eriocalyxin-b and Pancreatic-Neoplasms

Pancreatic cancer has a poor prognosis with a 5-year survival rate of <5%. It does not respond well to either chemotherapy or radiotherapy, due partly to apoptotic resistance (AR) of the cancer cells. AR has been attributed to certain genetic abnormalities or defects in apoptotic signaling pathways. In pancreatic cancer, significant mutations of K-ras and p53, constitutive activation of NFκB, over-expression of heat shock proteins (Hsp90, Hsp70), histone deacetylase (HDACs) and the activities of other proteins (COX-2, Nrf2 and bcl-2 family members) are closely linked with resistance to apoptosis and invasion. AR has also been associated with aberrant signaling of MAPK, PI3K-AKT, JAK/STAT, SHH, Notch, and Wnt/β-catenin pathways. Strategies targeting these signaling molecules and pathways provide an alternative for overcoming AR in pancreatic cancer. The use of herbal medicines or natural products (HM/NPs) alone or in combination with conventional anti-cancer agents has been shown to produce beneficial effects through actions upon multiple molecular pathways involved in AR. The current standard first-line chemotherapeutic agents for pancreatic cancer are gemcitabine (Gem) or Gem-containing combinations; however, the efficacy is dissatisfied and this limitation is largely attributed to AR. Meanwhile, emerging data have pointed to a combination of HM/NPs that may augment the sensitivity of pancreatic cancer cells to Gem. Greater understanding of how these compounds affect the molecular mechanisms of apoptosis may propel development of HM/NPs as anti-cancer agents and/or adjuvant therapies forward. In this review, we give a critical appraisal of the use of HM/NPs alone and in combination with anti-cancer drugs. We also discuss the potential regulatory mechanisms whereby AR is involved in these protective pathways.

Topics: Apoptosis; Biological Products; Diterpenes; Drug Resistance, Neoplasm; Herbal Medicine; Humans; Medicine, Chinese Traditional; Pancreatic Neoplasms; Quassins; Reactive Oxygen Species

Pancreatic cancer, associated with poor prognosis and low survival rate, has been the fourth leading cause of cancer-related death in the US. Although gemcitabine (Gem) is the first-line chemotherapeutic drug in the management of pancreatic cancer, the median survival extension is only 1.5 months, indicating unsatisfactory clinical results. Therefore, exploring agents that can enhance the anti-cancer activity of Gem would be an attractive strategy.. Our previous studies have demonstrated that eriocalyxin b (EriB), an ent‑kaurane diterpenoid isolated from Isodon eriocalyx (Dunn.) Hara, possesses anti-pancreatic cancer effects, thus acting as a potential therapeutic agent. In this study, we further investigated whether EriB or the ethanol extract of I. eriocalyx (Isodon) could potentiate the cytotoxic activity of Gem in human pancreatic adenocarcinoma cells. In addition, the mechanism associated with their effects was also studied.. The anti-proliferation effect was assessed by MTT assay and Ki-67 immunostaining. The combination effect (addition, synergism and antagonism) of various agents was calculated by the Calcusyn software (Biosoft), utilizing the T.C. Chou Method. Apoptosis was detected using Annexin V and PI double staining followed by quantitative flow cytometry. Protein expression regulated by various treatments was analyzed by western blotting.. The combination index revealed that Gem and EriB (or Isodon extract) had synergistic anti-proliferative effect. Both cellular apoptotic and anti-proliferative effects of Gem were significantly increased after combination with EriB (or Isodon extract). The underlying mechanisms involved in the combination effects were elucidated, which include: (1) increased activation of the caspase cascade; (2) reduction of PDK1 and AKT phosphorylation; (3) induction of JNK phosphorylation by Isodon and Gem combination.. Gem and EriB (or Isodon extract) taken together in combination regulated PDK1/AKT1/caspase and JNK signaling and promoted apoptosis synergistically, which may contribute to the much increased anti-proliferative activity compared to either agent alone.

Topics: Adenocarcinoma; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspases; Cell Line, Tumor; Deoxycytidine; Diterpenes; Gemcitabine; Humans; Isodon; MAP Kinase Signaling System; Pancreatic Neoplasms; Phosphorylation; Plant Extracts; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Pyruvate Dehydrogenase Acetyl-Transferring Kinase

Thiol-containing antioxidant systems play an important role in regulating cellular redox homeostasis. Several anti-cancer agents act by targeting these systems by inducing the production of reactive oxygen species (ROS). Our earlier studies have shown that Eriocalyxin B (EriB), a diterpenoid isolated from Isodon eriocalyx, possesses anti-pancreatic tumour activities in vitro and in vivo. The present study further demonstrated that only thiol-containing antioxidants, N-acetylcysteine (NAC) or dithiothreitol (DTT), inhibited EriB-induced cytotoxicity and apoptosis. EriB suppressed the glutathione and thioredoxin antioxidant systems, thus increasing the intracellular ROS levels and regulating the MAPK, NFκB pathways. Treatment with EriB depleted the intracellular thiol-containing proteins in CAPAN-2 cells. In vivo studies also showed that EriB treatment (2.5 mg/kg) reduced the pancreatic tumour weights significantly in nude mice with increased superoxide levels. Taken together, our results shed important new light on the molecular mechanisms of EriB acting as an apoptogenic agent and its therapeutic potential for pancreatic cancer.

Topics: Animals; Antioxidants; Apoptosis; Cell Line, Tumor; Diterpenes; Glutathione; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Reactive Oxygen Species; Signal Transduction

Pancreatic cancer is difficult to detect early and responds poorly to chemotherapy. A breakthrough in the development of new therapeutic agents is urgently needed. Eriocalyxin B (EriB), isolated from the Isodon eriocalyx plant, is an ent-kaurane diterpenoid with promise as a broad-spectrum anti-cancer agent. The anti-leukemic activity of EriB, including the underlying mechanisms involved, has been particularly well documented. In this study, we demonstrated for the first time EriB's potent cytotoxicity against four pancreatic adenocarcinoma cell lines, namely PANC-1, SW1990, CAPAN-1, and CAPAN-2. The effects were comparable to that of the chemotherapeutic camptothecin (CAM), but with much lower toxicity against normal human liver WRL68 cells. EriB's cytoxicity against CAPAN-2 cells was found to involve caspase-dependent apoptosis and cell cycle arrest at the G2/M phase. Moreover, the p53 pathway was found to be activated by EriB in these cells. Furthermore, in vivo studies showed that EriB inhibited the growth of human pancreatic tumor xenografts in BALB/c nude mice without significant secondary adverse effects. These results suggest that EriB should be considered a candidate for pancreatic cancer treatment.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Camptothecin; Caspases; Cell Line; Cell Line, Tumor; Diterpenes; G2 Phase Cell Cycle Checkpoints; Humans; Liver; M Phase Cell Cycle Checkpoints; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Pancreatic Neoplasms; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays