Anti-inflammatory/antioxidant use in long-term maintenance cancer therapy: a new therapeutic approach to disease progression and recurrence

Abstract

The chronic, progressive clinical characteristics of many adult solid tumor malignancies suggest that a more effective therapeutic approach to cancer management may require long-term intervention using nontoxic systemic agents that block critical components of abnormal tumor physiology. Two highly promising systemic targets common to the development, progression and recurrence of many common cancers are dysregulated inflammatory and oxidation/reduction (redox) pathways. Compelling clinical data support the use of anti-inflammatory and antioxidant agents as a therapeutic modality for long-term use in patients diagnosed with several common cancers, including colon cancer and breast cancer. The therapeutic paradigm presented in this paper is the product of a synthesis of what is currently understood about the biological effects of inflammation and oxidative stress that contribute to tumorigenesis, disease progression and recurrence as well as results obtained from research on the use of prophylactics with anti-inflammatory or antioxidant properties in cancer prevention and treatment.

Keywords: anti-inflammatory agents; antioxidants; chemotherapy; long-term maintenance cancer therapy.

Figure 1.

Age-adjusted mortality rates for all cancers combined, US SEER data [Howlader et al. 2011]. SEER, surveillance, epidemiology and end results program; CDC, centers for disease control.

Figure 2.

Primary relationships among carcinogens, activated reactive oxygen species (ROS) and inflammatory responses mediated by nuclear factor κB (NFκB) [Singh et al. 2011]. IκB, inhibitor of κB.

Figure 3.

Inflammation, oxidative stress and tumor physiology: a ‘perfect storm’ for tumor spread, metastasis and recurrence. Reactive oxygen species (ROS)/hypoxia damage mitochondria and results in further ROS production and the glycolytic switch to activate inflammatory pathways. Hypoxia inducible factor 1α (HIF-1α) drives survival and metastatic pathways, involving nuclear factor κB (NFκB), STAT-1 and autophagy. Integrin-associated focal adhesion complexes also enhance ROS to destabilize cadherin-associated adherens junctions [Maiti, 2012].TNF, tumor necrosis factor. APEX-1, multi-functional DNA repair enzyme; ARHGEF-6, rho guanine nucleotide exchange factor; CAT, catalase; CDK-6, cyclin dependent kinase; CYR61, cysteine-rich angiogenesis inducer; GPX-1, glutathione peroxidase; GSR, glutathione reductase; GSTM-1, glutathione S transferase; GSTP1, glutathione S transferase P1; HSP 1A,1B, heat shock protein; KEAP-1, kelch-like ECH associated protein; MAPK-8; mMAP kinase; MIR-154,-648,-1321, microRNA: NRF2, nuclear factor;NFE2L2, nuclear factor erythroid derived-like; PAK2, p21 protein activated kinase; PI3K, phosphatidyl inositol-3-kinase; PRDX-4, peroxyredoxin; SOD-2, superoxide dismutase; TNF, tumor necrosis factor; TP53, tumor suppressor protein; TXN, thioredoxin.

Figure 4.

Abnormal tumor microenvironment results from structural parameters generated in the process of solid tumor formation [Chandrasekaran and King, 2012].ATP, adenosine triphosphate.