Isoalantolactone Induces Reactive Oxygen Species Mediated Apoptosis in Pancreatic Carcinoma PANC-1 Cells

Abstract

Isoalantolactone, a sesquiterpene lactone compound possesses antifungal, antibacteria, antihelminthic and antiproliferative activities. In the present study, we found that isoalantolactone inhibits growth and induces apoptosis in pancreatic cancer cells. Further mechanistic studies revealed that induction of apoptosis is associated with increased generation of reactive oxygen species, cardiolipin oxidation, reduced mitochondrial membrane potential, release of cytochrome c and cell cycle arrest at S phase. N-Acetyl Cysteine (NAC), a specific ROS inhibitor restored cell viability and completely blocked isoalantolactone-mediated apoptosis in PANC-1 cells indicating that ROS are involved in isoalantolactone-mediated apoptosis. Western blot study showed that isoalantolactone increased the expression of phosphorylated p38 MAPK, Bax, and cleaved caspase-3 and decreased the expression of Bcl-2 in a dose-dependent manner. No change in expression of phosphorylated p38 MAPK and Bax was found when cells were treated with isoalantolactone in the presence of NAC, indicating that activation of these proteins is directly dependent on ROS generation. The present study provides evidence for the first time that isoalantolactone induces ROS-dependent apoptosis through intrinsic pathway. Furthermore, our in vivo toxicity study demonstrated that isoalantolactone did not induce any acute or chronic toxicity in liver and kidneys of CD1 mice at dose of 100 mg/kg body weight. Therefore, isoalantolactone may be a safe chemotherapeutic candidate for the treatment of human pancreatic carcinoma.

Evodiamine induces apoptosis in pancreatic carcinoma PANC-1 cells via NF κB inhibition

“…Human pancreatic cancer has a very poor prognosis; even after curative resection, and is currently fourth leading cause of cancer-related deaths in United States (Fujioka et al, 2003;Khan et al, 2012a). It is well established that NF-κB constitutively expressed in pancreatic cancer cells.…”

“…Cell viability was determined by MTT assay as described by us previously (Khan et al, 2012a). Briefly PANC-1 cells were seeded into 96-well culture plates in triplicates and treated with DMSO or various concentrations of evodiamine (0.1-10 μM) for 24 hours.…”

“…Currently, gemcitabine is the most effective chemotherapeutic drug for the treatment of pancreatic cancer. However, even with this drug the objective tumor response rate remains considerably low (Khan et al, 2012a;Ou et al, 2010). Furthermore, gemcitabine is reported to up-regulate nuclear factor-κB (NF-κB) in pancreatic cancer cells which is associated with the development of drug resistance (Ou et al, 2010).…”

“…Despite continuing advances in radiotherapy, surgery and chemotherapy, the overall 5-year survival rate remains less than 3 years (Khan et al, 2012a). Currently, gemcitabine is the most effective chemotherapeutic drug for the treatment of pancreatic cancer.…”

Tubeimoside-1 induces oxidative stress-mediated apoptosis and G0/G1 phase arrest in human prostate carcinoma cells in vitro

“…Cell viability was determined by the MTT assay as described previously [21] . Briefly, DU145 and PC3 cells were seeded in 96-well tissue culture plates and incubated in a CO 2 incubator for 24 h, and the cells were then exposed to different concentrations of TBMS1 (1-100 μmol/L) for 24 h. Following treatment, 10 μL MTT reagent (5 mg/mL) was added to each well, and cells were further incubated at 37 °C for 4 h. Subsequently, 150 μL DMSO was added to dissolve the formazan crystals, and absorbance was measured at 570 nm in a microplate reader (Thermo Scientific, Varioskan Flash, USA).…”