8-11-14-eicosatrienoic-acid and Neoplasm-Metastasis

We recently reported that siRNA-knockdown of delta-5-desaturase (D5D), the rate-limiting enzyme converting upstream ω - 6 dihomo-γ-linolenic acid (DGLA) to arachidonic acid, promoted formation of the anti-cancer byproduct 8-hydroxyoctanoic acid (8-HOA) from COX-2-catalyzed DGLA peroxidation, consequently suppressing pancreatic cancer cell growth, migration and invasion. In this study, we have further investigated the anti-tumor effects of D5D-knockdown and the resulting intensified COX-2-catalyzed DGLA peroxidation in subcutaneous xenograft tumors. Four-week old female nude mice (Jackson Laboratory, J:Nu-007850) were injected with human pancreatic cancer cell line BxPC-3 or its D5D knockdown counterpart (via shRNA), followed by 4-week treatments of: vehicle control, DGLA supplementation (8 mg/mouse, twice a week), gemcitabine (30 mg/kg, twice a week), and a combination of DGLA and gemcitabine. In D5D-knockdown tumors, DGLA supplementation promoted 8-HOA formation to a threshold level (> 0.3 µg/g) and resulted in significant tumor reduction (30% vs. control). The promoted 8-HOA not only induced apoptosis associated with altered expression of Bcl-2, cleaved PARP, procaspase 3 and procaspase 9, but also suppressed the tumor metastatic potential via altering MMP-2 and E-cadherin expression. DGLA supplementation resulted in similar anti-tumor effects to those of gemcitabine in our experiments, while the combined treatment led to most significant inhibitory effect on D5D-knockdown tumor growth (70% reduction vs. control). Compared to conventional COX-2 inhibition in cancer treatment, our new strategy that takes advantage of overexpressed COX-2 in cancer cells and tumors, and of abundant ω - 6 fatty acids in the daily diet, should lead us to develop a better and safer anti-pancreatic cancer therapy for patients.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Cell Line, Tumor; Cell Proliferation; Delta-5 Fatty Acid Desaturase; Deoxycytidine; Disease Models, Animal; Drug Synergism; Fatty Acid Desaturases; Female; Gemcitabine; Gene Expression Regulation, Neoplastic; Humans; Mice; Neoplasm Metastasis; Neoplasm Staging; Pancreatic Neoplasms; RNA Interference; RNA, Small Interfering; Xenograft Model Antitumor Assays

We previously demonstrated that knockdown of delta-5-desaturase via siRNA transfection together with dihomo-γ-linolenic acid supplementation inhibited colon cancer cell growth and migration, by promoting the production of the anti-cancer byproduct 8-hydroxyoctanoic acid from Cyclooxygenase-2-catalyzed dihomo-γ-linolenic acid peroxidation. Here, we extend our study to investigate the effects of delta-5-desaturase-knockdown and the resulting intensified dihomo-γ-linolenic acid peroxidation in xenograft tumor mice model.. Four-week old nude mice bearing the human colon cancer cell HCA-7/C29 vs. its delta-5-desaturase knockdown analog (via shRNA transfection) were subject to 4-week treatments of: vehicle control, dihomo-γ-linolenic acid supplementation, 5-Fluorouracil, and combination of dihomo-γ-linolenic acid and 5-Fluorouracil. Tumor growth was monitored during the treatment. At the endpoint, the mice were euthanized and the tumor tissues were collected for further mechanism analysis.. Delta-5-desaturase knockdown (shRNA) together with dihomo-γ-linolenic acid supplementation increased 8-hydroxyoctanoic acid production to a threshold level in xenograft tumors, which consequently induced p53-dependent apoptosis and reduced tumors significantly. The promoted 8-hydroxyoctanoic acid formation was also found to suppress the tumors' metastatic potential via regulating MMP-2 and E-cadherin expressions. In addition, our in vivo data showed that delta-5-desaturase knockdown along with dihomo-γ-linolenic acid supplementation resulted in anti-tumor effects comparable to those of 5-Fluorouracil.. We have demonstrated that our paradigm-shifting strategy of knocking down delta-5-desaturase and taking advantage of overexpressed Cyclooxygenase-2 in tumor cells can be used for colon cancer suppression. Our research outcome will lead us to develop a better and safer anti-cancer therapy for patients.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Antineoplastic Combined Chemotherapy Protocols; Cadherins; Caprylates; Cell Line, Tumor; Colonic Neoplasms; Cyclooxygenase 2; Delta-5 Fatty Acid Desaturase; Fatty Acid Desaturases; Fluorouracil; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Humans; Matrix Metalloproteinase 2; Mice; Neoplasm Metastasis; RNA, Small Interfering; Xenograft Model Antitumor Assays

Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibits the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo antitumor and antimetastasis activities against subcutaneous and orthotopic xenografts of CL1-5 cells in nude mice. Chemical proteomics showed that heat shock protein 90 (HSP90) and heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) bound PBT-1 in CL1-5 cells. Inhibition of HSP90 and hnRNP A2/B1 reduced the activation of AKT and Slug expression. Taken together, these findings suggest that PBT-1 binds to HSP90 and/or hnRNP A2/B1 and initiates antitumor activities by affecting Slug- and AKT-mediated metastasis and tumorigenesis.

Topics: 8,11,14-Eicosatrienoic Acid; Adenocarcinoma; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Cadherins; Cell Line, Tumor; Cell Movement; Heterogeneous-Nuclear Ribonucleoprotein Group A-B; HSP90 Heat-Shock Proteins; Humans; Lung Neoplasms; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Transplantation; Proto-Oncogene Proteins c-akt; Pseudopodia

Five cases of malignant insulinoma and 2 cases of benign insulinoma were studied lipid-chemically. Tissues were collected by surgical operation or biopsy under peritoneoscopy. The total lipid was extracted from each tissue, and one part of each total lipid was separated into phospholipid, triglyceride and other lipid fractions by a thin-layer chromatography (TLC) on silica gel. The fatty acid composition and fatty acid content of each lipid fraction were measured by a gas-liquid chromatography (GLC). The most remarkable difference between malignant and benign isulinoma tissues was a higher percentage value of eicosatrienoic acid in the phospholipid of malignant insulinoma tissues when compared with that of non-malignant insulinoma tissues; the values mentioned above distributed between 9.82 and 3.32 in 5 malignant cases, but were 2.89 and 2.57 in 2 benign cases. Those changes in the phospholipid fatty acid composition of malignant insulinoma tissues may represent one of the mechanisms of malignant growth in the malignant neoplastic tissue.

Topics: 8,11,14-Eicosatrienoic Acid; Adenoma, Islet Cell; Adult; Aged; Female; Humans; Insulin; Lipids; Liver Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Pancreas; Pancreatic Neoplasms; Phospholipids; Triglycerides