Oxidants, antioxidants and the current incurability of metastatic cancers

Area of Science:

• Oncology
• Cell Biology
• Pharmacology

Background:

• Conventional cancer therapies, including ionizing radiation and chemotherapy, primarily function by generating reactive oxygen species (ROS) to induce cell cycle arrest.
• Mesenchymal cancers, which arise from epithelial progenitors, exhibit elevated antioxidant levels, conferring resistance to ROS-inducing therapies.
• The anti-diabetic drug metformin demonstrates preferential cytotoxicity towards oxidant-deficient mesenchymal p53(- -) cancer cells.

Purpose of the Study:

• To elucidate the mechanisms by which mesenchymal cancers evade ROS-mediated cell death.
• To understand the selective anti-cancer activity of metformin against p53(- -) cancers.
• To advocate for accelerated development of novel therapeutic agents targeting p53(- -) cancers.

Main Methods:

• Analysis of reactive oxygen species generation by standard cancer therapeutics.
• Assessment of antioxidant levels in mesenchymal versus epithelial cancer cells.
• Investigation of metformin's mechanism of action in p53(- -) cancer models.

Main Results:

• Established that ROS-generating agents are a cornerstone of many cancer treatments.
• Demonstrated that heightened antioxidant capacity in mesenchymal cancers confers resistance to oxidative stress therapies.
• Confirmed metformin's preferential killing of p53(- -) cancer cells, which are deficient in oxidants.

Conclusions:

• The antioxidant defense mechanisms in mesenchymal cancers represent a significant barrier to conventional oxidant-based therapies.
• Metformin's selective efficacy against p53(- -) cancers highlights a potential therapeutic vulnerability.
• There is an urgent need to expedite the development of novel drugs specifically designed to combat p53(- -) cancers.