mahanine has been researched along with Adenocarcinoma* in 2 studies
2 other study(ies) available for mahanine and Adenocarcinoma
| Article | Year |
|---|---|
Mahanine drives pancreatic adenocarcinoma cells into endoplasmic reticular stress-mediated apoptosis through modulating sialylation process and Ca
Endoplasmic reticulum (ER) stress results from protein unfolding/misfolding during cellular maturation, which requires a coordinated action of several chaperones and enzymes and Ca Topics: Adenocarcinoma; Animals; Apoptosis; Calcium Signaling; Carbazoles; Endoplasmic Reticulum Stress; Female; Humans; Mice, Nude; Neuraminidase; Pancreatic Neoplasms; Protein Processing, Post-Translational; Reactive Oxygen Species; Sialic Acids; Sialyltransferases; Tumor Cells, Cultured; Unfolded Protein Response; Xenograft Model Antitumor Assays | 2018 |
Oxidative inhibition of Hsp90 disrupts the super-chaperone complex and attenuates pancreatic adenocarcinoma in vitro and in vivo.
Pancreatic cancer is almost always fatal, in part because of its delayed diagnosis, poor prognosis, rapid progression and chemoresistance. Oncogenic proteins are stabilized by the Hsp90, making it a potential therapeutic target. We investigated the oxidative stress-mediated dysfunction of Hsp90 and the hindrance of its chaperonic activity by a carbazole alkaloid, mahanine, as a strategic therapeutic in pancreatic cancer. Mahanine exhibited antiproliferative activity against several pancreatic cancer cell lines through apoptosis. It induced early accumulation of reactive oxygen species (ROS) leading to thiol oxidation, aggregation and dysfunction of Hsp90 in MIAPaCa-2. N-acetyl-L-cysteine prevented mahanine-induced ROS accumulation, aggregation of Hsp90, degradation of client proteins and cell death. Mahanine disrupted Hsp90-Cdc37 complex in MIAPaCa-2 as a consequence of ROS generation. Client proteins were restored by MG132, suggesting a possible role of ubiquitinylated protein degradation pathway. Surface plasmon resonance study demonstrated that the rate of interaction of mahanine with recombinant Hsp90 is in the range of seconds. Molecular dynamics simulation showed its weak interactions with Hsp90. However, no disruption of the Hsp90-Cdc37 complex was observed at an early time point, thus ruling out that mahanine directly disrupts the complex. It did not impede the ATP binding pocket of Hsp90. Mahanine also reduced in vitro migration and tube formation in cancer cells. Further, it inhibited orthotopic pancreatic tumor growth in nude mice. Taken together, these results provide evidence for mahanine-induced ROS-mediated destabilization of Hsp90 chaperone activity resulting in Hsp90-Cdc37 disruption leading to apoptosis, suggesting its potential as a specific target in pancreatic cancer. Topics: Acetylcysteine; Adenocarcinoma; Adenosine Triphosphate; Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Carbazoles; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Chaperonins; HSP90 Heat-Shock Proteins; Humans; Leupeptins; Mice; Mice, Nude; Oxidative Stress; Pancreatic Neoplasms; Reactive Oxygen Species; Sulfhydryl Compounds | 2013 |