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1.
Inhibitory effect of polyphenols (phenolic acids, lignans, and stilbenes) on cancer by regulating signal transduction pathways: a review.
Hazafa, A, Iqbal, MO, Javaid, U, Tareen, MBK, Amna, D, Ramzan, A, Piracha, S, Naeem, M
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico. 2022;(3):432-445
Abstract
Natural products, especially polyphenols (phenolic acids, lignans, and stilbenes) are suggested to be more potent anticancer drugs because of their no or less adverse effects, excess availability, high accuracy, and secure mode of action. In the present review, potential anticancer mechanisms of action of some polyphenols including phenolic acids, lignans, and stilbenes are discussed based on clinical, epidemiological, in vivo, and in vitro studies. The emerging evidence revealed that phenolic acids, lignans, and stilbenes induced apoptosis in the treatment of breast (MCF-7), colon (Caco-2), lung (SKLU-1), prostate (DU-145 and LNCaP), hepatocellular (hepG-2), and cervical (A-431) cancer cells, cell cycle arrest (S/G2/M/G1-phases) in gastric (MKN-45 and MKN-74), colorectal (HCT-116), bladder (T-24 and 5637), oral (H-400), leukemic (HL-60 and MOLT-4) and colon (Caco-2) cancer cells, and inhibit cell proliferation against the prostate (PC-3), liver (LI-90), breast (T47D and MDA-MB-231), colon (HT-29 and Caco-2), cervical (HTB-35), and MIC-1 cancer cells through caspase-3, MAPK, AMPK, Akt, NF-κB, Wnt, CD95, and SIRT1 pathways. Based on accumulated data, we suggested that polyphenols could be considered as a viable therapeutic option in the treatment of cancer cells in the near future.
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2.
Epigenetic scores for the circulating proteome as tools for disease prediction.
Gadd, DA, Hillary, RF, McCartney, DL, Zaghlool, SB, Stevenson, AJ, Cheng, Y, Fawns-Ritchie, C, Nangle, C, Campbell, A, Flaig, R, et al
eLife. 2022
Abstract
Protein biomarkers have been identified across many age-related morbidities. However, characterising epigenetic influences could further inform disease predictions. Here, we leverage epigenome-wide data to study links between the DNA methylation (DNAm) signatures of the circulating proteome and incident diseases. Using data from four cohorts, we trained and tested epigenetic scores (EpiScores) for 953 plasma proteins, identifying 109 scores that explained between 1% and 58% of the variance in protein levels after adjusting for known protein quantitative trait loci (pQTL) genetic effects. By projecting these EpiScores into an independent sample (Generation Scotland; n = 9537) and relating them to incident morbidities over a follow-up of 14 years, we uncovered 137 EpiScore-disease associations. These associations were largely independent of immune cell proportions, common lifestyle and health factors, and biological aging. Notably, we found that our diabetes-associated EpiScores highlighted previous top biomarker associations from proteome-wide assessments of diabetes. These EpiScores for protein levels can therefore be a valuable resource for disease prediction and risk stratification.
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3.
Decoding the Phosphatase Code: Regulation of Cell Proliferation by Calcineurin.
Masaki, T, Shimada, M
International journal of molecular sciences. 2022;(3)
Abstract
Calcineurin, a calcium-dependent serine/threonine phosphatase, integrates the alterations in intracellular calcium levels into downstream signaling pathways by regulating the phosphorylation states of several targets. Intracellular Ca2+ is essential for normal cellular physiology and cell cycle progression at certain critical stages of the cell cycle. Recently, it was reported that calcineurin is activated in a variety of cancers. Given that abnormalities in calcineurin signaling can lead to malignant growth and cancer, the calcineurin signaling pathway could be a potential target for cancer treatment. For example, NFAT, a typical substrate of calcineurin, activates the genes that promote cell proliferation. Furthermore, cyclin D1 and estrogen receptors are dephosphorylated and stabilized by calcineurin, leading to cell proliferation. In this review, we focus on the cell proliferative functions and regulatory mechanisms of calcineurin and summarize the various substrates of calcineurin. We also describe recent advances regarding dysregulation of the calcineurin activity in cancer cells. We hope that this review will provide new insights into the potential role of calcineurin in cancer development.
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4.
Next steps for clinical translation of adenosine pathway inhibition in cancer immunotherapy.
Augustin, RC, Leone, RD, Naing, A, Fong, L, Bao, R, Luke, JJ
Journal for immunotherapy of cancer. 2022;(2)
Abstract
Increasing evidence supports targeting the adenosine pathway in immuno-oncology with several clinical programs directed at adenosine A2 receptor (A2AR, A2BR), CD73 and CD39 in development. Through a cyclic-AMP-mediated intracellular cascade, adenosine shifts the cytokine and cellular profile of the tumor microenvironment away from cytotoxic T cell inflammation toward one of immune tolerance. A perpetuating cycle of tumor cell proliferation, tissue injury, dysregulated angiogenesis, and hypoxia promote adenosine accumulation via ATP catabolism. Adenosine receptor (eg, A2AR, A2BR) stimulation of both the innate and adaptive cellular precursors lead to immunosuppressive phenotypic differentiation. Preclinical work in various tumor models with adenosine receptor inhibition has demonstrated restoration of immune cell function and tumor regression. Given the broad activity but known limitations of anti-programmed cell death protein (PD1) therapy and other checkpoint inhibitors, ongoing studies have sought to augment the successful outcomes of anti-PD1 therapy with combinatorial approaches, particularly adenosine signaling blockade. Preliminary data have demonstrated an optimal safety profile and enhanced overall response rates in several early phase clinical trials with A2AR and more recently CD73 inhibitors. However, beneficial outcomes for both monotherapy and combinations have been mostly lower than expected based on preclinical studies, indicating a need for more nuanced patient selection or biomarker integration that might predict and optimize patient outcomes. In the context of known immuno-oncology biomarkers such as tumor mutational burden and interferon-associated gene expression, a comparison of adenosine-related gene signatures associated with clinical response indicates an underlying biology related to immunosuppression, angiogenesis, and T cell inflammation. Importantly, though, adenosine associated gene expression may point to a unique intratumoral phenotype independent from IFN-γ related pathways. Here, we discuss the cellular and molecular mechanisms of adenosine-mediated immunosuppression, preclinical investigation of adenosine signaling blockade, recent response data from clinical trials with A2AR, CD73, CD39 and PD1/L1 inhibitors, and ongoing development of predictive gene signatures to enhance combinatorial immune-based therapies.
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5.
The Potential Mechanisms by which Artemisinin and Its Derivatives Induce Ferroptosis in the Treatment of Cancer.
Hu, Y, Guo, N, Yang, T, Yan, J, Wang, W, Li, X
Oxidative medicine and cellular longevity. 2022;:1458143
Abstract
Artemisinin (ART) is a bioactive molecule derived from the Chinese medicinal plant Artemisia annua (Asteraceae). ART and artemisinin derivatives (ARTs) have been effectively used for antimalaria treatment. The structure of ART is composed of a sesquiterpene lactone, including a peroxide internal bridge that is essential for its activity. In addition to their well-known antimalarial effects, ARTs have been shown recently to resist a wide range of tumors. The antineoplastic mechanisms of ART mainly include cell cycle inhibition, inhibition of tumor angiogenesis, DNA damage, and ferroptosis. In particular, ferroptosis is a novel nonapoptotic type of programmed cell death. However, the antitumor mechanisms of ARTs by regulating ferroptosis remain unclear. Through this review, we focus on the potential antitumor function of ARTs by acting on ferroptosis, including the regulation of iron metabolism, generation of reactive oxygen species (ROS), and activation of endoplasmic reticulum stress (ERS). This article systematically reviews the recent progress in ferroptosis research and provides a basis for ARTs as an anticancer drug in clinical practice.
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6.
Direct Oral Anticoagulants for the Treatment of Cancer-Associated Venous Thromboembolism: A Latin American Perspective.
Athanazio, RA, Ceresetto, JM, Marfil Rivera, LJ, Cesarman-Maus, G, Galvez, K, Marques, MA, Tabares, AH, Ortiz Santacruz, CA, Santini, FC, Corrales, L, et al
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2022;:10760296221082988
Abstract
Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in patients with cancer. On the basis of results from randomized controlled trials, direct oral anticoagulants (DOACs) are now recommended for the treatment of cancer-associated VTE. The decision to use a DOAC requires consideration of bleeding risk, particularly in patients with gastrointestinal (GI) malignancies, the cost-benefit and convenience of oral therapy, and patient preference. While efficacy with apixaban, edoxaban, and rivaroxaban versus dalteparin has been consistent in the treatment of cancer-associated VTE, heterogeneity is evident with respect to major GI bleeding, with an increased risk with edoxaban and rivaroxaban but not apixaban. Although cost and accessibility vary in different countries of Latin America, DOACs should be considered for the long-term treatment of cancer-associated VTE in all patients who are likely to benefit. Apixaban may be the preferred DOAC in patients with GI malignancies and LMWH may be preferred for patients with upper or unresected lower GI tumors. Vitamin K antagonists should only be used for anticoagulation when DOACs and low molecular weight heparin are inaccessible or unsuitable.
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7.
SP and KLF Transcription Factors in Cancer Metabolism.
Orzechowska-Licari, EJ, LaComb, JF, Mojumdar, A, Bialkowska, AB
International journal of molecular sciences. 2022;(17)
Abstract
Tumor development and progression depend on reprogramming of signaling pathways that regulate cell metabolism. Alterations to various metabolic pathways such as glycolysis, oxidative phosphorylation, lipid metabolism, and hexosamine biosynthesis pathway are crucial to sustain increased redox, bioenergetic, and biosynthesis demands of a tumor cell. Transcription factors (oncogenes and tumor suppressors) play crucial roles in modulating these alterations, and their functions are tethered to major metabolic pathways under homeostatic conditions and disease initiation and advancement. Specificity proteins (SPs) and Krüppel-like factors (KLFs) are closely related transcription factors characterized by three highly conserved zinc fingers domains that interact with DNA. Studies have demonstrated that SP and KLF transcription factors are expressed in various tissues and regulate diverse processes such as proliferation, differentiation, apoptosis, inflammation, and tumorigenesis. This review highlights the role of SP and KLF transcription factors in the metabolism of various cancers and their impact on tumorigenesis. A better understanding of the role and underlying mechanisms governing the metabolic changes during tumorigenesis could provide new therapeutic opportunities for cancer treatment.
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8.
Nutritional Approach to Cancer Cachexia: A Proposal for Dietitians.
Tanaka, K, Nakamura, S, Narimatsu, H
Nutrients. 2022;(2)
Abstract
Cachexia is one of the most common, related factors of malnutrition in cancer patients. Cancer cachexia is a multifactorial syndrome characterized by persistent loss of skeletal muscle mass and fat mass, resulting in irreversible and progressive functional impairment. The skeletal muscle loss cannot be reversed by conventional nutritional support, and a combination of anti-inflammatory agents and other nutrients is recommended. In this review, we reviewed the effects of nutrients that are expected to combat muscle loss caused by cancer cachexia (eicosapentaenoic acid, β-hydroxy-β-methylbutyrate, creatine, and carnitine) to propose nutritional approaches that can be taken at present. Current evidence is based on the intake of nutrients as supplements; however, the long-term and continuous intake of nutrients as food has the potential to be useful for the body. Therefore, in addition to conventional nutritional support, we believe that it is important for the dietitian to work with the clinical team to first fully assess the patient's condition and then to safely incorporate nutrients that are expected to have specific functions for cancer cachexia from foods and supplements.
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9.
Phase 1A/1B dose-escalation and -expansion study to evaluate the safety, pharmacokinetics, food effects and antitumor activity of pamiparib in advanced solid tumours.
Lickliter, JD, Voskoboynik, M, Mileshkin, L, Gan, HK, Kichenadasse, G, Zhang, K, Zhang, M, Tang, Z, Millward, M
British journal of cancer. 2022;(4):576-585
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Abstract
BACKGROUND Pamiparib, a PARP1/2 inhibitor, demonstrated antitumor activity in preclinical models. METHODS This Phase 1A/1B dose-escalation/dose-expansion study enrolled adults (≥18 years) with advanced/metastatic cancer. The dose-escalation phase evaluated the recommended Phase 2 dose (RP2D), maximum tolerated dose (MTD), and pharmacokinetics; the dose-expansion phase evaluated the antitumor activity and food effects. RESULTS Patients (N = 101) were enrolled in dose-escalation (n = 64) and dose-expansion (n = 37). During BID dose-escalation, dose-limiting toxicities were Grade 2 nausea (n = 1, 40 mg; n = 1, 80 mg); Grade 2 nausea and Grade 2 anorexia (n = 1, 120 mg), Grade 2 nausea, Grade 3 fatigue and Grade 3 paraesthesia (n = 1, 120 mg); MTD was 80 mg BID and RP2D was 60 mg BID. Common adverse events (AEs) were nausea (69.3%), fatigue (48.5%) and anaemia (35.6%); the most common Grade ≥3 AE was anaemia (24.8%). There was a dose-proportional increase in pamiparib exposure; no food effects on pharmacokinetics were observed. In the efficacy-evaluable population (n = 77), objective response rate (ORR) was 27.3% (95% CI, 17.7-38.6%). Median duration of response was 14.9 months (95% CI, 8.7-26.3). In the epithelial ovarian cancer (EOC)-evaluable population (n = 51), ORR was 41.2% (95% CI, 27.6-55.8%). CONCLUSIONS Pamiparib was tolerated with manageable AEs, and antitumor activity was observed in patients with EOC. CLINICALTRIALS. GOV IDENTIFIER NCT02361723.
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Ketogenic diet for human diseases: the underlying mechanisms and potential for clinical implementations.
Zhu, H, Bi, D, Zhang, Y, Kong, C, Du, J, Wu, X, Wei, Q, Qin, H
Signal transduction and targeted therapy. 2022;(1):11
Abstract
The ketogenic diet (KD) is a high-fat, adequate-protein, and very-low-carbohydrate diet regimen that mimics the metabolism of the fasting state to induce the production of ketone bodies. The KD has long been established as a remarkably successful dietary approach for the treatment of intractable epilepsy and has increasingly garnered research attention rapidly in the past decade, subject to emerging evidence of the promising therapeutic potential of the KD for various diseases, besides epilepsy, from obesity to malignancies. In this review, we summarize the experimental and/or clinical evidence of the efficacy and safety of the KD in different diseases, and discuss the possible mechanisms of action based on recent advances in understanding the influence of the KD at the cellular and molecular levels. We emphasize that the KD may function through multiple mechanisms, which remain to be further elucidated. The challenges and future directions for the clinical implementation of the KD in the treatment of a spectrum of diseases have been discussed. We suggest that, with encouraging evidence of therapeutic effects and increasing insights into the mechanisms of action, randomized controlled trials should be conducted to elucidate a foundation for the clinical use of the KD.