Abstract
Cancer is a worldwide burden resulting in millions of deaths each year. In particular, gastrointestinal tumors are life-threatening malignancies and one of the leading reasons for death in developed countries. Phytochemicals can be found in grains, vegetables, fruits and several foods. Many phytochemicals, such as curcumin, genistein, luteolin, vitexin-2-O-xyloside, avenanthramides, quercetin, epigallocatechin-3-gallate (EGCG), resveratrol, sulforaphane, piperine and thymoquinone have been used in combination with different chemotherapeutic agents for their synergistic anticancer effects against various forms of cancer. In this review, we describe the antitumor properties and biological effects of combinations of phytochemicals and anticancer drugs against gastrointestinal tumors: colon cancer, gastric cancer, liver cancer, pancreatic cancer. We focus on the molecular pathways, oncoproteins and tumor suppressors modulated by the combination of phytochemicals with antitumor drugs and on the biomarkers of the hallmarks of cancer influenced by these therapeutic strategies in cancer cell lines, xenograft models and clinical trials. The increased knowledge of biomarkers and molecular pathways regulated by the combination of phytochemicals and conventional anticancer drugs in both in vitro and in vivo models will remarkably improve the efficacy of these therapeutic strategies against gastrointestinal tumors in future innovative clinical applications.
Highlights
Carcinogenesis is the process that characterizes the transformation of normal cells into tumor cells [1]
It has been demonstrated that the cells of the core of tumor mass live in hypoxic conditions, resulting in activation of hypoxia inducible factors (HIF-1α and HIF-2α), that are able to increase the expression of several genes, such as vascular endothelial growth factor A (VEGFA), leading to events of neo-angiogenesis and enhancement of vessel permeability [6]
Since initiation and growth share common molecular pathways and mechanisms, they were applied to anticancer therapy, but the use of phytochemicals in antitumor therapies present some limitations, including poor bioavailability of phytochemicals, improper systemic delivery and patient’s different genetic characteristics [33]
Summary
Carcinogenesis is the process that characterizes the transformation of normal cells into tumor cells [1]. The hallmar cancer include: increased signaling for proliferation, evading growth inhibitors, eva apoptosis, replicative immortality, increased angiogenesis, activated invasion and tastasis development, genome mutations, pro-inflammatory conditions, altered en metabolism evading immune destruction, to which the tumor micro-environ pro-inflammatory conditions,and altered energy metabolism and evading immune destruction, contributes [1] Another hallmark plays a pivotal role in cancer dev to which the tumor micro-environment contributes [1]. It was shown that enhanced proteasome activity, in turn, promotes the degradation of tumor suppressor proteins, resulting in cancer cell survival and proliferation as well as the development of drug resistance [27]. Increased proteasome activity in tumor cells can accelerate the degradation of the tumor suppressor Bcl-2-like protein 4 (Bax), reducing the Bax/Bcl-2 ratio [30] Another mechanism that leads to the MDR phenotype is represented by an increase of the drug efflux, which is mediated by ATP-binding cassette (ABC) transporters, including P-gp [31]. It was shown that proteasome inhibitors successfully reversed the resistance to anticancer drugs in tumor cells by decreasing P-gp levels [32]
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