Novel Approaches in Bladder Cancer Treatment

Topic Information

Dear Colleagues,

Bladder cancer is the ninth most common malignant ailment and the fourteenth most common cause of cancer death worldwide. Over the past decades, novel and potent agents have been developed and approved. However, although innovative approaches, such as targeted therapy and/or immunotherapy, have provided benefits for tumor patients, many challenges, such as low response rate and drug resistance, remain overt. Extensive research is required to refine and optimize the current bladder cancer treatment protocols. Dissatisfaction with the conventional treatment has meanwhile driven many cancer patients to seek “non-conventional” care options, including natural products, mind and body practices, or other non-conventional health approaches. From the scientists’ side, innovative and “risky” projects are under investigation focusing on cancer stem cell targeting, selective photodynamic technology, or anticancer vaccine therapy, among others. The purpose of this Special Issue is to collect original research articles and reviews on non-conventional medicine for bladder cancer. Both clinical trials and preclinical studies (in vitro and in vivo) are welcome that do not reflect the mainstream of cancer treatment but which are rather original and may open the mind for unconventional strategies.

Prof. Dr. Roman Blaheta
Prof. Dr. Beatrice E. Bachmeier
Topic Editors

Keywords

Participating Journals

Journal Name	Impact Factor	CiteScore	Launched Year	First Decision (median)	APC
Biomolecules biomolecules	4.8	9.4	2011	18.4 Days	CHF 2700
Cancers cancers	4.5	8.0	2009	17.4 Days	CHF 2900
Current Oncology curroncol	2.8	3.3	1994	19.8 Days	CHF 2200
International Journal of Molecular Sciences ijms	4.9	8.1	2000	16.8 Days	CHF 2900
Onco onco	-	-	2021	27.8 Days	CHF 1000

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Published Papers (5 papers)

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All Biomolecules Cancers Current Oncology IJMS Onco

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16 pages, 2984 KiB  

Open AccessArticle

Mistletoe Extracts from Different Host Trees Disparately Inhibit Bladder Cancer Cell Growth and Proliferation

by Eva Juengel, Jochen Rutz, Moritz Meiborg, Sascha D. Markowitsch, Sebastian Maxeiner, Timothy Grein, Anita Thomas, Felix K.-H. Chun, Axel Haferkamp, Igor Tsaur, Olesya Vakhrusheva and Roman A. Blaheta

Cancers 2023, 15(19), 4849; https://doi.org/10.3390/cancers15194849 - 4 Oct 2023

Cited by 1 | Viewed by 2224

Abstract

Extracts of European mistletoe (Viscum album) are popular as a complementary treatment for patients with many different cancer types. However, whether these extracts actually block bladder cancer progression remains unknown. The influence of different mistletoe extracts on bladder cancer cell growth [...] Read more.

Extracts of European mistletoe (Viscum album) are popular as a complementary treatment for patients with many different cancer types. However, whether these extracts actually block bladder cancer progression remains unknown. The influence of different mistletoe extracts on bladder cancer cell growth and proliferation was investigated by exposing RT112, UMUC3, and TCCSup cells to mistletoe from hawthorn (Crataegi), lime trees (Tiliae), willow trees (Salicis), or poplar trees (Populi). The tumor cell growth and proliferation, apoptosis induction, and cell cycle progression were then evaluated. Alterations in integrin α and β subtype expression as well as CD44 standard (CD44s) and CD44 variant (CD44v) expressions were evaluated. Cell cycle-regulating proteins (CDK1 and 2, Cyclin A and B) were also investigated. Blocking and knock-down studies served to correlate protein alterations with cell growth. All extracts significantly down-regulated the growth and proliferation of all bladder cancer cell lines, most strongly in RT112 and UMUC3 cells. Alterations in CD44 expression were not homogeneous but rather depended on the extract and the cell line. Integrin α3 was, likewise, differently modified. Integrin α5 was diminished in RT112 and UMUC3 cells (significantly) and TCCSup (trend) by Populi and Salicis. Populi and Salicis arrested UMUC3 in G0/G1 to a similar extent, whereas apoptosis was induced most efficiently by Salicis. Examination of cell cycle-regulating proteins revealed down-regulation of CDK1 and 2 and Cyclin A by Salicis but down-regulation of CDK2 and Cyclin A by Populi. Blocking and knock-down studies pointed to the influence of integrin α5, CD44, and the Cyclin–CDK axis in regulating bladder cancer growth. Mistletoe extracts do block bladder cancer growth in vitro, with the molecular action differing according to the cell line and the host tree of the mistletoe. Integrating mistletoe into a guideline-based treatment regimen might optimize bladder cancer therapy. Full article

(This article belongs to the Topic Novel Approaches in Bladder Cancer Treatment)

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16 pages, 3670 KiB  

Open AccessArticle

Targeting Pro-Survival Autophagy Enhanced GSK-3β Inhibition-Induced Apoptosis and Retarded Proliferation in Bladder Cancer Cells

by Yuko Shirono, Vladimir Bilim, Tsutomu Anraku, Hiroo Kuroki, Akira Kazama, Masaki Murata, Kaede Hiruma and Yoshihiko Tomita

Curr. Oncol. 2023, 30(6), 5350-5365; https://doi.org/10.3390/curroncol30060406 - 28 May 2023

Cited by 2 | Viewed by 2584

Abstract

Advanced bladder cancer (BC) (local invasive and/or metastatic) is not curable even with cytotoxic chemotherapy, immune checkpoint inhibitors, and targeted treatment. Targeting GSK-3β is a promising novel approach in advanced BC. The induction of autophagy is a mechanism of secondary resistance to various [...] Read more.

Advanced bladder cancer (BC) (local invasive and/or metastatic) is not curable even with cytotoxic chemotherapy, immune checkpoint inhibitors, and targeted treatment. Targeting GSK-3β is a promising novel approach in advanced BC. The induction of autophagy is a mechanism of secondary resistance to various anticancer treatments. Our objectives are to investigate the synergistic effects of GSK-3β in combination with autophagy inhibitors to evade GSK-3β drug resistance. Small molecule GSK-3β inhibitors and GSK-3β knockdown using siRNA promote the expression of autophagy-related proteins. We further investigated that GSK-3β inhibition induced the nucleus translocation of transcription factor EB (TFEB). Compared to the GSK-3β inhibition alone, its combination with chloroquine (an autophagy inhibitor) significantly reduced BC cell growth. These results suggest that targeting autophagy potentiates GSK-3β inhibition-induced apoptosis and retarded proliferation in BC cells. Full article

(This article belongs to the Topic Novel Approaches in Bladder Cancer Treatment)

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16 pages, 656 KiB  

Open AccessReview

New Approaches to Targeting Epigenetic Regulation in Bladder Cancer

by Daryl Thompson, Nathan Lawrentschuk and Damien Bolton

Cancers 2023, 15(6), 1856; https://doi.org/10.3390/cancers15061856 - 20 Mar 2023

Cited by 7 | Viewed by 2954

Abstract

Epigenetics is a growing field and in bladder cancer, it is of particular interest in advanced or metastatic disease. As opposed to genetic mutations in which the nucleotide sequence itself is altered, epigenetic alterations refer to changes to the genome that do not [...] Read more.

Epigenetics is a growing field and in bladder cancer, it is of particular interest in advanced or metastatic disease. As opposed to genetic mutations in which the nucleotide sequence itself is altered, epigenetic alterations refer to changes to the genome that do not involve nucleotides. This is of great interest in cancer research because epigenetic alterations are reversible, making them a promising target for pharmacological agents. While chemoimmunotherapy is the mainstay for metastatic disease, there are few alternatives for patients who have progressed on first- or second-line treatment. By targeting reversible epigenetic alterations, novel epigenetic therapies are important potential treatment options for these patients. A search of clinical registries was performed in order to identify and collate epigenetic therapies currently in human trials. A literature search was also performed to identify therapies that are currently in preclinical stages, whether this be in vivo or in vitro models. Twenty-five clinical trials were identified that investigated the use of epigenetic inhibitors in patients with bladder cancer, often in combination with another agent, such as platinum-based chemotherapy or pembrolizumab. The main classes of epigenetic inhibitors studied include DNA-methyltransferase (DNMT) inhibitors, histone deacetylase (HDAC) inhibitors, and histone methyltransferase (HMT) inhibitors. At present, no phase 3 clinical trials have been registered. Few trials have published results, though DNMT inhibitors have shown the most promise thus far. Many patients with advanced or metastatic bladder cancer have limited treatment options, particularly when first- or second-line chemoimmunotherapy fails. Epigenetic alterations, which are common in bladder cancer, are potential targets for drug therapies, and these epigenetic agents are already in use for many cancers. While they have shown promise in pre-clinical trials for bladder cancer, more research is needed to assess their benefit in clinical settings. Full article

(This article belongs to the Topic Novel Approaches in Bladder Cancer Treatment)

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16 pages, 3039 KiB  

Open AccessArticle

Hypomethylation of CLDN4 Gene Promoter Is Associated with Malignant Phenotype in Urinary Bladder Cancer

by Fumisato Maesaka, Masaomi Kuwada, Shohei Horii, Shingo Kishi, Rina Fujiwara-Tani, Shiori Mori, Kiyomu Fujii, Takuya Mori, Hitoshi Ohmori, Takuya Owari, Makito Miyake, Yasushi Nakai, Nobumichi Tanaka, Ujjal Kumar Bhawal, Yi Luo, Masuo Kondoh, Kiyohide Fujimoto and Hiroki Kuniyasu

Int. J. Mol. Sci. 2022, 23(12), 6516; https://doi.org/10.3390/ijms23126516 - 10 Jun 2022

Cited by 10 | Viewed by 2798

Abstract

The tight junction (TJ) protein claudin-4 (CLDN4) is overexpressed in bladder urothelial carcinoma (BUC) and correlates with cancer progression. However, the mechanism of CLDN4 upregulation and promotion of malignant phenotype is not clear. Here, we analyzed 157 cases of BUC and investigated the [...] Read more.

The tight junction (TJ) protein claudin-4 (CLDN4) is overexpressed in bladder urothelial carcinoma (BUC) and correlates with cancer progression. However, the mechanism of CLDN4 upregulation and promotion of malignant phenotype is not clear. Here, we analyzed 157 cases of BUC and investigated the hypomethylation of CpG island in the CLDN4 promoter DNA and its correlation with cancer progression. In hypomethylated cases, CLDN4 expression, cell proliferation, stemness, and epithelial-mesenchymal transition were increased. Treatment of three human BUC cell lines with the demethylating agent aza-2′-deoxycytidine (AZA) led to excessive CLDN4 expression, and, specifically, to an increase in CLDN4 monomer that is not integrated into the TJ. The TJ-unintegrated CLDN4 was found to bind integrin β1 and increase stemness, drug resistance, and metastatic ability of the cells as well as show an anti-apoptosis effect likely via FAK phosphorylation, which reduces upon knockdown of CLDN4. Thus, CLDN4 is overexpressed in BUC by an epigenetic mechanism and the high expression enhances the malignant phenotype of BUC via increased levels of TJ-unintegrated CLDN4. CLDN4 promoter DNA methylation is expected to be a novel indicator of BUC malignant phenotype and a new therapeutic target. Full article

(This article belongs to the Topic Novel Approaches in Bladder Cancer Treatment)

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16 pages, 1324 KiB  

Open AccessCommunication

Gold Glyconanoparticles Combined with 91–99 Peptide of the Bacterial Toxin, Listeriolysin O, Are Efficient Immunotherapies in Experimental Bladder Tumors

by Hector Terán-Navarro, Andrea Zeoli, David Salines-Cuevas, Marco Marradi, Noemi Montoya, Elena Gonzalez-Lopez, Javier Gonzalo Ocejo-Vinyals, Mario Dominguez-Esteban, Jose Luis Gutierrez-Baños, Felix Campos-Juanatey, Sonsoles Yañez-Diaz, Almudena Garcia-Castaño, Fernando Rivera, Ignacio Duran and Carmen Alvarez-Dominguez

Cancers 2022, 14(10), 2413; https://doi.org/10.3390/cancers14102413 - 13 May 2022

Cited by 12 | Viewed by 2870

Abstract

This study presents proof of concept assays to validate gold nanoparticles loaded with the bacterial peptide 91–99 of the listeriolysin O toxin (GNP-LLO_91–99 nanovaccines) as immunotherapy for bladder tumors. GNP-LLO_91–99 nanovaccines showed adjuvant abilities as they induce maturation and activation of [...] Read more.

This study presents proof of concept assays to validate gold nanoparticles loaded with the bacterial peptide 91–99 of the listeriolysin O toxin (GNP-LLO_91–99 nanovaccines) as immunotherapy for bladder tumors. GNP-LLO_91–99 nanovaccines showed adjuvant abilities as they induce maturation and activation of monocyte-derived dendritic cells (MoDCs) to functional antigen-presenting cells in healthy donors and patients with melanoma or bladder cancer (BC), promoting a Th1 cytokine pattern. GNP-LLO_91–99 nanovaccines were also efficient dendritic cell inducers of immunogenic tumor death using different bladder and melanoma tumor cell lines. The establishment of a pre-clinical mice model of subcutaneous BC confirmed that a single dose of GNP-LLO_91–99 nanovaccines reduced tumor burden 4.7-fold and stimulated systemic Th1-type immune responses. Proof of concept assays validated GNP-LLO_91–99 nanovaccines as immunotherapy by comparison to anti-CTLA-4 or anti-PD-1 antibodies. In fact, GNP-LLO_91–99 nanovaccines increased percentages of CD4⁺ and CD8⁺ T cells, B cells, and functional antigen-presenting DCs in tumor-infiltrated lymphocytes, while they reduced the levels of myeloid-derived suppressor cells (MDSC) and suppressor T cells (T_reg). We conclude that GNP-LLO_91–99 nanovaccines can work as monotherapies or combinatory immunotherapies with anti-CTLA-4 or anti-PD-1 antibodies for solid tumors with high T cell infiltration, such as bladder cancer or melanoma. Full article

(This article belongs to the Topic Novel Approaches in Bladder Cancer Treatment)

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