ReviewNatural compounds modulate the crosstalk between apoptosis- and autophagy-regulated signaling pathways: Controlling the uncontrolled expansion of tumor cells
Introduction
Cancer is a multifactorial and complete disease and represents a major factor of disease burden throughout the world [[1], [2], [3]], causing 233.5 million disability-adjusted life-years [4]. This complex multifactorial pathology is, in many instances, a combination of lifestyle, environmental factors, and genetic heritage. While the inherited predisposition for carcinogenesis is still considered a stable risk factor, a number of lifestyle and environmental toxic agents were related with carcinogenesis [1,5].
Diet has been established to be responsible for about 30 percent of cancers in western countries. Dietary phytochemicals intake was related to positive health outcomes. Phytochemicals are natural plant compounds present in natural sources (fruits, vegetables, grains, and tea) as functional foods or in the enriched form as nutraceuticals and dietary supplements. Phytochemicals have been used for centuries to prevent and to cure various diseases [1,5,6], such as infections [7], inflammation [5,8], diabetes [9,10], cardiovascular diseases [11], and cancer [1,[12], [13], [14]].
Various investigations reveal contradictory data on the biological effects of phytochemicals, probably due to a lack of understanding towards the particular characteristics of low stability and solubility [1,15,16]. The natural phytochemicals play an important role in the discovery and development of novel anticancer agents, considering the wide range of signaling pathways targeted by these constituents [[17], [18], [19], [20]].
Cancer still remains a shuddered disease, and the use of natural agents has revealed important therapeutic benefits, as chemopreventive or chemotherapeutic agent [12,18,21,22]. As chemopreventive [23] compounds, phytochemicals disrupt or minimize the development of a malignancy before the onset of the disease [21], mainly through lowering oxidative stress and chronic inflammation [24], and preventing early DNA damage and subsequent mutations [25]. From this perspective, the natural compounds with high antioxidant potency are very effective in cancer prevention [21,26].
The use of plant-derived compounds has a long history and many of today’s cancer chemotherapeutic drugs that are used on a large scale, such as paclitaxel, were initially isolated from a natural source [[27], [28], [29], [30], [31], [32], [33], [34]]. In the recent years, we have observed an increase in the of discovery and development of natural anti-cancer drugs not only for their efficacy and lower side effect, but also for low cost. There is strong evidence that phytochemicals act not only as therapeutic agents, but also as adjuvants to enhance the beneficial activity of classical chemotherapeutic agents, while minimizing their unwanted effects [35].
Due to the specific and selective biological effects on tumor cells, phytochemicals have been considered a valuable resource for drug development according to the United States Food and Drug Administration [17,18]. Therapies can be strategically developed to target a certain signaling pathway or can be used to cover as many pathways as possible in order to simultaneously inhibit multiple cancer hallmarks with limited and acceptable side effects [18,[36], [37], [38]]. Therefore, the latest preclinical studies are more focused on deciphering the affected cellular pathways or to identify the novel phytochemicals derivative with specific therapeutics properly [21,24]. A large number of studies reveals that phytochemicals have a wide range of cellular and molecular effects; the effect various signal transduction pathways, including inflammation cascade, oxidative stress, cell proliferation/migration, apoptosis, autophagy and cellular metabolism [1,24,39]. Initially, apoptosis was considered as the most frequent form of cell death induced by natural agents. However, in the last decade, this was expanded to include autophagy [14,24].
Section snippets
Classification of bioactive phytochemicals
Phytochemicals are plant secondary metabolites involved in the control of essential functions of reproduction and growth. Moreover, they enable the plants to fight against threats from the environment [[40], [41], [42]]. The most important classes of phytochemicals are polyphenols and phenolics, terpenes, alkaloids, and sulfur-containing compounds, including isothiocyanates, in free or glycosylated form [43]. The chemical structures of various phytochemical classes are depicted in Fig. 1.
Regulation of autophagy and apoptosis in cancer
Cell death is a fundamental cellular response that has a crucial role in a variety of biological processes by controlling development, multicellular organisms’ immune response and tissue homeostasis by eliminating unwanted cells. According to the literature, most studies focused on three major types of cell death: apoptosis (type I), cell death associated with autophagy (type II) and necrosis (type III). In mammalian cells, the apoptotic response was observed to be mediated by either an
Modulation of apoptosis by natural compounds
Apoptosis, a type of programmed cell death, represents a physiological barrier to cancer development [70]. The apoptotic pathways, both intrinsic (caspase-9-dependent) and extrinsic (caspase-8- and caspase-10-dependent), are key biological processes that can modulate the stress response to different stimuli, including natural phytochemicals [36]. The intrinsic pathway is related to mitochondria-associated proteins that have anti-apoptotic or proapoptotic functions. The anti-apoptotic proteins
Conclusions and perspectives
One of the most important unsolved problems in cancer therapy is the increase of tumor resistance to cancer treatment, in particular for the case of chemotherapy. This increased resistance is a consequence of defects in apoptosis. An alternative form of cell death is represented by autophagy, specifically activated by natural compounds. Therefore, different combined treatment scenarios using naturally occurring compounds can be a solution for this problem. The major challenge in this domain is
Declaration of Competing Interest
Authors declare no conflicts of interest.
Acknowledgment
This research was funded by a POC grant entitled “Clinical and economical impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance”-CANTEMIR (contract number 35/01.09.2016).
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These authors have contributed equally.