Bladder cancer (BC) is a representative of urological cancer with a high recurrence and metastasis potential. Currently, cisplatin-based chemotherapy and immune checkpoint inhibitors are used as standard therapy in patients with advanced/metastatic BC. However, these therapies often show severe adverse events, and prolongation of survival is unsatisfactory. Therefore, a treatment strategy using natural compounds is of great interest. In this review, we focused on the anti-cancer effects of isothiocyanates (ITCs) derived from cruciferous vegetables, which are widely cultivated and consumed in many regions worldwide. Specifically, we discuss the anti-cancer effects of four ITC compounds—allyl isothiocyanate, benzyl isothiocyanate, sulforaphane, and phenethyl isothiocyanate—in BC; the molecular mechanisms underlying their anti-cancer effects; current trends and future direction of ITC-based treatment strategies; and the carcinogenic potential of ITCs. We also discuss the advantages and limitations of each ITC in BC treatment, furthering the consideration of ITCs in treatment strategies and for improving the prognosis of patients with BC.

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)-β 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-β 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-β in the serum of patients, which is speculated to serve an important role in RJ-induced biological activities.

Background/Aim: Stage-specific embryonic antigen-4 (SSEA-4) expression is associated with malignant aggressiveness and is useful as a marker for identifying cancer stem cells. Our aim was to assess the relationship between hormonal therapy and SSEA-4 expression in prostate cancer (PC). Materials and Methods: SSEA-4 expression in paired specimens from PC patients who underwent neoadjuvant hormonal therapy (NHT) and radical prostatectomy (60 pre-NHT specimens and 60 post-NHT specimens) was evaluated using immunohistochemistry. Proliferation index (PI) and apoptotic index (AI) were also evaluated. Results: Post-NHT tissues had significantly elevated SSEA-4 expression whereas anti-tumor effects of NHT were inversely correlated with SSEA-4 expression level. SSEA-4 expression in post-NHT tissues was significantly associated with biochemical recurrence-free survival. SSEA-4 expression in the post-NHT tissues was positively associated with PI and negatively done with AI. Conclusion: SSEA-4 is a potential therapeutic target for limiting the malignant potential in hormone-naïve PC when considering the use of NHT.Prostate cancer (PC) is the most commonly diagnosed cancer among men and the second leading cause of cancer-related deaths among men in the United States (1). Although many patients with early PC have elevated serum concentrations of prostate-specific antigen (PSA), approximately one-third of patients already have metastasis at the time of diagnosis (2). In general, hormonal therapy involves androgendeprivation therapy (ADT), which is a standard and effective treatment for patients with metastatic PC. Unfortunately, the majority of androgen-dependent PC cells gradually become androgen-independent cells during ADT, which leads to metastatic PC becoming resistant to hormonal therapy and progressing to castration-resistant prostate cancer (CRPC) (3). There are various treatments for CRPC, which involve chemotherapeutic agents, androgen receptor-axis-targeted agents, and immunotherapeutic agents (4-6). While these treatments can improve survival outcomes in CRPC cases, the increase in progression-free survival (PFS) and overall survival (OS) remains suboptimal.The suboptimal outcomes in CRPC cases are partly related to our poor understanding of the molecular mechanisms that lead to hormonal therapy resistance. In this context, it is important to understand that cancer stem cells (CSCs) play important roles in PC tumor growth and treatment resistance, as their pluripotency and self-renewal capability allow these cells to differentiate into diverse new cancer cells (7). Sex determining region Y-box-2 (Sox-2) is a major CSC marker, and its expression in PC cells is increased after androgen deprivation. The latter has been positively associated with cell growth and resistance to anti-androgen agents in both androgen-dependent and androgen-independent PC cells (8). Therefore, it is important to understand the interactions between hormonal therapy and CSCs, which may provide insight regarding PC tumor development and resista...

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Inflammation is a common adverse event of anti-cancer therapy. Royal jelly (RJ) modulates inflammation by regulating the levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and interleukin (IL)-6 produced by macrophages. Macrophage colony stimulating factor (M-CSF) is a crucial regulator of macrophage activities, and we hypothesized that RJ alters M-CSF levels. In this randomized controlled trial, we investigated the association between M-CSF and adverse events in renal cell carcinoma patients treated with tyrosine kinase inhibitors (TKIs) after an oral intake of RJ (n = 16) or placebo (n = 17). The serum levels of M-CSF, TNF-α, TGF-β, and IL-6 were measured by an enzyme-linked immunosorbent assay, and their temporal changes and correlation between such changes were analyzed. The post-/pretreatment ratio of M-CSF levels was associated with anorexia after 2 weeks and fatigue after 2, 4, and 12 weeks. The M-CSF level in the RJ group was higher than that in the placebo group at the same timepoints. The TNF-α level in the RJ group was lower than that in the placebo group between 6 and 12 weeks, and the TGF-β level in the RJ group was higher than that in the placebo group; however, contrasting findings were detected after 12 weeks. Additionally, the M-CSF level was significantly correlated with the TGF-β level after 4 weeks and IL-6 level after 8 and 10 weeks. Among TNF-α, TGF-β, and IL-6, the post-/pretreatment ratio of TGF-β after 12 weeks was associated with TKI-induced anorexia, and the ratios after 10 and 12 weeks were associated with fatigue. Our results demonstrated that an oral intake of RJ suppressed anorexia and fatigue via complex mechanisms associated with inflammation-related factors, such as M-CSF and TGF-β in renal cell carcinoma patients treated with TKIs. In addition, we newly found that such RJ-related effects were dependent on the treatment duration.

c-Met is a receptor tyrosine kinase that binds a specific ligand, namely hepatocyte growth factor (HGF). The HGF/c-Met system is important for malignant aggressiveness in various types of cancer, including bladder cancer (BC). However, although phosphorylation is the essential step required for biological activation of c-Met, pathological roles of phosphorylated c-Met at the clinical and molecular levels in patients with BC are not fully understood. In the present study, the expression levels of c-Met and the phosphorylation of two of its tyrosine residues (pY1234/pY1235 and pY1349) were immunohistochemically examined in 185 BC tissues. The associations between these expression levels and cancer cell invasion, metastasis, and cyclooxygenase-2 (COX-2), heme oxygenase-1 (HO-1), VEGF-A and programmed death ligand 1 (PD-L1) levels were investigated. c-Met was associated with muscle invasion (P= 0.021), as well as the expression levels of HO-1 (P= 0.028) and PD-L1 (P<0.001), whereas pY1349 c-Met was associated with muscle invasion (P=0.003), metastasis (P=0.025), and COX-2 (P=0.017), HO-1 (P=0.031) and PD-L1 (P= 0.001) expression. By contrast, pY1234/1235 c-Met was associated with muscle invasion and metastasis (P= 0.006 and P= 0.012, respectively), but not with the panel of cancer-associated molecules. Furthermore, COX-2 and PD-L1 expression were associated with muscle invasion and metastasis, respectively (P= 0.045 and P= 0.036, respectively). Hence, c-Met serves important roles in muscle invasion by regulating HO-1 and PD-L1, whereas its phosphorylation at Y1349 is associated with muscle invasion and metastasis via the regulation of COX-2, HO-1 and PD-L1 in patients with BC. Furthermore, phosphorylation at Y1234/1235 may lead to muscle invasion and metastasis via alternate mechanisms associated with c-Met and pY1349 c-Met.

Background/Aim: Immune checkpoint inhibitors are often unsuitable for patients with urothelial cancer with a poor performance status (PS 2 or 3). The aim of this study was to assess the safety and usefulness of combined therapy with low-dose gemcitabine and paclitaxel every 4 weeks. Patients and Methods: Thirty patients were treated with gemcitabine (700 mg/m 2 on day 1) and paclitaxel (70 mg/m 2 on day 1) every 4 weeks. The predictive value of human antigen-R (HuR) and class III β-tubulin (TUBB3) were also analyzed. Results: There was no severe adverse event nor significant decrease in quality of life. The survival period of patients treated with this regimen was significantly longer than that of those treated with best supportive care. The expression pattern of HuR negativity and TUBB3 positivity predicted significantly worse overall survival. Conclusion: Our regimen was suitable as second-line therapy for patients with advanced platinum-resistant UC with a poor PS. However, a HuR-negative and TUBB3-positive expression pattern appears to confer poorer outcome.

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