Reactive oxygen species and cancer paradox: To promote or to suppress?

There is highly credible evidence that melatonin mitigates cancer at the initiation, progression and metastasis phases. In many cases, the molecular mechanisms underpinning these inhibitory actions have been proposed. What is rather perplexing, however, is the large number of processes by which melatonin reportedly restrains cancer development and growth. These diverse actions suggest that what is being observed are merely epiphenomena of an underlying more fundamental action of melatonin that remains to be disclosed. Some of the arresting actions of melatonin on cancer are clearly membrane receptor-mediated while others are membrane receptor-independent and involve direct intracellular actions of this ubiquitously-distributed molecule. While the emphasis of melatonin/cancer research has been on the role of the indoleamine in restraining breast cancer, this is changing quickly with many cancer types having been shown to be susceptible to inhibition by melatonin. There are several facets of this research which could have immediate applications at the clinical level. Many studies have shown that melatonin’s co-administration improves the sensitivity of cancers to inhibition by conventional drugs. Even more important are the findings that melatonin renders cancers previously totally resistant to treatment sensitive to these same therapies. Melatonin also inhibits molecular processes associated with metastasis by limiting the entrance of cancer cells into the vascular system and preventing them from establishing secondary growths at distant sites. This is of particular importance since cancer metastasis often significantly contributes to death of the patient. Another area that deserves additional consideration is related to the capacity of melatonin in reducing the toxic consequences of anti-cancer drugs while increasing their efficacy. Although this information has been available for more than a decade, it has not been adequately exploited at the clinical level. Even if the only beneficial actions of melatonin in cancer patients are its ability to attenuate acute and long-term drug toxicity, melatonin should be used to improve the physical wellbeing of the patients. The experimental findings, however, suggest that the advantages of using melatonin as a co-treatment with conventional cancer therapies would far exceed improvements in the wellbeing of the patients.

Melatonin, a Full Service Anti-Cancer Agent: Inhibition of Initiation, Progression and Metastasis.

Formation and repair of oxidatively generated damage in cellular DNA.

Evidence indicates that hypoxia and oxidative stress can control metabolic reprogramming of cancer cells and other cells in tumor microenvironments and that the reprogrammed metabolic pathways in cancer tissue can also alter the redox balance. Thus, important steps toward developing novel cancer therapy approaches would be to identify and modulate critical biochemical nodes that are deregulated in cancer metabolism and determine if the therapeutic efficiency can be influenced by changes in redox homeostasis in cancer tissues. In this review, we will explore the molecular mechanisms responsible for the metabolic reprogramming of tumor microenvironments, the functional modulation of which may disrupt the effects of or may be disrupted by redox homeostasis modulating cancer therapy.

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ROS homeostasis and metabolism: a critical liaison for cancer therapy.

Reactive oxygen species (ROS) produced by cellular metabolism play an important role as signaling messengers in immune system. ROS elevated in the tumor microenvironment are associated with tumor-induced immunosuppression. T cell-based therapy has been recently approved to be effective for cancer treatment. However, T cells often become dysfunctional after reaching the tumor site. It has been reported that ROS participate extensively in T cells activation, apoptosis, and hyporesponsiveness. The sensitivity of T cells to ROS varies among different subsets. ROS can be regulated by cytokines, amino acid metabolism, and enzymatic activity. Immunosuppressive cells accumulate in the tumor microenvironment and induce apoptosis and functional suppression of T cells by producing ROS. Thus, modulating the level of ROS may be important to prolong survival of T cells and enhance their antitumor function. Combining T cell-based therapy with antioxidant treatment such as administration of ROS scavenger should be considered as a promising strategy in cancer treatment, aiming to improve antitumor T cells immunity.

https://downloads.hindawi.com/journals/omcl/2016/1580967.pdf

Reactive Oxygen Species Regulate T Cell Immune Response in the Tumor Microenvironment.

The presence of ROS is a constant feature in living cells metabolizing O2. ROS concentration and compartmentation determine their physiological or pathological effects. ROS overproduction is a feature of cancer cells and plays several roles during the natural history of malignant tumor. ROS continuously contribute to each step of cancerogenesis, from the initiation to the malignant progression, acting directly or indirectly. In this review, we will (a) underline the role of ROS in the pathway leading a normal cell to tumor transformation and progression, (b) define the multiple roles of ROS during the natural history of a tumor, (c) conciliate many conflicting data about harmful or beneficial effects of ROS, (d) rethink the importance of oncogene and tumor suppressor gene mutations in relation to the malignant progression, and (e) collocate all the cancer hallmarks in a mechanistic sequence which could represent a "physiological" response to the initial growth of a transformed stem/pluripotent cell, defining also the role of ROS in each hallmark. We will provide a simplified sketch about the relationships between ROS and cancer. The attention will be focused on the contribution of ROS to the signaling of HIF, NFκB, and Sirtuins as a leitmotif of cancer initiation and progression.

/pdf/the-interplay-of-reactive-oxygen-species-hypoxia-wt8kb6dlri.pdf

The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression.

Purpose To evaluate the safety and feasibility of ureteroscopy plus elective double-J stent as an outpatient procedure in an unselected population with regard to the treatment for ureteral calculi and to present a multivariate analysis of factors predict hospitalization. Materials and methods Ureteroscopy was performed as an outpatient procedure on 308 consecutive patients with ureteral stones. Contraindication for day case surgery was the only exclusion criteria from the study. All causes that led to immediate hospitalization were recorded; at the same time, all causes of hospitalization that occurred within 72 h from the procedure were also recorded and included in the final analysis. Results The overall stone-free rate and the rate of hospitalization were 94.5 and 9.7% respectively. Intraoperative complications were observed in 16 patients (5.1%). In terms of the variables related to hospitalization, the univariate analysis showed a statistical significant association between the American Society of Anesthesiologists (ASA) score (p Conclusions In our experience, semirigid ureteroscopy is a safe and effective treatment that is independent of intraoperative local conditions or stone size. Elective Double-J stenting avoids major complications as the first reason for hospitalization. We suggest that ASA score > 2 should be taken into account when ureterorenoscopy is planning as an outpatient procedure.

Predictors of Hospitalization After Ureteroscopy Plus Elective Double-J Stent as an Outpatient Procedure.

Molecular Nutrient Targeting with Mediterranean Diets

Background: Ureteral strictures are a recurrent chronic condition that leads to severe side effects and poor quality of life. Management of ureteral stricture is a great challenge for urologists and no specific guidelines exist. Retrograde Allium® ureteral stent (AUS) is a newly developed ureteral stent to treat either bulbar urethral or ureteral stenosis. Case Presentation: We describe a case of a 74-year-old Caucasian adult male presenting with a severe ureteral stricture secondary to an ureteroscopy for stone disease. Treatment with retrograde AUS placement produced a complete loss of renal function after 36 months, probably because of the development of a long achalasic stretch of the ureter. Conclusions: AUS is a new and promising device for the treatment of ureteral stenosis. However, a lack of standardization of the technique recommends a close instrumental follow-up after the procedure to decide the optimal time for stent removal.

Loss of Renal Function After Retrograde Ureteral Placement of an Allium Stent for Severe Ureteral Stricture

Objectives To evaluate the effectiveness and safety of the Allium™ ureteral stent as a curative treatment of benign ureteral strictures. Materials and methods We retrospectively reviewed the electronic database of the two centers of patients who underwent ureteral Allium™ positioning for different types of stenosis (benign or malignant). Between April 2017 and May 2021, 151 patients were treated with the Allium™ stent for ureteral strictures including benign and malignant stenosis. In total, 83 of them met the inclusion criteria for benign ureteral stricture and were included in final analysis. Results About the etiology of strictures, 79 (95.18%) were secondary to ureteroscopy or impacted stones and 4 (4.82%) were secondary to pelvic surgery. The median operating time was 47.9 ± 15.53 min, and the median length of strictures was 2.51 ± 0.84 (1-4) cm. The median time of follow-up was 18 months (range 1–48 months), the overall success rate was 85.5% (71/83), and no intraoperative or perioperative major complications were recorded. Among patients with failure (12 pts, 14.5%): 10 (83.33%) presented ureteral strictures again; among them, 8/10 were patients with a stricture length between 2 and 4 cm, 2 (16.67%) patients with pyelus–ureteral junction stenosis experienced the migration of the stent. All patients who experienced failure were treated surgically either with a robotic or laparoscopic approach. Conclusions In our preliminary experience, the Allium™ stent seems to be an effective and safe surgical treatment for benign ureteral stricture. Further analysis and prospective trials are necessary to better define the role of the Allium™ stent in the treatment of benign ureteral strictures.

Milena Polese

Papers

The Interplay of Reactive Oxygen Species, Hypoxia, Inflammation, and Sirtuins in Cancer Initiation and Progression.

Predictors of Hospitalization After Ureteroscopy Plus Elective Double-J Stent as an Outpatient Procedure.

Molecular Nutrient Targeting with Mediterranean Diets

Loss of Renal Function After Retrograde Ureteral Placement of an Allium Stent for Severe Ureteral Stricture

Allium stent as a curative treatment for benign ureteral strictures: Preliminary experience, surgical technique, and functional results