Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer DOI Creative Commons
Feng‐Chih Kuo, Jerry Cheng‐Yen Lai,

Hui-Ru Shieh

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 697 - 697

Published: March 21, 2024

Histamine modulates immunity by binding to histamine receptor 2 (H2R). Cimetidine, an H2R antagonist that inhibits gastric acid secretion and treats gastrointestinal ulcers, interferes with histamine-mediated immunomodulation may have anticancer activity. This study examined cimetidine’s effect on the of anti-PD-L1 in colon cancer. The MTT assay, colony formation DNA histograms assessed cell viability, clonogenicity, cycle distribution, respectively. Flow cytometry measured PD-L1 expression estimated specific immune lineages. For vivo study, tumor cells were subcutaneously implanted into right flank BALB/c mice. Cimetidine had no significant CT26 or distribution. It also did not affect levels cells. In vivo, anti-PD-1 suppressed growth, whereas cimetidine showed mild antitumor combined experiment, significantly attenuated anti-PD-L1′ effects without major toxicity. microenvironment, increased CD3+ T, CD4+ CD8+ T M1 macrophages. Combined treatment reversed this. anti-PD-L1′s decrease circulating tumor-associated neutrophils. modulated microenvironment

Language: Английский

Anticancer properties of histone deacetylase inhibitors – what is their potential? DOI
Kajetan Kiełbowski, Agata Szwedkowicz,

Paulina Plewa

et al.

Expert Review of Anticancer Therapy, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 16

Published: Jan. 10, 2025

Introduction Histone modifications are crucial epigenetic mechanisms for regulating gene expression. acetyltransferases and deacetylases (HDACs) catalyze histone acetylation, a process that mediates transcription. Over recent decades, studies have demonstrated targeting acetylation can be effective in cancer treatment, leading to the development approval of several HDAC inhibitors.

Language: Английский

Citations

1
Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies DOI Open Access

Ziqian Huang,

Ling Li, Binbin Cheng

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 178, P. 117218 - 117218

Published: July 30, 2024

Histone deacetylase 6 (HDAC6) plays a crucial role in the initiation and progression of various cancers, as its overexpression is linked to tumor growth, invasion, migration, survival, apoptosis, angiogenesis. Therefore, HDAC6 has emerged an attractive target for anticancer drug discovery past decade. However, development conventional inhibitors been hampered by their limited clinical efficacy, acquired resistance, inability inhibit non-enzymatic functions HDAC6. To overcome these challenges, new strategies, such dual-acting inhibitors, targeted protein degradation (TPD) technologies (including PROTACs, HyT), are essential enhance activity inhibitors. In this review, we focus on recent advances design modulators, including isoform-selective HDAC6-based dual-target degraders (PROTACs, from perspectives rational design, pharmacodynamics, pharmacokinetics, status. Finally, discuss challenges future directions cancer therapy.

Language: Английский

Citations

4
Discovery of Novel and Highly Potent Dual PD-L1/Histone Deacetylase 6 Inhibitors with Favorable Pharmacokinetics for Cancer Immunotherapy DOI
Zhihao Hu, Shuqing Li,

Haiqi He

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 20, 2025

A series of novel PD-L1/HDAC6 dual inhibitors were designed and synthesized, compound HP29 was identified as the most potent candidate, which demonstrated excellent selective HDAC6 inhibitory activity (IC50 = 78 nM, SI > 1282), high anti-PD-1/PD-L1 26.8 nM). Further studies showed that could bind with affinity to PD-L1 protein. Furthermore, possessed favorable in vivo pharmacokinetic properties, such decent oral bioavailability (F 15.3%). Moreover, exhibited significant antitumor efficacy a melanoma tumor model greater growth inhibition (TGI) (65.5%) than NP19 (43.2%), ACY-1215 (45.6%), combination group (53.9%). Mechanistically, percentages tumor-infiltrating lymphocytes (TILs) HP29-treated tissues significantly higher or inhibitor monotherapy group, suggesting potential synergistic immune effects. Collectively, represents deserving further investigation cancer immunomodulating agent.

Language: Английский

Citations

0
Unlocking the potential of novel Tetrahydro-β-Carboline-based HDAC6 inhibitors for colorectal Cancer therapy: Design, synthesis and biological evaluation DOI

Noreen Hemida,

Dalia S. El‐Gamil, Ahmed K. ElHady

et al.

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108454 - 108454

Published: April 1, 2025

Language: Английский

Citations

0
Histone Deacetylase 6 Inhibitor 5-Phenylcarbamoylpentyl Selenocyanide (SelSA) Suppresses Hepatocellular Carcinoma by Downregulating Phosphorylation of the Extracellular Signal-Regulated Kinase 1/2 Pathway DOI Creative Commons

Zeping Yang,

Bin Guo,

Zihao Jiao

et al.

ACS Pharmacology & Translational Science, Journal Year: 2024, Volume and Issue: 7(7), P. 2196 - 2203

Published: June 18, 2024

Histone deacetylase 6 (HDAC6) enzyme plays a crucial role in variety of cellular processes related to cancer, and inhibition HDAC6 is emerging as an effective strategy for cancer treatment. Although several hydroxamate-based inhibitors showed promising anticancer activities, the intrinsic defects such poor selectivity, stability, pharmacokinetics limited their application. In this study, potent selenocyanide-bearing inhibitor, 5-phenylcarbamoylpentyl selenocyanide (SelSA), was evaluated its antihepatocellular carcinoma (HCC) activity further explored antitumor mechanisms. vitro studies demonstrated that SelSA exhibited excellent antiproliferative against three HCC cells HepG2 (2.3 ± 0.29 μM), Huh7 (0.83 0.48 LM3 (2.6 0.24 μM). Further indicated could downregulate expression extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, inhibit growth, invasion, migration cells, promote apoptosis. Moreover, significantly suppressed tumor growth xenograft mouse models. Our findings suggest be potential therapeutic agent HCC.

Language: Английский

Citations

3
Selective HDAC6 Inhibition Has the Potential for Anti-Cancer Effect in Renal Cell Carcinoma DOI Open Access
Tsutomu Anraku, Masaki Murata,

Hiroo Kuroki

et al.

Journal of Personalized Medicine, Journal Year: 2024, Volume and Issue: 14(7), P. 704 - 704

Published: June 30, 2024

Despite significant advancements in systemic therapy for renal cell carcinoma (RCC), the prognosis patients with metastatic RCC remains poor, as they are often incurable. Consequently, there is an urgent need innovative therapeutic strategies to further enhance efficacy of treatment and improve patient outcomes. One such promising avenue lies targeting histone deacetylase (HDAC) 6, a protein known regulate numerous crucial biological processes implicated cancer progression by modulating acetylation status various cytoplasmic proteins. To explore potential HDAC6 inhibition RCC, our study focused on investigating effects inhibitors cultured cells. Utilizing panel 12 small molecule selective employing genetic knockdown techniques, we examined impact cellular dynamics. Our findings revealed that exerted profound effect cells, resulting decreased viability DNA replication. Importantly, this was attributed induction apoptosis. provides valuable insights into mechanisms underlying anticancer RCC. A detailed understanding molecular important new

Language: Английский

Citations

2
The role of histone post-translational modifications in cancer and cancer immunity: functions, mechanisms and therapeutic implications DOI Creative Commons
Xiaohong Duan,

Zhiyao Xing,

Lu Qiao

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Nov. 15, 2024

Histones play crucial roles in both promoting and repressing gene expression, primarily regulated through post-translational modifications (PTMs) at specific amino acid residues. Histone PTMs, including methylation, acetylation, ubiquitination, phosphorylation, lactylation, butyrylation, propionylation, act as important epigenetic markers. These influence not only chromatin compaction but also expression. Their importance extends to the treatment prevention of various human diseases, particularly cancer, due their involvement key cellular processes. Abnormal histone enzymes responsible for these alterations often serve critical drivers tumor cell proliferation, invasion, apoptosis, stemness. This review introduces PTMs modifications, examining impact on tumorigenesis cancer progression. Furthermore, it explores therapeutic strategies targeting offers recommendations identifying new potential targets.

Language: Английский

Citations

2
Cimetidine Attenuates Therapeutic Effect of Anti-PD-1 and Anti-PD-L1 and Modulates Tumor Microenvironment in Colon Cancer DOI Creative Commons
Feng‐Chih Kuo, Jerry Cheng‐Yen Lai,

Hui-Ru Shieh

et al.

Biomedicines, Journal Year: 2024, Volume and Issue: 12(3), P. 697 - 697

Published: March 21, 2024

Histamine modulates immunity by binding to histamine receptor 2 (H2R). Cimetidine, an H2R antagonist that inhibits gastric acid secretion and treats gastrointestinal ulcers, interferes with histamine-mediated immunomodulation may have anticancer activity. This study examined cimetidine’s effect on the of anti-PD-L1 in colon cancer. The MTT assay, colony formation DNA histograms assessed cell viability, clonogenicity, cycle distribution, respectively. Flow cytometry measured PD-L1 expression estimated specific immune lineages. For vivo study, tumor cells were subcutaneously implanted into right flank BALB/c mice. Cimetidine had no significant CT26 or distribution. It also did not affect levels cells. In vivo, anti-PD-1 suppressed growth, whereas cimetidine showed mild antitumor combined experiment, significantly attenuated anti-PD-L1′ effects without major toxicity. microenvironment, increased CD3+ T, CD4+ CD8+ T M1 macrophages. Combined treatment reversed this. anti-PD-L1′s decrease circulating tumor-associated neutrophils. modulated microenvironment

Language: Английский

Citations

1