Therapeutics of Oxidative Stress and Stemness in Breast Cancer

Oxidative stress (OS) is induced by chemical reactions triggered inside our body by generation of reactive oxygen and nitrogen species and externally by environmental insults and other stresses. However, balance exists between oxidative stress and anti-oxidative mechanisms to maintain homeostasis. OS has a role in cancer initiation, promotion and progression. Most chemotherapeutic drugs, radiation and other therapeutic modalities mainly target highly proliferating cancer cells of various organs, while sparing small number of rare dormant low cycling cells with stem-like properties which may further encounter mutations, chromosomal aberrations, changes in transcriptome, epigenetic changes and genomic instability. Cancer progression, being evolution-like process, is governed by various selection pressures. Oxidative stress could be a crucial component of selective pressure(s) triggered by a variety of mechanisms such as metabolic stress. Oxidative stress can also change microenvironment, e.g., rendering it pro-inflammatory, and as cancer reaches to advanced stage, highly abnormal and adaptable cancer cells are selected. Hence, in advanced stage, cancer cells can dictate changes in microenvironment to suit them. Targeting oxidative stress as therapeutic intervention is difficult due to tumor heterogeneity, wherein OS and its connected networks may serve different functions in different subpopulations of cancer cells. Strategies for modeling highly adaptable cancer cells that survive high OS and other bottlenecks in driving cancer will aid drug discovery effort at halting cancer progression. Applying this strategy in resistant breast cancer, low-dose 6-mercaptopurine, which is a safe and effective inhibitor of chronic inflammation, appears suitable for inhibiting highly adaptable cancer cells.