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High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids.

ABSTRACT: Non-muscle invasive bladder cancer is treated with intravesical chemotherapy (IVC) after transurethral resection (TUR) to reduce the probability of recurrence. Despite improvement, the recurrence rate remains high. Intravesical chemotherapeutics at high doses are expected to ablate unresected tumors and floating cancer cells after TUR, although the fate of bladder cancer cells exposed to high-dose chemotherapeutics remains unclear. In this study, we utilized cancer tissue-originated spheroids (CTOS) prepared from bladder cancers or patient-derived xenografts, which may recapitulate human tumors better than 2-D cultures of established cell lines. We exposed CTOS to 1 mg/mL of epirubicin (EPI) or mitomycin C (MMC) for 2 h. EPI was promptly and homogeneously distributed into cancer cells in the CTOS. Two hours after exposure to MMC, the mitochondrial membrane potential decreased and the mitochondria were fragmented, while plasma membrane integrity was maintained. ATP levels rapidly decreased in CTOS after exposure to EPI or MMC. Although activation of the apoptotic pathway was confirmed by the advent of cleaved poly (ADP-ribose) polymerase, fragmentation of DNA (a hallmark of apoptosis) was not observed in CTOS after exposure to EPI and MMC. In the CTOS prepared directly from 19 surgical specimens exposed to EPI and MMC, the decrease of ATP levels varied among patients. Further establishment of the test might help the drug selection and the prediction of recurrence for individual patients.

SUBMITTER: Yoshida T

PROVIDER: S-EPMC4317779 | biostudies-other | 2015 Jan

REPOSITORIES: biostudies-other

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High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids.

Yoshida Takahiro T Okuyama Hiroaki H Nakayama Masashi M Endo Hiroko H Nonomura Norio N Nishimura Kazuo K Inoue Masahiro M

Cancer science 20141208 1

Non-muscle invasive bladder cancer is treated with intravesical chemotherapy (IVC) after transurethral resection (TUR) to reduce the probability of recurrence. Despite improvement, the recurrence rate remains high. Intravesical chemotherapeutics at high doses are expected to ablate unresected tumors and floating cancer cells after TUR, although the fate of bladder cancer cells exposed to high-dose chemotherapeutics remains unclear. In this study, we utilized cancer tissue-originated spheroids (C ...[more]

PMID: 25363302

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Project description:BackgroundDue to the poor prognosis, the treatment of high-risk bladder cancer (HRBC) remains controversial. This meta-analysis aims to access the efficacy of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IC) versus IC alone after bladder-sparing surgery in HRBC.MethodsA systematic search of PubMed, Cochrane Library databases, EMBASE (until June 2020) was conducted. PRISMA checklist was followed. The data were analyzed by RevMan v5.3.0.ResultsA total of five articles including 843 patients were studied. The analysis demonstrated that the IAC + IC group had a greater improvement of overall survival (P = 0.02) and significant reduction in terms of tumor recurrence rate (P = 0.0006) and tumor progression rate (P = 0.008) compared with the IC group. The recurrence-free survival in the IAC + IC group was significantly higher than that in the IC group (P = 0.004), but there was no significant difference in progression-free survival between the two groups (P = 0.32). In addition, the combination of IAC and IC significantly extended tumor recurrence interval (P = 0.0001) and reduced tumor-specific death rate (P = 0.01) for patients with HRBC compared with IC alone. For side effects related with IAC, although about half of the patients experienced some toxicities, most of them were mild and reversible (grades 1-2, 22.3% vs. grade 3-4, 2.7%), mainly including nausea/vomiting (P = 0.0001), neutropenia (P = 0.002), and alanine aminotransferase (P = 0.0001).ConclusionPatients with HRBC treated with IAC + IC after bladder-sparing surgery had a marked improvement in the overall survival, recurrence-free survival, time interval to first recurrence, tumor recurrence rate, tumor progression rate, and tumor-specific death rate than patients treated with IC alone. However, progression-free survival was not significantly correlated with treatment strategy. In addition, patients seemed to tolerate well the toxicities related with IAC.Systematic review registrationPROSPERO, identifier CRD42021232679.

Project description:IntroductionIntravesical therapy (IVT), including Bacillus Calmette-Guérin (BCG), is the standard of care for high grade (HG) non-muscle invasive bladder cancer (NMIBC). Despite the use of IVT, many patients recur after treatment. The bladder microbiome and its role in disease processes has recently risen to prominence. We aim to characterize changes that occur in the bladder microbiome over the course of intravesical therapy and assess whether these changes correlate with outcomes in patients with NMIBC.MethodsPatients with NMIBC undergoing induction BCG or intravesical therapy were prospectively enrolled from January 2019 to March 2020. Patients with clinical T2 or greater pathology or active urinary tract infection at enrollment were excluded. Twenty-nine patients had catheterized (bladder) urine samples collected prior to induction intravesical therapy and prior to each IVT instillation. Twenty-seven received BCG while 2 received intravesical gemcitabine. Bacteria were identified using 16S ribosomal RNA gene sequencing. Bladder microbiome changes were evaluated and differences between patients who recurred and patients who did not recur after IVT were investigated.ResultsAcross the 29 patients analyzed, bacterial richness decreased significantly following intravesical therapy (Richness, P=0.01). Evenness and overall diversity did not change significantly (Pielou, P=0.62; Shannon, P=0.13). Patients who experienced recurrence had a higher relative abundance of Aerococcus in their urine (P<0.01), while those who did not recur had significantly more Ureaplasma (P=0.01) and Escherichia/Shigella species (P=0.05). Patients with decreased levels of alpha diversity were more likely to fall within the non-recurrence cohort.ConclusionIVT for NMIBC appears to change the urinary microbiome by decreasing richness while not altering evenness or overall diversity. The presence of Aerococcus species may be predictive of a poor cancer response to IVT, while the presence of Ureaplasma and Escherichia/Shigella may predict a favorable response to IVT. Further studies are warranted to elucidate and confirm the significance of changes in the bladder microbiome.

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High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids.

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High-dose chemotherapeutics of intravesical chemotherapy rapidly induce mitochondrial dysfunction in bladder cancer-derived spheroids.

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