Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy

Abstract

The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid-derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune-depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity.

Figure 1

Potential effects and concerns of selected natural compounds as adjuvant in cancer therapy. Based on experiments “in vitro,” epigallocatechin gallate (EGCG), tocotrienols, curcumin, quercetin, genistein, resveratrol, silybin, phenyl isothiocyanate (PEITC), sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, phloretin might be useful in prevention and therapy of cancer. Gero- and cancer preventive activity include (1) induction senescence or apoptosis in normal damaged and potentially precancerous cells, (2) protection of normal cells by damage via modulation of antioxidant/cytoprotective pathways, and (3) anti-inflammatory activity that might reduce negative effects of the senescence-associated secretory phenotype (SASP) produced by senescent cells. In cancer therapy, natural bioactive compound might help (4) to induce apoptosis and senescence in cancer cells thus helping to reduce dosage of chemo- and radiotherapy while keeping efficacy. The major concern regards the possibility that these compounds might act as cytoprotective in some cancer cells (as in normal cells), thus aggravating the problem of resistance of cancer to therapy (5). However, failure to clearance senescent cells (6), as it might occur in immune-compromised subjects, might represent a serious challenge for these applications. Inclusion of additional strategies (7) with other natural compounds (i.e., phloretin, fisetin, piperlongumine, and quercetin) able to induce selective death of senescent cells should be evaluated in future preclinical studies to reduce relapses and side effects of chemo- or radiotherapy.

Figure 2

Potential mechanisms leading to senescence by NRF2-activating compounds in cancer cells. The response under NRF2 signaling involve the activation of glutamylcysteine ligase (γ-GCL), glutathione peroxidase (GPx), heme oxygenase 1 (HO-1), superoxide dismutase (SOD), glutathione S-transferase (GST), and many other enzymes involved in the antioxidant cytoprotective response that lead to suppression of senescence-related pathways (i.e., p53, p21, and p16). However, this response include and interact with additional genes, such as Notch-1, NADPH-quinone oxidoreductase (NQO1), the aryl hydrocarbon receptor (AhR), the Jun dimerization protein 2 (JDP2), and perhaps epigenetic changes that may be involved in sensing stress and damage and that are known to participate in processes leading to cellular senescence. In the case of (particular) cancer cells, the persistence of unresolved damage can eventually lead these pathways to the reactivation of the senescence program.