Chapter 3: Management of kidney injury caused by cancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022.

Cisplatin should be administered with diuretics and Magnesium supplementation under adequate hydration to avoid renal impairment. Patients should be evaluated for eGFR (estimated glomerular filtration rate) during the treatment with pemetrexed, as kidney injury has been reported. Pemetrexed should be administered with caution in patients with a CCr (creatinine clearance) < 45 mL/min. Mesna is used to prevent hemorrhagic cystitis in patients receiving ifosfamide. Febuxostat is effective in avoiding hyperuricemia induced by TLS (tumor lysis syndrome). Preventative rasburicase is recommended in high-risk cases of TLS. Thrombotic microangiopathy could be triggered by anticancer drugs and there is no evidence of efficacy of plasma exchange therapy. When proteinuria occurs during treatment with anti-angiogenic agents or multi-kinase inhibitors, dose reductions or interruptions based on grading should be considered. Grade 3 proteinuria and renal dysfunction require urgent intervention, including drug interruption or withdrawal, and referral to a nephrologist should be considered. The first-line drugs used for blood pressure elevation due to anti-angiogenic agents are ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin receptor blockers). The protein binding of drugs and their pharmacokinetics are considerably altered in patients with hypoalbuminemia. The clearance of rituximab is increased in patients with proteinuria, and the correlation with urinary IgG suggests similar pharmacokinetic changes when using other antibody drugs. AIN (acute interstitial nephritis) is the most common cause of ICI (immune checkpoint inhibitor)-related kidney injury that is often treated with steroids. The need for renal biopsy in patients with kidney injury that occurs during treatment with ICI remains controversial.

Pathological and Pharmacological Roles of Mitochondrial Reactive Oxygen Species in Malignant Neoplasms: Therapies Involving Chemical Compounds, Natural Products, and Photosensitizers.

Oxidative stress plays an important role in cellular processes. Consequently, oxidative stress also affects etiology, progression, and response to therapeutics in various pathological conditions including malignant tumors. Oxidative stress and associated outcomes are often brought about by excessive generation of reactive oxygen species (ROS). Accumulation of ROS occurs due to dysregulation of homeostasis in an otherwise strictly controlled physiological condition. In fact, intracellular ROS levels are closely associated with the pathological status and outcome of numerous diseases. Notably, mitochondria are recognized as the critical regulator and primary source of ROS. Damage to mitochondria increases mitochondrial ROS (mROS) production, which leads to an increased level of total intracellular ROS. However, intracellular ROS level may not always reflect mROS levels, as ROS is not only produced by mitochondria but also by other organelles such as endoplasmic reticulum and peroxisomes. Thus, an evaluation of mROS would help us to recognize the biological and pathological characteristics and predictive markers of malignant tumors and develop efficient treatment strategies. In this review, we describe the pathological significance of mROS in malignant neoplasms. In particular, we show the association of mROS-related signaling in the molecular mechanisms of chemically synthesized and natural chemotherapeutic agents and photodynamic therapy.

Erratum: Oral intake of royal jelly improves anti-cancer effects and suppresses adverse events of molecular targeted therapy by regulating TNF-α and TGF-ß in renal cell carcinoma: A preliminary study based on a randomized double-blind clinical trial.

[This corrects the article DOI: 10.3892/mco.2020.2099.].

Oral intake of royal jelly improves anti-cancer effects and suppresses adverse events of molecular targeted therapy by regulating TNF-α and TGF-ß in renal cell carcinoma: A preliminary study based on a randomized double-blind clinical trial.

Molecular targeted therapies are commonly used in patients with metastatic renal cell carcinoma (RCC). However, the efficacy and safety of these therapeutic interventions require enhancement to improve prognosis in these patients. Royal jelly (RJ) has anti-cancer effects and adverse events across a variety of types of malignancy. The present study investigated the detailed mechanism underlying the effects of oral administration of RJ in patients with advanced RCC that were treated with molecular targeted agents in a randomized clinical trial. The study cohort comprised 16 patients treated with RJ and 17 patients treated with a placebo. Serum levels of tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-ß were measured using enzyme-linked immunosorbent assays. The results of the present study demonstrated a larger decrease in tumor size upon supplementing patients with RJ following molecular targeted therapy compared with that in patients administered with the placebo. Patients exhibited reduced anorexia and fatigue in the RJ group compared with the placebo group. The relative dose intensity for patients in the RJ group was higher than that in patients in the placebo group. Post- and pre-treatment ratios of the serum levels of TNF-α and TGF-ß in patients in the RJ group were lower than those in patients in the placebo group, and these ratios correlated with decreasing tumor size and frequency of anorexia or fatigue in patients. In conclusion, the results of the present study indicated that oral intake of RJ improved the efficacy and safety of molecular targeted therapy in patients with RCC and changed the levels of TNF-α and TGF-ß in the serum of patients, which is speculated to serve an important role in RJ-induced biological activities.

Anti-Cancer Effects of Green Tea Polyphenols Against Prostate Cancer.

Prostate cancer is the most common cancer among men. Green tea consumption is reported to play an important role in the prevention of carcinogenesis in many types of malignancies, including prostate cancer; however, epidemiological studies show conflicting results regarding these anti-cancer effects. In recent years, in addition to prevention, many investigators have shown the efficacy and safety of green tea polyphenols and combination therapies with green tea extracts and anti-cancer agents in in vivo and in vitro studies. Furthermore, numerous studies have revealed the molecular mechanisms of the anti-cancer effects of green tea extracts. We believe that improved understanding of the detailed pathological roles at the molecular level is important to evaluate the prevention and treatment of prostate cancer. Therefore, in this review, we present current knowledge regarding the anti-cancer effects of green tea extracts in the prevention and treatment of prostate cancer, with a particular focus on the molecular mechanisms of action, such as influencing tumor growth, apoptosis, androgen receptor signaling, cell cycle, and various malignant behaviors. Finally, the future direction for the use of green tea extracts as treatment strategies in patients with prostate cancer is introduced.

Anti-Cancer and Protective Effects of Royal Jelly for Therapy-Induced Toxicities in Malignancies.

Royal jelly (RJ) is a glandular secretion produced by worker honeybees and is a special food for the queen honeybee. It results in a significant prolongation of the lifespan of the queen honeybee compared with the worker honeybees through anti-inflammatory, anti-oxidant and anti-microbial activities. Consequently, RJ is used as cosmetic and dietary supplement throughout the world. In addition, in vitro studies and animal experiments have demonstrated that RJ inhibits cell proliferation and stimulates apoptosis in various types of malignant cells and affects the production of various chemokines, anti-oxidants and growth factors and the expression of cancer-related molecules in patients with malignancies, especially in patients treated with anti-cancer agents. Therefore, RJ is thought to exert anti-cancer effects on tumor growth and exhibit protective functions against drug-induced toxicities. RJ has also been demonstrated to be useful for suppression of adverse events, the maintenance of the quality of life during treatment and the improvement of prognosis in animal models and patients with malignancies. To understand the mechanisms of the beneficial effects of RJ, knowledge of the changes induced at the molecular level by RJ with respect to cell survival, inflammation, oxidative stress and other cancer-related factors is essential. In addition, the effects of combination therapies of RJ and other anti-cancer agents or natural compounds are important to determine the future direction of RJ-based treatment strategies. Therefore, in this review, we have covered the following five issues: (1) the anti-cancer effects of RJ and its main component, 10-hydroxy-2-decenoic acid; (2) the protective effects of RJ against anti-cancer agent-induced toxicities; (3) the molecular mechanisms of such beneficial effects of RJ; (4) the safety and toxicity of RJ; and (5) the future directions of RJ-based treatment strategies, with a discussion on the limitations of the study of the biological activities of RJ.

High Consumption of Green Tea Suppresses Urinary Tract Recurrence of Urothelial Cancer via Down-regulation of Human Antigen-R Expression in Never Smokers.

BACKGROUND/AIM: Smoking is a risk factor for carcinogenesis and progression of urothelial cancer (UC). Green tea polyphenol inhibits these malignant behaviors and suppresses human antigen R (HuR) expression, which is associated with malignant aggressiveness. This study aimed to clarify the anti-cancer effects of green tea based on the smoking status of UC patients. PATIENTS AND METHODS: Three hundred and sixty (260 with bladder cancer, BC and 100 with upper tract UC) patients were divided into three groups based on consumption of green tea: low (<1 cup/day, n=119), middle (1-4 cup/day, n=160), and high (>5 cup/day, n=81). HuR immunoreactivity was evaluated immunohistochemically in formalin-fixed specimens. RESULTS: In never smokers, multivariate analysis showed that the frequency of green tea consumption was a significant predictor (middle: hazard ratio, HR, 0.36, p=0.002; high: HR, 0.20, p=0.003) of urinary tract recurrence. A high consumption of green tea was associated with low rates of urinary tract recurrence and up-grading in UC patients. In BC, high consumption was associated with a lower risk of up-grading (p=0.011) and up-staging (p=0.041) in recurrent cancer. HuR expression in the high-consumption group was lower (p=0.019) than that in other groups. These significant findings were not detected in ever smokers. CONCLUSION: High consumption of green tea suppressed urinary tract recurrence and the risks of up-grading and up-staging by recurrence in never smokers. Our results suggested that HuR expression played important roles in such mechanisms.

The natural flavonoid myricetin inhibits gastric H+, K+-ATPase.

Myricetin (3,3',4',5,5',7-hexahydroxyflavone), a major flavonoid in berries and red wine, has been recently used as a health food supplement based on its antioxidant and antitumor properties. We report here that myricetin preferentially exerts inhibitory effects on gastric H+, K+-ATPase. Myricetin inhibited H+, K+-ATPase with a sub-micromolar IC50 value in an enzyme assay using freeze-dried tubulovesicles prepared from hog stomach. Na+, K+-ATPase and Ca2+-ATPase were also inhibited by myricetin in a dose-dependent manner, but the IC50 values for these enzymes were approximately an order of magnitude higher compared to the H+, K+-ATPase. In structure-inhibitory functional analysis of sixteen myricetin derivatives, several phenolic hydroxy groups attached to the flavonoid backbone were highlighted as essential modifications for the inhibition of P2-type ATPases. Furthermore, oral administration of myricetin significantly attenuated histamine-induced gastric acid secretion in an in vivo mouse assessment. Therefore, myricetin derivatives seem to be useful seed compounds for developing new drugs and supplements to alleviate gastric acid secretion.

Green Tea Polyphenol Induces Changes in Cancer-Related Factors in an Animal Model of Bladder Cancer.

Green tea polyphenol (GTP) suppresses carcinogenesis and aggressiveness in many types of malignancies including bladder cancer. However, the mechanistic basis of these effects is not well understood. This was investigated in the present study using a mouse model of chemically induced bladder cancer. C3H/He mice (8 weeks old; n = 46) were treated with 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) solution for 14-24 weeks. Mice in the BBN + GTP group (n = 47) were also treated with 0.5% GTP solution over the same period. Tumor cell proliferation and microvessel density were evaluated along with immunohistochemical analysis of human antigen (Hu)R, vascular endothelial growth factor (VEGF)-A, cyclooxygenase (COX)-2, and hemeoxygenase (HO)-1 expression. Cytoplasmic HuR expression in cancer cells was higher at 14 and 24 weeks in the BBN than in the control group and was associated with increased invasion of tumor cells in muscle. However, these effects were not observed in the BBN + GTP group. A multivariate analysis of GTP intake and cytoplasmic HuR expression revealed that GTP was independently associated with COX-2 and HO-1 expression, while cytoplasmic HuR expression was associated with COX-2 and VEGF-A levels. Expression of COX-2 and HO-1 was associated with cell proliferation and that of VEGF-A and HO-1 was associated with angiogenesis. Nuclear HuR expression was not associated with any parameters such as carcinogenesis, muscle invasion, and GTP intake. These results indicate that GTP intake can suppress tumor progression and malignant behavior in an animal model of bladder cancer. We also speculate that GTP directly and indirectly suppresses tumor cell proliferation and angiogenesis via HuR-related pathways in bladder cancer.

Comparison Between a Combined Transrectal and Transperineal Approach and a Transrectal Approach for Prostate Rebiopsy.

AIM: To evaluate whether a combination method involving the transrectal (TR) and transperineal (TP) approach can increase the cancer detection rate relative to the TR approach regarding repeat prostate biopsy. PATIENTS AND METHODS: One thousand and nineteen patients underwent initial prostate biopsies and 298 repeat prostate biopsies. All initial biopsies were conducted transrectally. Of the repeat biopsies, 179 (60.1%) were performed using the combined transrectal and transperineal (TR+TP) approach; 113 (37.9%) were carried out transrectally. All biopsies were performed under ultrasound guidance using a 16-gauge core biopsy needle; 651 were diagnosed as prostate cancer; 224 patients underwent radical prostatectomies (RPs). We evaluated the cancer detection rates between the biopsy methods in the repeat biopsy cohort and compared the clinical and pathological features of the RP specimens between the initial and repeat biopsy groups. RESULTS: A median of 12 and 20 cores were obtained in the initial and repeat biopsy patients, respectively. Cancer detection rates regarding biopsies 1, 2, 3, 4 and 5 were 49.2% (551/1,119), 34.7% (75/216), 33.3% (20/60), 26.7% (4/15) and 14.3% (1/7), respectively. There were no significant differences between the TR and the TR+TP approach (32.7% vs. 33.5%). RP specimens diagnosed using repeat biopsies showed more anterior dominant tumors relative to those diagnosed using the initial biopsies (59.5% vs. 35.9%; p<0.001). CONCLUSION: The TR+TP combination approach could not increase cancer detection rates relative to the TR approach in the repeat biopsy cohort. However, 16-gauge needle biopsy demonstrated acceptable cancer detection rates in the comparatively small number of biopsy cores.

Safety and efficacy of combination therapy with low-dose gemcitabine, paclitaxel, and sorafenib in patients with cisplatin-resistant urothelial cancer.

Various regimens including molecular targeted agents have been examined in patients with cisplatin (CDDP)-resistant urothelial cancer (UC). However, some studies have been stopped owing to the development of severe adverse events. The main aim of this study was to examine the anticancer effects, changes in the quality of life (QoL), and safety of combined therapy of low-dose gemcitabine, paclitaxel, and sorafenib (LD-GPS) in patients with CDDP-resistant UC. Twenty patients were treated with gemcitabine (700 mg/m(2) on day 1), paclitaxel (70 mg/m(2) on day 1), and sorafenib (400 mg/day on days 8-22). QoL and pain relief were evaluated using the short-form survey (SF)-36 for bodily pain and the visual analog scale (VAS). VAS scores were significantly decreased by both the second- and third-line therapies (P = 0.012 and 0.028, respectively). The bodily pain score from the SF-36 survey was also significantly (P = 0.012) decreased. Complete responses, partial responses, and stable disease were found in 0 (0.0 %), 1 (5.0 %), and 13 patients (65 %), respectively. The median (interquartile range) period of overall survival after starting of this therapy was 7 (5-11) months. Three patients (15.0 %) stopped therapy because of grade 3 fatigue and hand-foot reactions. LD-GPS therapy was well tolerated by patients with CDDP-resistant UC. QoL was maintained, and improvements in their pain levels were found after treatment; pain relief was detected after third-line therapy. We suggest that this treatment regimen is worthy of consideration as second- and third-line therapy for patients with CDDP-resistant UC.

Awareness of folic acid use increases its consumption, and reduces the risk of spina bifida.

The majority of neural tube defects were believed to be folic acid (FA)-preventable in the 1990s. The Japanese government recommended women planning pregnancy to take FA supplements of 400 µg/d in 2000, but the incidence of spina bifida has not decreased. We aimed to evaluate the OR of having an infant with spina bifida for women who periconceptionally took FA supplements and the association between an increase in supplement use and possible promoters for the increase. This is a case-control study which used 360 case women who gave birth to newborns afflicted with spina bifida, and 2333 control women who gave birth to healthy newborns during the first 12 years of this century. They were divided into two 6-year periods; from 2001 to 2006 and from 2007 to 2012. Logistic regression analyses were conducted to compute OR between cases and controls. The adjusted OR of having an infant with spina bifida for supplement users was 0.48 in the first period, and 0.53 in the second period. The proportion of women who periconceptionally consumed supplements significantly increased from 10 % in the first period to 30 % in the second period. Awareness of the preventive role of FA was a promoter for an increase in supplement use, and thus an FA campaign in high school seems rational and effective. The failure of the current public health policy is responsible for an epidemic of spina bifida. Mandatory food fortification with FA is urgent and long overdue in Japan.

Interfacial and emulsifying properties of soybean peptides with different degrees of hydrolysis.

In this study, the effects of the degree of hydrolysis on the interfacial and emulsifying properties of soybean peptides were evaluated based on surface and interfacial tension, dynamic light scattering (DLS), and freeze-fracture transmission electron microscopy (FF-TEM) analyses. Of the five evaluated soybean peptides (SP95, SP87, SP75, SP49, and SP23), those with higher degrees of hydrolysis (SP95 and SP87) did not exhibit noticeable surface-active properties in water, whereas those with relatively low degrees of hydrolysis (SP75, SP49, and SP23) exhibited remarkable surface tension-lowering activity. The latter set (SP75, SP49, and SP23) also formed giant associates with average sizes ranging from 64.5 nm to 82.6 nm above their critical association concentration (CAC). Moreover, SP23 with the lowest degree of hydrolysis exhibited excellent emulsifying activity for soybean oil, and FF-TEM analysis demonstrated that the emulsions were stabilized by a lamella-like multilayer peptide structure on the oil droplets that prevented coagulation. The peptide with the lowest degree of hydrolysis (SP23) was effective not only for soybean oil emulsification, but also for the emulsification of liquid paraffin and silicon oil that are generally difficult to emulsify.

Physico-chemical properties of cationic niosomes loaded with fraction of rice (Oryza sativa) bran extract.

The aim of this study was to investigate the physico-chemical properties of cationic niosomes (Tween61/cholesterol/CTAB) loaded with fraction No. 3 of Oryza sativa bran extract (OSF3) at 0.1, 0.5, 1.0 and 2.0% (w/v), respectively, before and after ultra-centrifugation. More white milky translucent appearance of the niosomes was observed at the higher loaded amount of OSF3. The entrapment efficiency of 0.5% OSF3 in niosomes was 86.22 +/- 1.43%. The sizes of the niosomes were slightly increased (120-220 nm) and the zeta potential values were decreased from 80 to the range of 40-60 mV after loaded with OSF3. All niosomes both blank and loaded with OSF3 were in the uni-lamellar structures determined by FF-TEM and SAXS. The transitions temperature (T(c)) of niosomes significant increased from 75 to 80 degrees C when loaded with OSF3 at 0.1 and 0.5%. Moreover, blank niosomes showed the highest microviscosity with the most rigid membrane at 25 degrees C, followed by the niosomes loaded with 0.1, 0.5, 1.0 and 2.0% of OSF3, respectively. The fluorescence polarizations of all niosomal formulations indicated the sharp descending phases at about 40 and 70 degrees C. After ultra-centrifugation to eliminate the non-loaded negatively charged OSF3, the increased vesicular sizes and zeta potential values of the blank, loaded niosomes with 0.1 and 0.5% OSF3 were observed. All niosomal formulations gave the same transition temperatures at about 71 degrees C and the same microviscosities at 25 degrees C. The results from this study can be applied for the niosomal formulation development of the rice bran semi-purified fraction for anti-hair loss products.

Packing density of glycolipid biosurfactant monolayers give a significant effect on their binding affinity toward immunoglobulin G.

Mannosylerythritol lipid-A (MEL-A) is one of the most promising glycolipid biosurfactants, and abundantly produced by Pseudozyma yeasts. MEL-A gives not only excellent self-assembling properties but also a high binding affinity toward human immunoglobulin G (HIgG). In this study, three kinds of MEL-A were prepared from methyl myristate [MEL-A (m)], olive oil [MEL-A (o)], and soybean oil [MEL-A (s)], and the effect of interfacial properties of each MEL-A monolayer on the binding affinity toward HIgG was investigated using surface plasmon resonance (SPR) and the measurement of surface pressure (pi)-area (A) isotherms. Based on GC-MS analysis, the main fatty acids were C(8) and C(10) acids in all MEL-A, and the content of unsaturated fatty acids was 0% for MEL-A (m), 9.1% for MEL-A (o), 46.3% for MEL-A (s), respectively. Interestingly, the acid content significantly influenced on their binding affinity, and the monolayer of MEL-A (o) gave a higher binding affinity than that of MEL-A (m) and MEL-A (s). Moreover, the mixed MEL-A (o)/ MEL-A (s) monolayer prepared from 1/1 molar ratio, which comprised of 27.8% of unsaturated fatty acids, indicated the highest binding affinity. At the air/water interface, MEL-A (o) monolayer exhibited a phase transition at 13 degrees C from a liquid condensed monolayer to a liquid expanded monolayer, and the area per molecule significantly expanded above 13 degrees C, while the amount of HIgG bound to the liquid expanded monolayer was much higher than that bound to liquid condensed monolayer. The binding affinity of MEL-A toward HIgG is thus likely to closely relate to the monolayer packing density, and may be partly controlled by temperature.

Claudin-16 is directly phosphorylated by protein kinase A independently of a vasodilator-stimulated phosphoprotein-mediated pathway.

Claudin-16 (CLDN-16) is involved in the paracellular reabsorption of Mg(2+) in the thick ascending limb of Henle. The tight junctional localization and Mg(2+) transport of CLDN-16 are regulated by cAMP/PKA-dependent phosphorylation. Here, we examined whether PKA phosphorylates CLDN-16 in a direct or indirect manner. CLDN-16 was stably expressed in Madin-Darby canine kidney (MDCK) cells using a Tet-OFF system. The phosphorylation of CLDN-16 is upregulated by fetal calf serum (FCS). This phosphorylation was completely inhibited by a PKA inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride. Without FCS, dibutyryl cAMP (DBcAMP) increased the phosphoserine level of CLDN-16 in a concentration-dependent manner. The phosphorylated CLDN-16 elicited increases of transepithelial electrical resistance (TER) and transepithelial transport of Mg(2+). Vasodilator-stimulated phosphoprotein (VASP) was also phosphorylated in the presence of FCS or DBcAMP. In the glutathione-S-transferase (GST) pull down assay, a cytosolic carboxyl domain of CLDN-16 was associated with PKA, but not with VASP. Furthermore, PKA was immunoprecipitated with CLDN-16 in MDCK cells, but VASP was not. In cells expressing a dephosphorylated mutant (Ser160Ala) of VASP, CLDN-16 was phosphorylated by DBcAMP and was associated with ZO-1, a tight junctional-scaffolding protein, without integral cell-cell junctions. We suggest that PKA directly phosphorylates CLDN-16, resulting in the localization to tight junctions (TJs) and the maintenance of Mg(2+) reabsorption.

Formation of W/O microemulsion based on natural glycolipid biosurfactant, mannosylerythritol lipid-a.

Mannosylerythritol lipid-A (MEL-A) is a glycolipid biosurfactant abundantly produced from soybean oil by microorganisms at a yield of up to 100 g/L. In this study, the formation of water-in-oil (W/O) microemulsion based on the single component of MEL-A was confirmed using dynamic light scattering (DLS) and freeze fracture electron microscopy (FF-EM). DLS and FF-EM measurements revealed that the diameter of the microemulsion increases with an increase in water-to-surfactant mole ratio (W(0)) ranging from 20 to 60 nm, and the maximum W(0) value was found to be 20, which is as high as that of soybean lecithin. Glycolipid biosurfactant has a great potential for the formation of W/O microemulsion without using any cosurfactants.