pancreatic Cancer (PC). Guggulsterone (GS) exhibits potent anti-proliferative effects against various cancer cells and has emerged as an attractive candidate for use in complementary or preventive cancer therapies. However, the knowledge regarding the therapeutic potential of GS in PC is still limited and needs to be explored. We studied the effect of GS on PC cell growth, motility and invasion and elucidated the molecular mechanisms associated with its anti-tumor effects. Treatment of Capan1 and CD18/HPAF PC cells with GS resulted in dose- and time-dependent growth inhibition and decreased colony formation. Further, GS treatment induced apoptosis and cell cycle arrest as assessed by Annexin-V assay and FACS analysis. Increased apoptosis following GS treatment was accompanied with Bad dephosphorylation and its translocation to the mitochondria, increased Caspase-3 activation, decreased Cyclin D1, Bcl-2 and xIAP expression. Additionally, GS treatment decreased motility and invasion of PC cells by disrupting cytoskeletal organization, inhibiting activation of FAK and Src signaling and decreased MMP9 expression. More importantly, GS treatment decreased mucin MUC4 expression in Capan1 and CD18/HPAF cells through transcriptional regulation by inhibiting Jak/STAT pathway. In conclusion, our results support the utility of GS as a potential therapeutic agent for lethal PC.

Topics: Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cytoskeleton; Dose-Response Relationship, Drug; Focal Adhesion Kinase 1; Humans; Immunoblotting; Isoenzymes; Janus Kinases; Microscopy, Confocal; Mucin-4; Neoplasm Metastasis; Pancreatic Neoplasms; Pregnenediones; Promoter Regions, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; src-Family Kinases; STAT Transcription Factors; STAT1 Transcription Factor; STAT3 Transcription Factor; Time Factors

Guggulsterone is a dietary plant sterone possessing therapeutic potential against cancers. However, the antitumor effect of this natural compound on pancreatic cancer has not been determined yet. This study was designed to investigate the therapeutic efficacy of guggulsterone in pancreatic cancer.. In this study, we examined the effect of guggulsterone on cell proliferation and apoptosis in pancreatic cancer cell lines, and then, we investigated the mechanisms responsible for the effect of guggulsterone. Finally, we investigated whether the combination of guggulsterone and gemcitabine had an additional therapeutic effect compared to gemcitabine single regimen in pancreatic cancer cell lines (in vitro) and in a xenograft model using nude mice (in vivo).. In vitro, the combination treatment resulted in more growth inhibition and apoptosis through the down-regulation of nuclear factor κB activity with suppression of Akt and BcL-2 and through the activation of c-Jun NH(2)-terminal kinase and Bax in pancreatic cancer cell lines. In vivo, the combination therapy augmented tumor growth inhibition through the same mechanisms in tumor tissue.. The combination of guggulsterone to gemcitabine enhanced antitumor efficacy through apoptosis induction by suppressing Akt and nuclear factor κB activity and by modulating apoptosis-related protein expression in pancreatic cancer.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Deoxycytidine; DNA; Drug Synergism; Gemcitabine; Humans; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred BALB C; Mice, Nude; NF-kappa B; Oncogene Protein v-akt; Pancreatic Neoplasms; Pregnenediones; Xenograft Model Antitumor Assays