Abstract
Combination therapy consists in the simultaneous administration of a conventional chemotherapy drug (or sometimes, a radiotherapy protocol) together with one or more natural bioactives (usually from plant or fungal origin) of small molecular weight. This combination of anticancer drugs may be applied to cell cultures of tumor cells, or to an animal model for a cancer type (or its xenograft), or to a clinical trial in patients. In this review, we summarize current knowledge describing diverse synergistic effects on colorectal cancer cell cultures, animal models, and clinical trials of various natural bioactives (stilbenes, flavonoids, terpenes, curcumin, and other structural families), which may be important with respect to diminish final doses of the chemotherapy drug, although maintaining its biological effect. This is important as these approaches may help reduce side effects in patients under conventional chemotherapy. Also, these molecules may exerts their synergistic effects via different cell cycle pathways, including different ones to those responsible of resistance phenotypes: transcription factors, membrane receptors, adhesion and structural molecules, cell cycle regulatory components, and apoptosis pathways.
Highlights
CRC is the third most common cancer in men and the second in women worldwide, with a prevalence of 10.0 and 9.2%, respectively (Merrill and Anderson, 2011; Bray et al, 2013; Ferlay et al, 2015)
Apigenin induces the expression of death receptor 5 (DR5) in a dose-dependent manner preventing the degradation of this protein by acting as a proteasome inhibitor and increasing its expression in the membrane, so this up-regulation of DR5 acts in a synergic form sensitizing to the treatment with exogenous soluble recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in CRC DLD-1 cells, showing a greater apoptotic effect than the treatment with TRAIL alone
The inhibitory effect of apigenin on ERK phosphorylation levels is significant when CRC HCT116 cells are cotreated with ABT-263 (Shao et al, 2013). All these findings were verified in vivo in a SCID mice model bearing HCT116 xenografts, in which treatment with ABT263 or apigenin alone resulted in a 30% inhibition of tumor growth compared with untreated control, but this percentage was increased to 70% by combination therapy, with decreased Mcl-1 levels as well as phosphorylated prosurvival mediators ERK or AKT (Table 2; Shao et al, 2013)
Summary
CRC is the third most common cancer in men (after lung and prostate cancers) and the second in women (after breast cancer) worldwide, with a prevalence of 10.0 and 9.2%, respectively (Merrill and Anderson, 2011; Bray et al, 2013; Ferlay et al, 2015). Unlike mitomycin C, resveratrol can induce p21WAF1/CIP1 overexpression regardless of p53 status, and a combined treatment of these two compounds has inhibited synergistically the proliferation of mitomycin C-resistant CRC cells (Ali and Braun, 2014).
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