Original ArticlesPhytochemicals as potent modulators of autophagy for cancer therapy
Introduction
Phytochemicals (phyton means “plant” in Greek) are naturally occurring plant-based compounds. They are mostly composed of non-nutrient chemicals that are found in grains, vegetables, and fruits [1,2]. While over ten thousand phytochemicals have been identified, many others remain unknown and need to be identified [[1], [2], [3]]. Important groups of phytochemicals include phenolic compounds, alkaloids, terpenes, organosulfides, and glucosinolates [1,4,5]. The health benefits of phytochemicals are mostly associated with reducing the risk of developing diverse human diseases [3,5,6]. Such plant-based compounds are easily accessible, often with less toxic effects than synthetic molecules, and possess a wide range of biological and pharmacological effects, including anti-microbial, anti-tumoral, anti-mutagenic, and anti-oxidant or pro-oxidant activities [1,3,[5], [6], [7], [8], [9]]. Positive outcomes in clinical trials have led to the introduction of several phytochemicals into clinical practice in recent decades [6,10]. Particularly in cancer and other chronic diseases that are associated with excessive production of reactive oxygen species (ROS), both the anti-oxidant and pro-oxidant properties of phytochemicals can be utilized to prevent or eradicate cancer, respectively [3,9,[11], [12], [13]]. For example, enriched flavonoids from vegetables and fruits show potent ROS modulating and anti-cancer effects, alone or in combination with standard chemotherapy [14]. Mechanistically, the anti-cancer effects of phytochemicals are mostly mediated through induction of cell-cycle arrest or apoptotic cell death [[7], [8], [9],15]. In addition, recent studies have uncovered an important role for phytochemicals in governing the autophagy network [7,[15], [16], [17]]. In both normal and malignant cells, autophagy is induced by certain cellular stresses in order to preserve cell survival [18,19]. However, if the stress is not resolved, autophagy leads ultimately to programmed cell death [[18], [19], [20], [21], [22]]. In the context of cancer, autophagy acts as a tumor suppressor at early steps of tumorigenesis. Alternatively, autophagy can promote the growth and survival of established tumors during migration and epithelial-to-mesenchymal transition (EMT) as well as in response to chemotherapy [18,23,24]. In addition, autophagy is involved in cancer stem cell (CSC) survival, escape from immune surveillance and resistance to anoikis [25]. Therefore, autophagy with a double face role inhibits early stages of tumorigenesis while it becomes a driver of tumor invasion and metastasis at later stages [[26], [27], [28]]. Accordingly, manipulation of key factors in the autophagy pathway may be exploited as a novel therapeutic strategy for cancer therapies [20]. However, before proposing phytochemical as anti-cancer and autophagy-modulating agents, a better understanding of their complex mechanism of action needs to be addressed more deeply [5,16,17]. In this review, we represent common phytochemicals as a group of promising autophagy modulators and discuss their therapeutic importance in treating various cancers.
Section snippets
Autophagy machinery and its regulation
The term “autophagy” was coined by Christian de Duve in 1963. It was derived from Greek meaning “eating of self” [29]. Macroautophagy (hereafter called autophagy) is responsible for the turnover of cellular components that are sequestered into the double-membrane-bound vesicle, called autophagosome that originates from a precursor structure called phagophore [19,30]. The primarily goal of autophagy is to sustain cell survival under stressful conditions (e.g., starvation and nutrient
Phytochemicals as a valuable source of autophagy modulation agents
Epidemiological studies demonstrated that there is a strong association between diet and human cancer mortality so that daily consumption of phytochemicals declines the incidence of different types of cancer [2,52]. Therefore, a lot of research efforts focus on nutrients and non-nutritive phytochemicals to evaluate their chemopreventive and chemotherapeutic potential in in vitro and in vivo models of cancer [2,6,9,10]. In clinical oncology, natural compounds induce cell death pathways, mostly
Challenges in using phytochemicals as drugs
Despite the therapeutic benefits of phytochemicals, two main obstacles including, poor bioavailability [316] and lack of correlation between in vitro and in vivo concentrations, hinder their clinical use [317]. The term “bioavailability” means the concentration of the absorbed compound, or its metabolite, in a specific organ that is related to the primary target for the therapeutic action and is determined by the chemical structure of the compounds [318]. Pharmacokinetic studies showed that low
Conclusion and prospective
Despite the growing knowledge of cancer pathogenesis and its treatment, developing targeted chemotherapeutics remains a major challenge in modern medicine. Current cancer therapies are unable to target cancer stem cells, and in most cases, a relapse of the disease might be observed. Additionally, multi-drug resistance is another substantial problem in the clinical application of current chemotherapeutic drugs. In this line, autophagy modulators may serve as promising anti-cancer agents to
Conflicts of interest
None.
Acknowledgments
The authors acknowledge National Institute for Medical Research Development (NIMAD) project no. 940943 and National Research Institute for Science Policy (NRISP) no. 1456 for financial support of this work. AM appreciates National Institute for Genetic Engineering and Biotechnology grants. MR appreciates Cancer Biology Research Center grants. Atanas G. Atanasov acknowledges the support by the Polish KNOW (Leading National Research Centre) Scientific Consortium “Healthy Animal—Safe Food,”
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These two authors contributed equally.