Molecular Mechanisms of redox-active cerium oxide nanoparticles in inhibition of tumor progression

• Applicant: Professor Peter Brenneisen, Ph.D.
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine ; Biochemistry ; Cell Biology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 418596969

• Final Report Year: 2024

Final Report Abstract

In addition to numerous tasks in cell metabolism, mitochondria are the largest endogenous source of reactive oxygen species (ROS). An altered redox balance and the resulting oxidative modifications on proteins are characteristic of many tumor types. The altered redox status of tumor cells therefore represents a potential target for a "redox-based therapy". Some chemotherapeutic agents, such as the anthracycline derivative doxorubicin (DOX), exhibit cytotoxic and prooxidative properties. Although these cytostatic agents are used against numerous types of tumors, some of them also have a toxic effect on healthy, non-transformed cells. They are often associated with severe side effects such as high cardiotoxicity, which severely limit the use of these quite effective substances. The molecular mechanisms involved are the subject of a controversial discussion, but it seems that increased ROS production in the mitochondria initiated by doxorubicin may trigger mitochondrial dysfunction. The use of nanotechnology and the use of purified “natural compounds (NCs)” now offer promising possibilities for a redox-based therapy with fewer side effects. Our mainly carried out in-vitro studies with specific cerium oxide nanoparticles (CNP) and NCs such as cardamonin or gossypol have shown a selective prooxidative-cytotoxic effect in various tumor cells, while the identical particles or substances in the same concentration tend to provide protection against oxidative damage in healthy cells. Initial in-vivo data also suggest that CNPs may be useful in cancer therapy. In the planned project, the applicability of redox-active cerium oxide nanoparticles for a later potential chemotherapeutic approach without or in combination with doxorubicin should primarily be examined by elucidating the underlying molecular mechanisms of action of CNP, doxorubicin and their combination comparatively in non-transformed cells and cancer cells with a special focus on the mitochondria. Melanoma cells which still represent a major challenge for therapeutic approaches today, served as a model for cancer cells. Based on reproducible data, it quickly became apparent that the nanoparticles used at that time did not have the desired selective effect in combination with doxorubicin, so that the naturally occurring chalcone cardamonin (CD) was used for further investigations. Here, it was shown that CD has a rather protective effect on cytotoxicity triggered by DOX in healthy cells, whereas a combination of low doses of DOX with CD in tumor cells has a similar cytotoxic effect as high concentrations of DOX used as single drug. Changes in mitochondrial membrane permeability, increased production of ROS and a significantly lowered mitochondrial oxygen consumption rate (OXPHOS) in tumor cells seem to be the trigger of an apoptotic cell death induced by CD and DOX. The basic research results obtained show that a combination of doxorubicin with cardamonin could be a promising therapeutic approach, as both substances address different target structures in the tumor cells and trigger cell death mechanisms, in contrast to normal (healthy) cells.

Publications

• In vitro selective cytotoxicity of the dietary chalcone cardamonin (CD) on melanoma compared to healthy cells is mediated by apoptosis. PLOS ONE, 14(9), e0222267.
  Berning, Lena; Scharf, Lisa; Aplak, Elif; Stucki, David; von Montfort, Claudia; Reichert, Andreas S.; Stahl, Wilhelm & Brenneisen, Peter
  
• CNP mediated selective toxicity on melanoma cells is accompanied by mitochondrial dysfunction. PLOS ONE, 15(1), e0227926.
  Aplak, Elif; von Montfort, Claudia; Haasler, Lisa; Stucki, David; Steckel, Bodo; Reichert, Andreas S.; Stahl, Wilhelm & Brenneisen, Peter
  
• The BH3 mimetic (±) gossypol induces ROS-independent apoptosis and mitochondrial dysfunction in human A375 melanoma cells in vitro. Archives of Toxicology, 95(4), 1349-1365.
  Haasler, Lisa; Kondadi, Arun Kumar; Tsigaras, Thanos; von Montfort, Claudia; Graf, Peter; Stahl, Wilhelm & Brenneisen, Peter
  
• Involvement of necroptosis in the selective toxicity of the natural compound (±) gossypol on squamous skin cancer cells in vitro. Archives of Toxicology, 97(7), 1997-2014.
  Haasler, Lisa; von Montfort, Claudia; Kondadi, Arun Kumar; Golombek, Mathias; Ebbert, Lara; Wenzel, Chantal-Kristin; Stahl, Wilhelm; Reichert, Andreas S. & Brenneisen, Peter
  
• The Antimalarial Drug Artesunate Mediates Selective Cytotoxicity by Upregulating HO-1 in Melanoma Cells. Biomedicines, 11(9), 2393.
  Jochims, Finn; Strohm, Rebecca; von Montfort, Claudia; Wenzel, Chantal-Kristin; Klahm, Niklas; Kondadi, Arun Kumar; Stahl, Wilhelm; Reichert, Andreas S. & Brenneisen, Peter
  
• The natural chalcone cardamonin selectively induces apoptosis in human neuroblastoma cells. Toxicology in Vitro, 91, 105625.
  Wenzel, Chantal-Kristin; von Montfort, Claudia; Ebbert, Lara; Klahm, Niklas P.; Reichert, Andreas S.; Stahl, Wilhelm & Brenneisen, Peter