Entering a drug-tolerant persister (DTP) state of cancer cells is a transient self-adaptive mechanism by which a residual cell subpopulation accelerates tumor progression. Here, we identified the acquisition of a DTP phenotype in multidrug-resistant (MDR) cancer cells as a tolerance response to routine combination treatment. Characterization of MDR cancer cells with a DTP state by RNA-seq revealed that these cells partially prevented chemotherapytriggered oxidative stress by promoting NPC1L1-regulated uptake of vitamin E. Treatment with the NPC1L1 inhibitor ezetimibe further enhanced the therapeutic effect of combinatorial therapy by inducing methuosis. Mechanistically, we demonstrated that NRF2 was involved in transcriptional regulation of NPC1L1 by binding to the À205 to À215 bp site on its promoter. Decreased DNA methylation was also related partially to this process. Furthermore, we confirmed that a triple-combination of chemotherapeutic agents, verapamil, and ezetimibe, had a significant anti-tumor effect and prevented tumor recurrence in mice. Together, our study provides a novel insight into the role of DTP state and emphasizes the importance of disrupting redox homeostasis during cancer therapy.

Flavonoids are considered as pleiotropic, safe, and readily obtainable molecules. A large number of recent studies have proposed that flavonoids have potential in the treatment of tumors by the modulation of autophagy. In many cases, flavonoids suppress cancer by stimulating excessive autophagy or impairing autophagy flux especially in apoptosis-resistant cancer cells. However, the anti-cancer activity of flavonoids may be attenuated due to the simultaneous induction of protective autophagy. Notably, flavonoids-triggered protective autophagy is becoming a trend for preventing cancer in the clinical setting or for protecting patients from conventional therapeutic side effects in normal tissues. In this review, focusing on the underlying autophagic mechanisms of flavonoids, we hope to provide a new perspective for clinical application of flavonoids in cancer therapy. In addition, we highlight new research ideas for the development of new dosage forms of flavonoids to improve their various pharmacological effects, establishing flavonoids as ideal candidates for cancer prevention and therapy in the clinic.

No abstract

Oxidative stress (OS), characterized by the excessive accumulation of reactive oxygen species (ROS), is an emerging hallmark of cancer. Tumorigenesis and development driven by ROS require an aberrant redox homeostasis, that activates onco-signaling and avoids ROS-induced programmed death by orchestrating antioxidant systems. These processes are revealed to closely associate with noncoding RNAs (ncRNAs). On the basis of the available evidence, ncRNAs have been widely identified as multifarious modulators with the involvement of several key redox sensing pathways, such as NF-κB and Nrf2 signaling, therefore potentially becoming effective targets for cancer therapy. Furthermore, the vast majority of ncRNAs with property of easy detected in fluid samples (e.g., blood and urine) facilitate clinicians to monitor redox homeostasis, indicating a novel method for cancer diagnosis. Herein, focusing on carcinoma initiation, metastasis and chemoradiotherapy resistance, we aimed to discuss the ncRNAs-ROS network involved in cancer progression, and the potential clinical application as biomarkers and therapeutic targets.

As of 2020 the human genome and proteome are both at >90% completion based on high stringency analyses. This has been largely achieved by major technological advances over the last 20 years and has enlarged our understanding of human health and disease, including cancer, and is supporting the current trend towards personalized/precision medicine. This is due to improved screening, novel therapeutic approaches and an increased understanding of underlying cancer biology. However, cancer is a complex, heterogeneous disease modulated by genetic, molecular, cellular, tissue, population, environmental and socioeconomic factors, which evolve with time. In spite of recent advances in treatment that have resulted in improved patient outcomes, prognosis is still poor for many patients with certain cancers (e.g., mesothelioma, pancreatic and brain cancer) with a high death rate associated with late diagnosis. In this review we overview key hallmarks of cancer (e.g., autophagy, the role of redox signaling), current unmet clinical needs, the requirement for sensitive and specific biomarkers for early detection, surveillance, prognosis and drug monitoring, the role of the microbiome and the goals of personalized/precision medicine, discussing how emerging omics technologies can further inform on these areas. Exemplars from recent onco-proteogenomic-related publications will be given. Finally, we will address future perspectives, not only from the standpoint of perceived advances in treatment, but also from the hurdles that have to be overcome.

Cancer is one of the most common disease worldwide, with complex changes and certain traits which have been described as "The Hallmarks of Cancer." Despite increasing studies on in-depth investigation of these hallmarks, the molecular mechanisms associated with tumorigenesis have still not yet been fully defined. Recently, accumulating evidence supports the observation that microRNAs and long noncoding RNAs (lncRNAs), two main classes of noncoding RNAs (ncRNAs), regulate most cancer hallmarks through their binding with DNA, RNA or proteins, or encoding small peptides. Reactive oxygen species (ROS), the byproducts generated during metabolic processes, are known to regulate every step of tumorigenesis by acting as second messengers in cancer cells. The disturbance in ROS homeostasis leads to a specific pathological state termed "oxidative stress", which plays essential roles in regulation of cancer progression. In addition, the interplay between oxidative stress and ncRNAs is found to regulate the expression of multiple genes and the activation of several signaling pathways involved in cancer hallmarks, revealing a potential mechanistic relationship involving ncRNAs, oxidative stress and cancer. In this review, we provide evidence that shows the essential role of ncRNAs and the interplay between oxidative stress and ncRNAs in regulating cancer hallmarks, which may expand our understanding of ncRNAs in the cancer development from the new perspective.