Cephalomannine as in vitro and in vivo anticancer agent in mesothelioma cells: mechanisms of action

Background In our previous drug screening, cephalomannine, fludarabine, and crenolanib were among the most active compounds against permanent cell lines of Pleural Mesothelioma (PM). Methods Here, firstly we assessed the efficacy of these compounds on PM-xenograft NOD-SCID mice and evaluated the overall survival (OS) as major endpoint. Then, we evaluated in vitro the underlying mechanisms involving CPM (at 0.1 mu M) as anticancer agent on REN (derived from PM) and MeT-5A, a mesothelial cell line often used as a non-malignant model of mesothelial cells. We measured the oxygen consumption rate (OCR), the intracellular reactive oxygen species (ROS) production and the protein level of BAX and Bcl2, as proxy for apoptosis. Moreover, we measured IL-18 levels, as marker of the inflammasome pathway activation. Results While no effects were found for fludarabine (40, 100, or 200 mg/kg body weight) and crenolanib (15 mg/kg body weight), for cephalomannine (CPM, 2 mg/kg body weight) we observed a prolonged median OS in the treated group (75 days) vs vehicle control group (55 days; P = 0.0021). We found an increase in ROS production and a reduction in OCR in the REN cell line, compared to MeT-5A. We also noticed an activation of apoptosis, but not of inflammation. Conclusions These results confirm the effectiveness of CPM on PM, suggesting novel targets and pathways for investigation.