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1.
Resveratrol and other Stilbenes: Effects on Dysregulated Gene Expression in Cancers and Novel Delivery Systems.
Poltronieri, P, Xu, B, Giovinazzo, G
Anti-cancer agents in medicinal chemistry. 2021;(5):567-574
Abstract
Trans-resveratrol (RESV), pterostilbene, trans-piceid and trans-viniferins are bioactive stilbenes present in grapes and other plants. Several groups applied biotechnology to introduce their synthesis in plant crops. Biochemical interaction with enzymes, regulation of non-coding RNAs, and activation of signaling pathways and transcription factors are among the main effects described in literature. However, solubility in ethanol, short half-life, metabolism by gut bacteria, make the concentration responsible for the effects observed in cultured cells difficult to achieve. Derivatives obtained by synthesis, trans-resveratrol analogs and methoxylated stilbenes show to be more stable and allow the synthesis of bioactive compounds with higher bioavailability. However, changes in chemical structure may require testing for toxicity. Thus, the delivery of RESV and its natural analogs incorporated into liposomes or nanoparticles, is the best choice to ensure stability during administration and appropriate absorption. The application of RESV and its derivatives with anti-inflammatory and anticancer activity is presented with description of novel clinical trials.
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2.
Upregulation of lncRNA NIFK-AS1 in hepatocellular carcinoma by m6A methylation promotes disease progression and sorafenib resistance.
Chen, YT, Xiang, D, Zhao, XY, Chu, XY
Human cell. 2021;(6):1800-1811
Abstract
Long non-coding RNAs (LncRNAs) have recently emerged as vital regulators in the development and progression of hepatocellular carcinoma (HCC), providing new opportunities as novel therapeutic targets. Here we identified the lncRNA NIFK-AS1 as being highly expressed in HCC tissues and cells and showed this up-regulation resulted from METTL3-dependent m6A methylation. Functionally, knockdown of NIFK-AS1 inhibited the proliferation, colony formation, migration, and invasion of HCC cells. Moreover, these effects were elicited though AKT1 and we uncovered a ceRNA network involving an NIFK-AS1/miR-637/AKT1 axis with downstream effects on HCC progression involving regulation of MMP-7 and MMP-9 expression. From the clinical perspective, we showed that knockdown of NIFK-AS1 sensitized HCC cells to sorafenib through the up-regulation of the drug transporters OATP1B1 and OATP1B3. Clinical investigations showed HCC patients with low NIFK-AS1 expression benefited from sorafenib therapy and this phenomenon was reproduced in patient-derived tumor xenograft models (PDX) comparing HCC with low and high expression of NIFK-AS1. Taken together, these results suggest an essential role for NIFK-AS1 in HCC progression and promote NIFK-AS1 as a new therapeutic target and predictor of sorafenib benefit in HCC patients.
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3.
Emerging role of RNF2 in cancer: From bench to bedside.
Yan, Q, Chen, BJ, Hu, S, Qi, SL, Li, LY, Yang, JF, Zhou, H, Yang, CC, Chen, LJ, Du, J
Journal of cellular physiology. 2021;(8):5453-5465
Abstract
RNF2 (also known as ding, Ring1B or Ring2) is a member of the Ring finger protein family, which functions as E3 ubiquitin ligase for monoubiquitination of histone H2A at lysine 119 (H2AK119ub). RNF2 gene is located at the 1q25.3 site of human chromosome and the coding region is composed of 9 exons, encoding 336 amino acids in total. Many studies have demonstrated that overexpressed RNF2 was involved in the pathological progression of multiple cancers and has an impact on their clinical features. For instance, the upregulated expression level of RNF2 is positively correlated with the occurrence and progression of hepatocellular carcinoma, melanoma, prostate cancer, breast cancer, pancreatic cancer, gastric cancer, and bladder urothelial carcinoma, as well as with the radioresistance of lung cancer and chemoresistance of ovarian cancer. This review provides an up-to-date perspective on the relationship between RNF2 and several cancers and highlights recent studies on RNF2 regulation. In particular, the relevant cellular signaling pathways and potential clinical value of RNF2 in cancers are also discussed, suggesting its potential as an epigenetic biomarker and therapeutic target for these cancers.
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4.
New promising developments for potential therapeutic applications of high-dose ascorbate as an anticancer drug.
Testa, U, Pelosi, E, Castelli, G
Hematology/oncology and stem cell therapy. 2021;(3):179-191
Abstract
Vitamin C (ascorbate) is an essential dietary requirement, with fundamental redox, anti-oxidant functions at physiologic concentrations. Vitamin C is a cofactor for Fe2+ and 2-oxoglutarate-dependent dioxygenases, englobing large families of enzymes, including also epigenetic regulators of DNA and histone methylation. Importantly, vitamin C is involved in the control of the activity of TET (ten-eleven translocation) enzymes, key epigenetic regulators. For this spectrum of activities, often involving pathways deregulated in cancer cells, vitamin C possesses some pharmacologic activities that can be exploited in anticancer therapy. In particular, the capacity of pharmacological doses of vitamin C to target redox imbalance and to rescue deregulated epigenetic program observed in some cancer cells represents a consistent therapeutic potentiality. Several recent studies have identified some cancer subsets that could benefit from the pharmacological activities of vitamin C. The identification of these potentially responsive patients will help to carefully define controlled clinical trials aiming to evaluate the anticancer activity of Vitamin C.
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5.
Autophagy and Extracellular Vesicles, Connected to rabGTPase Family, Support Aggressiveness in Cancer Stem Cells.
Brunel, A, Bégaud, G, Auger, C, Durand, S, Battu, S, Bessette, B, Verdier, M
Cells. 2021;(6)
Abstract
Even though cancers have been widely studied and real advances in therapeutic care have been made in the last few decades, relapses are still frequently observed, often due to therapeutic resistance. Cancer Stem Cells (CSCs) are, in part, responsible for this resistance. They are able to survive harsh conditions such as hypoxia or nutrient deprivation. Autophagy and Extracellular Vesicles (EVs) secretion are cellular processes that help CSC survival. Autophagy is a recycling process and EVs secretion is essential for cell-to-cell communication. Their roles in stemness maintenance have been well described. A common pathway involved in these processes is vesicular trafficking, and subsequently, regulation by Rab GTPases. In this review, we analyze the role played by Rab GTPases in stemness status, either directly or through their regulation of autophagy and EVs secretion.
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6.
Akt scaffold proteins: the key to controlling specificity of Akt signaling.
Bao, F, Hao, P, An, S, Yang, Y, Liu, Y, Hao, Q, Ejaz, M, Guo, XX, Xu, TR
American journal of physiology. Cell physiology. 2021;(3):C429-C442
Abstract
The phosphatidylinositol 3-kinase-Akt signaling pathway plays an essential role in regulating cell proliferation and apoptosis. Akt kinase is at the center of this signaling pathway and interacts with a variety of proteins. Akt is overexpressed in almost 80% of tumors. However, inhibiting Akt has serious clinical side effects so is not a suitable treatment for cancer. During recent years, Akt scaffold proteins have received increasing attention for their ability to regulate Akt signaling and have emerged as potential targets for cancer therapy. In this paper, we categorize Akt kinase scaffold proteins into four groups based on their cellular location: membrane-bound activator and inhibitor, cytoplasm, and endosome. We describe how these scaffolds interact with Akt kinase, how they affect Akt activity, and how they regulate the specificity of Akt signaling. We also discuss the clinical application of Akt scaffold proteins as targets for cancer therapy.
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7.
Targeting SUMO Signaling to Wrestle Cancer.
Kroonen, JS, Vertegaal, ACO
Trends in cancer. 2021;(6):496-510
Abstract
The small ubiquitin-like modifier (SUMO) signaling cascade is critical for gene expression, genome integrity, and cell cycle progression. In this review, we discuss the important role SUMO may play in cancer and how to target SUMO signaling. Recently developed small molecule inhibitors enable therapeutic targeting of the SUMOylation pathway. Blocking SUMOylation not only leads to reduced cancer cell proliferation but also to an increased antitumor immune response by stimulating interferon (IFN) signaling, indicating that SUMOylation inhibitors have a dual mode of action that can be employed in the fight against cancer. The search for tumor types that can be treated with SUMOylation inhibitors is ongoing. Employing SUMO conjugation inhibitory drugs in the years to come has potential as a new therapeutic strategy.
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8.
Modification of miRNA Expression through plant extracts and compounds against breast cancer: Mechanism and translational significance.
Ahmed, F, Ijaz, B, Ahmad, Z, Farooq, N, Sarwar, MB, Husnain, T
Phytomedicine : international journal of phytotherapy and phytopharmacology. 2020;:153168
Abstract
BACKGROUND Cancer is hyper-proliferative, multi-factorial and multi-step, heterogeneous group of molecular disorders. It is the second most reported disease after heart diseases. Breast carcinoma is the foremost death causing disease in female population worldwide. Cancer can be controlled by regulating the gene expression. Current therapeutic options are associated with severe side effects and are expensive for the people living in under-developed countries. Plant derived substances have potential application against different diseases like cancer, inflammation and viral infections. HYPOTHESIS The mechanism of action of the medicinal plants is largely unknown. Targeting gene network and miRNA using medicinal plants could help in improving the therapeutic options against cancer. METHODS The literature from 135 articles was reviewed by using PubMed, google scholar, Science direct to find out the plants and plant-based compounds against breast cancer and also the studies reporting their mechanistic route of action both at coding and noncoding RNA levels. RESULTS Natural products act as selective inhibitors of the cancerous cells by targeting oncogenes and tumor suppressor genes or altering miRNA expression. Natural compounds like EGCG from tea, Genistein from fava beans, curcumin from turmeric, DIM found in cruciferous, Resveratrol a polyphenol and Quercetin a flavonoid is found in various plants have been studied for their anticancer activity. The EGCG was found to inhibit proliferative activity by modulating miR-16 and miR-21. Similarly, DIM was found to down regulate miR-92a which results to modulate NFkB and stops cancer development. Another plant-based compound Glyceollins found to upregulate miR-181c and miR-181d having role in tumor suppression. It also found to regulate miR-22, 29b and c, miR-30d, 34a and 195. Quercetin having anti-cancer activity induce the apoptosis through regulating miR-16, 26b, 34a, let-7g, 125a and miR-605 and reduce the miRNA expression like miR-146a/b, 503 and 194 which are involved in metastasis. CONCLUSION Targeting miRNA expression using natural plant extracts can have a reverse effect on cell proliferation; turning on and off tumor-inducing and suppressing genes. It can be efficiently adopted as an adjuvant with the conventional form of therapies to increase their efficacy against cancer progression.
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9.
Statins as the Controlling Agents for Non-Hodgkin's Lymphomas via Increasing the Casein Kinase 2 Interacting Protein-1: A Hypothesis.
Kazemi, K, Mozafari, N, Ashrafi, H, Rafiei, P, Azadi, A
Current drug discovery technologies. 2020;(5):616-618
Abstract
BACKGROUND Non-Hodgkin's lymphomas (NHL), derived from B- or T-cell, consist of a heterogeneous group of malignant lymphoproliferative disorders. Knockdown of Casein kinase 2 interacting protein-1 (CKIP-1) in NHL promoted cell proliferation and inhibited apoptosis via enhancing phosphorylated Protein Kinase B (PKB or AKT) expression. Statins are the class of drugs that inhibit the ratelimiting step of the mevalonate pathway, which is essential for the biosynthesis of various compounds, including cholesterol. Also, statins have anticancer properties being mediated by different mechanisms. METHODS A search on databases like Scopus and PubMed with keywords such as statin and non- Hodgkin's lymphomas was performed and Kyoto Encyclopedia of Genes and Genomes (KEGG) website was used to evaluate and reconfirm the involved cellular signaling pathway. RESULTS CKIP-1 is involved in the regulation of cell proliferation and apoptosis while plays an important role in many cancers. We can hypothesize that statins may increase the expression levels of CKIP-1 which could contribute to the reductions in phospho-AKT level. Hence, they may ameliorate the NHL patients via suppressing AKT phosphorylation and increasing CKIP- expression. CONCLUSION Present review confirms the positive effect of statins on NHL by increasing CKIP-1 and reducing cell proliferation, subsequently.
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10.
Carotenoids in Cancer Metastasis-Status Quo and Outlook.
Koklesova, L, Liskova, A, Samec, M, Zhai, K, Abotaleb, M, Ashrafizadeh, M, Brockmueller, A, Shakibaei, M, Biringer, K, Bugos, O, et al
Biomolecules. 2020;(12)
Abstract
Metastasis represents a major obstacle in cancer treatment and the leading cause of cancer-related deaths. Therefore, the identification of compounds targeting the multi-step and complex process of metastasis could improve outcomes in the management of cancer patients. Carotenoids are naturally occurring pigments with a plethora of biological activities. Carotenoids exert a potent anti-cancer capacity in various cancer models in vitro and in vivo, mediated by the modulation of signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of the epithelial-mesenchymal transition and regulatory molecules, such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), urokinase plasminogen activator (uPA) and its receptor (uPAR), hypoxia-inducible factor-1α (HIF-1α), and others. Moreover, carotenoids modulate the expression of genes associated with cancer progression and inflammatory processes as key mediators of the complex process involved in metastasis. Nevertheless, due to the predominantly preclinical nature of the known anti-tumor effects of carotenoids, and unclear results from certain carotenoids in specific cancer types and/or specific parts of the population, a precise analysis of the anti-cancer effects of carotenoids is essential. The identification of carotenoids as effective compounds targeting the complex process of cancer progression could improve the outcomes of advanced cancer patients.