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Traditional supplements of selenium generally have a low degree of absorption and increased toxicity. Therefore, it is imperative to develop innovative systems as transporters of selenium compounds, which would raise the bioavailability of this element and allow its controlled release in the organism. Nanoscale selenium has attracted a great interest as a food additive especially in individuals with selenium deficiency, but also as a therapeutic agent without significant side effects in medicine. This review is focused on the incorporation of nanotechnological applications, in particular exploring the possibilities of a more effective way of administration, especially in selenium-deficient organisms. In addition, this review summarizes the survey of knowledge on selenium nanoparticles, their biological effects in the organism, advantages, absorption mechanisms, and nanotechnological applications for peroral administration.

Autophagy is a conserved biological phenomenon that maintains cellular homeostasis through the clearing of damaged cellular components under cellular stress and offers the cell building blocks for cellular survival. Aberrations in autophagy subsidize to various human pathologies, such as dementia, cardiovascular diseases, leishmaniosis, influenza, hepatic diseases, and cancer, including hepatocellular carcinoma (HCC). HCC is the fifth common mortal type of liver cancer globally, with an inhomogeneous topographical distribution and highest incidence tripled in men than women. Existing treatment procedures with liver cancer patients result in variable success rates and poor prognosis due to their drug resistance and toxicity. One of the pathophysiological mechanisms that are targeted during the development of anti-liver cancer drugs is autophagy. Generally, overactivated autophagy may lead to a non-apoptotic form of programmed cell death (PCD) or autophagic cell death or type II PCD. Emerging evidence suggests that manipulation of autophagy could induce type II PCD in cancer cells, acting as a potential tumor suppressor. Hence, altering autophagic signaling offers new hope for the development of novel drugs for the therapy of resistant cancer cells. Natural polyphenolic compounds, including flavonoids and non-flavonoids, execute their anticarcinogenic mechanism through upregulating tumor suppressors and autophagy by modulating canonical (Beclin-1-dependent) and non-canonical (Beclin-1-independent) signaling pathways. Additionally, there is evidence signifying that plant polyphenols target angiogenesis and metastasis in HCC via interference with multiple intracellular signals and decrease the risk against HCC. The current review offers a comprehensive understanding of how natural polyphenolic compounds exhibit their anti-HCC effects through regulation of autophagy, the non-apoptotic mode of cell death.

Nuclear factor erythroid 2 p45-related factor (2Nrf2) is an essential leucine zipper protein (bZIP) that is primarily located in the cytoplasm under physiological conditions. Nrf2 principally modulates endogenous defense in response to oxidative stress in the brain.In this regard, Nrf2 translocates into the nucleus and heterodimerizes with the tiny Maf or Jun proteins. It then attaches to certain DNA locations in the nucleus, such as electrophile response elements (EpRE) or antioxidant response elements (ARE), to start the transcription of cytoprotective genes. Many neoplasms have been shown to have over activated Nrf2, strongly suggesting that it is responsible for tumors with a poor prognosis. Exactly like curcumin, Zinc–curcumin Zn (II)–curc compound has been shown to induce Nrf2 activation. In the cancer cell lines analyzed, Zinc–curcumin Zn (II)–curc compound can also display anticancer effects via diverse molecular mechanisms, including markedly increasing heme oxygenase-1 (HO-1) p62/SQSTM1 and the Nrf2 protein levels along with its targets. It also strikingly decreases the levels of Nrf2 inhibitor, Kelch-like ECH-associated protein 1 (Keap1) protein.As a result, the crosstalk between p62/SQSTM1 and Nrf2 could be used to improve cancer patient response to treatments. The interconnected anti-inflammatory and antioxidative properties of curcumin resulted from its modulatory effects on Nrf2 signaling pathway have been shown to improve insulin resistance. Curcumin exerts its anti-inflammatory impact through suppressing metabolic reactions and proteins such as Keap1 that provoke inflammation and oxidation. A rational amount of curcumin-activated antioxidant Nrf2 HO-1 and Nrf2-Keap1 pathways and upregulated the modifier subunit of glutamate-cysteine ligase involved in the production of the intracellular antioxidant glutathione. Enhanced expression of glutamate-cysteine ligase, a modifier subunit (GLCM), inhibited transcription of glutamate-cysteine ligase, a catalytic subunit (GCLC). A variety of in vivo, in vitro and clinical studies has been done so far to confirm the protective role of curcumin via Nrf2 regulation. This manuscript is designed to provide a comprehensive review on the molecular aspects of curcumin and its derivatives/analogs via regulation of Nrf2 regulation.

Exosomes are biological nanovesicles that are intrinsically loaded with thousands of biomacromolecules and are principally responsible for cell-to-cell communication. Inspired by the natural payload, they have been extensively investigated as drug delivery vehicles; however, the drug distribution, whether into or onto exosomes, is still debatable. In the present work, we have tried to investigate it systemically by selecting 5-fluorouracil (5-FU) (hydrophilic) and paclitaxel (PAC) (hydrophobic), drugs with very different physicochemical characteristics, for the loading to the exosomes. Exosomes were obtained from bovine milk, and the drugs were loaded using three different methods: incubation, sonication, and triton x-100. The particle size was found to be approximately 100 nm in all the cases; however, the highest drug loading was found in the sonication method. Fluorescence spectrophotometer, EDX analysis, EDX mapping, XPS, and XRD analysis indicated the possible presence of more drugs over the surface in the case of the incubation method. Drugs loaded by the sonication method had more controlled release than simple incubation and triton x-100. The method of drug loading had an insignificant effect on the cytotoxicity while in line with our previous observation, the combination (PAC and 5-FU) exhibited synergism as evidenced by ROS assay, colony formation assay, and mitochondrial membrane potential assay. Graphical Abstract

The anti-cancer effect of high doses of intravenous vitamin C (high-dose vitamin C) remains controversial despite growing evidence that high-dose vitamin C exerts anti-tumorigenic activity by increasing the amount of reactive oxygen species in cancer cells without meaningful toxicities. Therefore, this study attempted to demonstrate the in vitro anti-cancer activity of high-dose vitamin C in combination with conventional treatment in breast cancer. The pro-apoptotic effects of high-dose vitamin C (1.25 to 20 mM) with or without anti-cancer agents (eribulin mesylate, tamoxifen, fulvestrant, or trastuzumab) were estimated using an MTT assay to measure the cell viability of a variety of breast cancer cell lines (MCF7, SK-BR3, and MDA-MB-231), as well as normal breast epithelial cells (MCF10A). High-dose vitamin C (≥10 mM) significantly decreased cell viability of all breast cancer cell lines, particularly of MCF-7 cells. The catalase activities of MCF7 and MDA-MD-231 cells were also lower than those of MCF10A cells. Moreover, cell viability of both MCF7 and MDA-MD-231 cells was decreased further when combining high-dose vitamin C and eribulin mesylate, and this was also true for MCF-7 cells when combining high-dose vitamin C with tamoxifen or fulvestrant and for SK-BR3 cells when combining high-dose vitamin C with trastuzumab in comparison with chemotherapy or endocrine therapy alone. Combining high-dose vitamin C with conventional anti-cancer drugs can have therapeutic advantages against breast cancer cells.

The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.

Zoledronic acid (ZA) is one of the most important and effective class of anti-resorptive drug available among bisphosphonate (BP), which could effectively reduce the risk of skeletal-related events, and lead to a treatment paradigm for patients with skeletal involvement from advanced cancers. However, the exact molecular mechanisms of its anticancer effects have only recently been identified. In this review, we elaborate the detail mechanisms of ZA through inhibiting osteoclasts and cancer cells, which include the inhibition of differentiation of osteoclasts via suppressing receptor activator of nuclear factor κB ligand (RANKL)/receptor activator of nuclear factor κB (RANK) pathway, non-canonical Wnt/Ca2+/calmodulin dependent protein kinase II (CaMKII) pathway, and preventing of macrophage differentiation into osteoclasts, in addition, induction of apoptosis of osteoclasts through inhibiting farnesyl pyrophosphate synthase (FPPS)-mediated mevalonate pathway, and activation of reactive oxygen species (ROS)-induced pathway. Furthermore, ZA also inhibits cancer cells proliferation, viability, motility, invasion and angiogenesis; induces cancer cell apoptosis; reverts chemoresistance and stimulates immune response; and acts in synergy with other anti-cancer drugs. In addition, some new ways for delivering ZA against cancer is introduced. We hope this review will provide more information in support of future studies of ZA in the treatment of cancers and bone cancer metastasis.

Nowadays, much attention has been paid to diet and dietary supplements as a cost-effective therapeutic strategy for prevention and treatment of a myriad of chronic and degenerative diseases. Rapidly accumulating scientific evidence achieved through high-throughput technologies has greatly expanded the understanding about the multifaceted nature of cancer. Increasingly, it is being realized that deregulation of spatio-temporally controlled intracellular signaling cascades plays a contributory role in the onset and progression of cancer. Therefore, targeting regulators of oncogenic signaling cascades is essential to prevent and treat cancer. A plethora of preclinical and epidemiological evidences showed promising role of phytochemicals against several types of cancer. Oleanolic acid, a common pentacyclic triterpenoid, is mainly found in olive oil, as well as several plant species. It is a potent inhibitor of cellular inflammatory process and a well-known inducer of phase 2 xenobiotic biotransformation enzymes. Main molecular mechanisms underlying anticancer effects of oleanolic acid are mediated by caspases, 5′ adenosine monophosphate-activated protein kinase, extracellular signal–regulated kinase 1/2, matrix metalloproteinases, pro-apoptotic Bax and bid, phosphatidylinositide 3-kinase/Akt1/mechanistic target of rapamycin, reactive oxygen species/apoptosis signal-regulating kinase 1/p38 mitogen-activated protein kinase, nuclear factor-κB, cluster of differentiation 1, CKD4, s6k, signal transducer and activator of transcription 3, as well as aforementioned signaling pathways . In this work, we critically review the scientific literature on the molecular targets of oleanolic acid implicated in the prevention and treatment of several types of cancer. We also discuss chemical aspects, natural sources, bioavailability, and safety of this bioactive phytochemical.

The use of cancer-derived exosomes has been studied in several cancer types, but the cancer-targeting efficacy of glioma-derived exosomes has not been investigated in depth for malignant glioblastoma (GBM) cells. In this study, exosomes were derived from U87MG human glioblastoma cells, and selumetinib, a new anticancer drug, was loaded into the exosomes. We observed the tropism of GBM-derived exosomes in vitro and in vivo. We found that the tropism of GBM-derived exosomes is in contrast to the behavior of non-exosome-enveloped drugs and non-GBM-specific exosomes in vitro and in vivo in an animal GBM model. We found that the tropism exhibited by GBM-derived exosomes can be utilized to shuttle selumetinib, with no specific targeting moiety, to GBM tumor sites. Therefore, our findings indicated that GBM-derived exosomes loaded with selumetinib had a specific antitumor effect on U87MG cells and were non-toxic to normal brain cells. These exosomes offer improved therapeutic prospects for glioblastoma therapy.

Ferroptosis is a recently discovered iron-dependent mode of oxidatively regulated cell death. It is not only associated with a wide range of diseases, but it is also a key component of many signaling pathways. In general, ferroptosis is a double-edged sword. On one hand, it induces nonapoptotic destruction of cancer cells, but on the other, it may lead to organ damage. Therefore, ferroptosis can be drug-targeted as a novel means of therapy. The properties of curcumin have been known for many years. It has a positive impact on the treatment of diseases such as cancer and inflammation. In this review, we focus on the regulation of ferroptosis by curcumin and its derivatives and review the main mechanisms by which curcumin affects ferroptosis. In conclusion, curcumin is a ferroptosis inducer with excellent anticancer efficacy, although it also exhibits organ protective and reparative effects by acting as a ferroptosis inhibitor. The differential regulation of ferroptosis by curcumin may be related to dose and cell type.