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

Our plain-English summary of Cephalomannine as in vitro and in vivo anticancer agent in mesothelioma cells: mechanisms of action, by F. Morani, I. Dell'Anno, A. Daga, et al (BMC Cancer, 2025).

The study

• Authors: F. Morani, I. Dell'Anno, A. Daga, S. Doccini, L. Bisceglia, F. Gemignani, S. Landi
• Journal: BMC Cancer
• Published: 2025;25(1):1625
• Read it: PubMed · Publisher · Free full text

Abstract

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 µM) 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.

In plain English

This laboratory study tested three drugs (fludarabine, crenolanib and cephalomannine, or CPM) against pleural mesothelioma. It did not study asbestos exposure. Female immunodeficient NOD-SCID mice were injected in the abdomen with human REN pleural mesothelioma cells, with survival as the main measure. Fludarabine at 200, 100 or 40 mg/kg, crenolanib at 15 mg/kg, and the two combined did not significantly change survival versus controls. Mice given CPM at 2 mg/kg had a median survival of 75 days, versus 55 days for vehicle-treated controls (P = 0.0021; 10 mice each). In cell cultures, CPM increased reactive oxygen species in REN cells by about 85%, reduced their oxygen consumption, raised the apoptosis-related protein BAX and lowered Bcl2. In non-malignant MeT-5A cells, BAX and Bcl2 also changed significantly; the authors called the ratio change moderate. CPM did not change the inflammation marker IL-18. The authors concluded that CPM could be a promising anticancer agent in pleural mesothelioma, and called for human clinical trials. As limitations, they noted few doses, little data on CPM's behavior in the body and a modest survival gain.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment (mouse xenograft survival study) combined with in vitro cell-line experiments
• Who was studied: Six-week-old female NOD-SCID mice (Genoa, Italy) injected intraperitoneally with luciferase-labelled human REN pleural mesothelioma cells. The methods state twenty mice were inoculated, and the CPM experiment had 10 control and 10 treated mice. Group sizes for the other drug experiments are not stated. In vitro work used the malignant REN cell line and the non-malignant MeT-5A mesothelial cell line.
• Exposure: No asbestos exposure was studied. The exposures were drugs given intraperitoneally to mice: fludarabine at 200, 100 or 40 mg/kg; crenolanib at 15 mg/kg; fludarabine 40 mg/kg plus crenolanib 15 mg/kg; and cephalomannine (CPM) at 2 mg/kg, once a day for 5 consecutive days over 2 consecutive weeks. Cells were treated with CPM at 0.1 micromolar, or with a DMSO vehicle.
• Main results:
  • Fludarabine at all three doses did not significantly change overall survival compared with controls (P = 0.6176 at 200 mg/kg, P = 0.2899 at 100 mg/kg, P = 0.1341 at 40 mg/kg).
  • Crenolanib at 15 mg/kg did not significantly change survival compared with controls (P = 0.2906).
  • The fludarabine plus crenolanib combination did not significantly change overall survival.
  • CPM-treated mice had a median overall survival of 75 days, versus 55 days for vehicle-treated control mice (P = 0.0021).
  • In REN cells, CPM produced significantly more reactive oxygen species than vehicle. The authors put the increase at about 85% after 24 hours at 0.1 micromolar.
  • CPM significantly reduced oxygen consumption rate in REN cells compared with control cells.
  • After CPM treatment, BAX increased and Bcl2 decreased, which the authors read as apoptosis. The figure legend reports both changes as statistically significant in both cell lines, including the non-malignant MeT-5A line.
  • For MeT-5A cells, the results text describes the change in the BAX/Bcl-2 ratio as moderate.
  • IL-18, the inflammasome marker, did not change with CPM treatment in either MeT-5A or REN cells.
• The authors' conclusion: The authors concluded that their study, along with previous research, suggests CPM could be a promising anticancer agent, especially in pleural mesothelioma. They said clinical trials are still needed in humans.
• Limitations the authors state:
  • Only a small number of doses was tested.
  • Little data is available on how CPM behaves in the body (pharmacokinetics).
  • The extension of survival in mice was modest.
  • Tumour imaging signals could not be quantified because of hemorrhages, so the images are only a rough qualitative representation.
  • Not all molecular pathways leading to apoptosis, or all effects on mitochondria, were investigated.
  • Giving the drug intraperitoneally could lead to faster metabolism of the drug.
  • Clinical trials are still needed to evaluate CPM's safety and efficacy in humans.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Pleural Mesothelioma, Overall Survival, Mesothelial Cells, Reactive Oxygen Species (ROS), Apoptosis, Inflammation.

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