br Autophagy in cancer br Phytochemicals as a

Autophagy in cancer
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 apoptosis and autophagy, and are considered as a major resource for drug development and improving novel anticancer strategies [2,5,6,8,9]. Although autophagic effects of natural products have been reported in a few recent reviews, their mode of action is highly complex, and thus, the full therapeutic potential of phytochemicals still needs to be discussed [5,7,8]. Given the fundamental importance of autophagy in cancer therapy, we discuss the representative examples of phytochemicals that showed convincing evidence in regulating autophagy-signaling pathways.
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 solubility and rapid metabolism are the most critical reasons for the low bioavailability of phytochemicals in in vivo studies [319]. Nanotechnology offers a novel promising solution for enhancing bioavailability of phytochemicals [320]. Nanoparticles (NPs) and nano-size drug carriers, such as micelles, dendrimers, and liposomes, are extremely useful to increase bioavailability and to enhance anti-cancer agent delivery [316,319,321]. Many phytochemicals, such as polyphenols and carotenoids, are poorly soluble and the delivery of such phytochemicals can be significantly improved by the use of nano-carriers that modulate their solubility, crystallinity, lipophilicity, and other physicochemical properties [322]. For example, complexation of curcumin with phospholipids significantly increased the half-life and maximum plasma concentration (Cmax) of the drug when administrated to male rats orally at a dose of 100  mg/kg. The Cmax of curcumin free form was 267 ng/mL, while it increased up to 600 ng/mL for the curcumin-phospholipid complex [319,323]. Microemulsion of curcumin with a particle size less than 100 nm showed approximately 3.9-fold increase in cl 2 in comparison with curcumin suspension in mice models [324]. In vivo pharmacokinetic study indicated that polymeric micellar curcumin exhibited 60-fold higher biological half-life compared to plain curcumin in rats [325]. Moreover, a formulation of curcumin solid lipid NPs with P-glycoprotein enhanced solubility and bioavailability of curcumin. The curcumin suspension showed Cmax value of 0.24 ± 0.05 μg/mL with Tmax of 30 min (poor oral absorption), while curcumin solid lipid NPs indicated significantly higher Cmax values (0.58 ± 0.03 μg/mL) [326]. Similar nano-based strategies could also enhance bioavailability of many other phytochemicals, such as taxol, resveratrol and quercetin [232,327,328]. For example, novel nanomaterials based on liposomes, nanocapsules and microspheres have been known to optimize bioavailability and therapeutic efficacy of quercetin [329].
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 combat the unresolved problem of drug resistance and improve current cancer therapeutic strategies. Currently, over 30 clinical trials are studying the effects of autophagy modulators, alone or in combination with chemotherapeutic drugs, in various human cancers [17]. The results of these clinical trials are critical for better understanding the role of autophagy in cancer biology and therapy. In this context, natural products can be considered as an important resource for drug development due to their inducing effects on both apoptosis and autophagy. The autophagic potential of phytochemicals can aid overcoming drug resistance or might be used as an alternative approach for inducing cell death in apoptotic-resistant cells. In this review, we discussed the most common phytochemicals that showed autophagy-modulating properties. The autophagic effects of phytochemicals depend on dose and treatment times, as well as on type and content of the cells. For example, baicalein induces both autophagy and apoptosis in different cancer models. The autophagic response induced by baicalein is cytoprotective in human hepatocellular carcinoma cells, while an apoptotic cell death response is occurring following autophagy induction by this phytochemical in prostate cancer cells. The anticancer effects of fisetin are higher in human breast cancer MCF-7 than in MDA-MB-231 cells. The induction of cell death in caspase-3-deficient MCF-7 cells by fisetin is mediated through autophagy inhibition as additional route to prompt its anticancer activity. Also, anticancer effects of ursolic acid are mediated through autophagy blockage in apoptosis-resistant colorectal cancer cells. Therefore, phytochemicals may induce or inhibit autophagy and such autophagy-modulating effects of phytochemicals may suppress or promote apoptosis. Moreover, autophagic potential of phytochemicals might be considered as an alternative way for cell death in cells resistant to apoptosis. Since these natural compounds have been proved to possess low cytotoxicity and reduced side effects, they can be considered as a good choice for a single therapy or in combination with FDA-approved drugs for the treatment of cancer. However, phytochemicals have limitations such as poor bioavailability and multi-target properties, which hinder their clinical applications. Novel nanotechnology strategies, including liposomes, polymer micelles, phospholipid complexes, microemulsions, and NPs, are promising to address these limitations. NPs can interact with phenolic compounds through hydrogen bonds and hydrophobic interactions to encapsulate phenolic compounds and promote their aqueous solubility. Moreover, nano-capsules can protect drug degradation in biological fluids and improve their cell penetration. Finally, because NPs represent potent autophagic activity per se, they can synergize the autophagic potential of phytochemicals as therapeutic or even theragnostic (both for therapy and diagnosis) agents.