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Journal of Cellular and Molecular... May 2024Urothelial carcinoma (UC) urgently requires new therapeutic options. Histone deacetylases (HDAC) are frequently dysregulated in UC and constitute interesting targets for...
Urothelial carcinoma (UC) urgently requires new therapeutic options. Histone deacetylases (HDAC) are frequently dysregulated in UC and constitute interesting targets for the development of alternative therapy options. Thus, we investigated the effect of the second generation HDAC inhibitor (HDACi) quisinostat in five UC cell lines (UCC) and two normal control cell lines in comparison to romidepsin, a well characterized HDACi which was previously shown to induce cell death and cell cycle arrest. In UCC, quisinostat led to cell cycle alterations, cell death induction and DNA damage, but was well tolerated by normal cells. Combinations of quisinostat with cisplatin or the PARP inhibitor talazoparib led to decrease in cell viability and significant synergistic effect in five UCCs and platinum-resistant sublines allowing dose reduction. Further analyses in UM-UC-3 and J82 at low dose ratio revealed that the mechanisms included cell cycle disturbance, apoptosis induction and DNA damage. These combinations appeared to be well tolerated in normal cells. In conclusion, our results suggest new promising combination regimes for treatment of UC, also in the cisplatin-resistant setting.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Cisplatin; DNA Damage; Drug Synergism; Histone Deacetylase Inhibitors; Hydroxamic Acids; Phthalazines; Poly(ADP-ribose) Polymerase Inhibitors; Urinary Bladder Neoplasms; Urologic Neoplasms
PubMed: 38693852
DOI: 10.1111/jcmm.18342 -
Human Cell Mar 2024Pseudomyxoma peritonei (PMP) is a rare phenomenon, characterized by accumulation of mucus in the abdominal cavity due to a mucinous neoplasm. Histologically, PMP is...
Pseudomyxoma peritonei (PMP) is a rare phenomenon, characterized by accumulation of mucus in the abdominal cavity due to a mucinous neoplasm. Histologically, PMP is divided into three prognostic classes, namely low-grade mucinous carcinoma peritonei (LGMCP), high-grade mucinous carcinoma peritonei (HGMCP), and high-grade mucinous carcinoma peritonei with signet ring cells (HGMCP-S); HGMCP-S exhibits the worst prognosis. Complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have been established as the standard therapy for PMP. However, 50% of patients with PMP experience a recurrence, and 30-40% are unable to receive the standard treatment due to invasive diseases. Therefore, novel therapies are required for their treatment. Although patient-derived cell lines are important tools for basic and pre-clinical research, PMP cell lines derived from patients with HGMCP-S have never been reported. Thus, we established a novel PMP cell line NCC-PMP2-C1, using surgically resected tumor tissue from a patient with HGMCP-S. NCC-PMP2-C1 cells were maintained for more than five months and passaged 30 times under culture conditions. NCC-PMP2-C1 cells exhibited multiple deletions and somatic mutations, slow growth, histological features, and dissemination of tumor cells in nude mice. Screening for the anti-proliferative effects of anti-cancer drugs on cells revealed that bortezomib, mubritinib, and romidepsin had a significant response against NCC-PMP2-C1 cells. Thus, the NCC-PMP2-C1 cell line is the first PMP cell line harboring signet ring cells and will be a valuable resource for basic and preclinical studies of HGMCP-S.
Topics: Animals; Mice; Humans; Pseudomyxoma Peritonei; Mice, Nude; Peritoneal Neoplasms; Adenocarcinoma, Mucinous; Carcinoma, Signet Ring Cell; Myelin P2 Protein
PubMed: 38143259
DOI: 10.1007/s13577-023-01015-0 -
Leukemia & Lymphoma Jun 2024Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently...
Phase II study of the novel antifolate agent pralatrexate in combination with the histone deacetylase inhibitor romidepsin for the treatment of patients with mature T-cell lymphoma.
Previously, we conducted a Phase I study of the combination of pralatrexate and romidepsin in patients with relapsed/refractory (R/R) lymphomas and subsequently conducted a multicenter Phase II study in patients with untreated or R/R mature T cell lymphomas (MTCL). Patients received pralatrexate 25 mg/m and romidepsin 12 mg/m every 2 weeks. Fourteen patients were evaluable for efficacy. Overall response rate was 35.7% with CR in 14.3% and disease control in 50%. The mDOR was 8.2 months, mPFS was 3.6 months, and mOS was 20.2 months. Gastrointestinal side effects were most common in up to 33%; there was only one hematologic toxicity of grade 3 anemia. Combining results of MTCL patients from the Phase I and II studies ( = 28), the ORR was 53.5% with CR in 21.4%, disease control in67.8%, and DOR of 7.2 months. The combination was safe however does not out-perform other combination strategies. www.clinicaltrials.gov (NCT01947140).
Topics: Humans; Aminopterin; Depsipeptides; Male; Middle Aged; Female; Aged; Antineoplastic Combined Chemotherapy Protocols; Adult; Lymphoma, T-Cell; Histone Deacetylase Inhibitors; Treatment Outcome; Folic Acid Antagonists; Aged, 80 and over
PubMed: 38517235
DOI: 10.1080/10428194.2024.2329996 -
Nature Communications Jun 2024Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly...
Despite the importance of spliceosome core components in cellular processes, their roles in cancer development, including hepatocellular carcinoma (HCC), remain poorly understood. In this study, we uncover a critical role for SmD2, a core component of the spliceosome machinery, in modulating DNA damage in HCC through its impact on BRCA1/FANC cassette exons and expression. Our findings reveal that SmD2 depletion sensitizes HCC cells to PARP inhibitors, expanding the potential therapeutic targets. We also demonstrate that SmD2 acetylation by p300 leads to its degradation, while HDAC2-mediated deacetylation stabilizes SmD2. Importantly, we show that the combination of Romidepsin and Olaparib exhibits significant therapeutic potential in multiple HCC models, highlighting the promise of targeting SmD2 acetylation and HDAC2 inhibition alongside PARP inhibitors for HCC treatment.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Acetylation; Poly(ADP-ribose) Polymerase Inhibitors; Spliceosomes; Cell Line, Tumor; Phthalazines; Exons; Piperazines; Animals; BRCA1 Protein; Depsipeptides; Mice; DNA Damage; Gene Expression Regulation, Neoplastic
PubMed: 38890388
DOI: 10.1038/s41467-024-49573-7 -
Molecular Medicine (Cambridge, Mass.) May 2024Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and...
Human malignant pleural mesothelioma (hMPM) is an aggressive, rare disease with a poor prognosis. Histologically, MPM is categorized into epithelioid, biphasic, and sarcomatoid subtypes, with the epithelioid subtype generally displaying a better response to treatment. Conversely, effective therapies for the non-epithelioid subtypes are limited. This study aimed to investigate the potential role of FK228, a histone deacetylase inhibitor, in the suppression of hMPM tumor growth. We conducted a comprehensive analysis of the histological and molecular characteristics of two MPM cell lines, CRL-5820 (epithelioid) and CRL-5946 (non-epithelioid). CRL-5946 cells and non-epithelioid patient-derived xenografted mice exhibited heightened growth rates compared to those with epithelioid MPM. Both CRL-5946 cells and non-epithelioid mice displayed a poor response to cisplatin. However, FK228 markedly inhibited the growth of both epithelioid and non-epithelioid tumor cells in vitro and in vivo. Cell cycle analysis revealed FK228-induced G1/S and mitotic arrest in MPM cells. Caspase inhibitor experiments demonstrated that FK228-triggered apoptosis occurred via a caspase-dependent pathway in CRL-5946 but not in CRL-5820 cells. Additionally, a cytokine array analysis showed that FK228 reduced the release of growth factors, including platelet-derived and vascular endothelial growth factors, specifically in CRL-5946 cells. These results indicate that FK228 exhibits therapeutic potential in MPM by inducing cytotoxicity and modulating the tumor microenvironment, potentially benefiting both epithelioid and non-epithelioid subtypes.
Topics: Humans; Animals; Mesothelioma, Malignant; Cell Line, Tumor; Mice; Mesothelioma; Apoptosis; Xenograft Model Antitumor Assays; Cell Proliferation; Depsipeptides; Lung Neoplasms; Pleural Neoplasms; Antineoplastic Agents; Female; Epithelioid Cells; Cell Cycle
PubMed: 38822233
DOI: 10.1186/s10020-024-00835-6 -
BMJ Case Reports Jan 2024Relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) has a poor prognosis, with limited treatment options and generally no durable response. However, long-term...
Relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) has a poor prognosis, with limited treatment options and generally no durable response. However, long-term remission with the histone deacetylase (HDAC) inhibitor romidepsin has been reported, especially in angioimmunoblastic T cell lymphoma (AITL). Recently, tucidinostat, a novel oral HDAC inhibitor that selectively inhibits class I and class IIb HDACs, was approved for R/R PTCL in China and Japan. We present the case of a patient with AITL whose gastrointestinal symptoms and health-related quality of life improved after switching from romidepsin to tucidinostat as maintenance therapy. Romidepsin and tucidinostat appear to have different safety profiles; non-haematological toxicities such as nausea, vomiting, constipation, anorexia and fatigue may be reported less frequently with tucidinostat than with romidepsin. This case suggests that switching to tucidinostat therapy may be a viable option for patients with PTCL suffering from severe gastrointestinal adverse events with romidepsin.
Topics: Humans; Quality of Life; Neoplasm Recurrence, Local; Lymphoma, T-Cell, Peripheral; Depsipeptides; Aminopyridines; Benzamides
PubMed: 38199657
DOI: 10.1136/bcr-2023-256315 -
Gynecologic Oncology Jul 2024Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need...
BACKGROUND
Low grade serous ovarian carcinoma (LGSOC) is a distinct histotype of ovarian cancer characterised high levels of intrinsic chemoresistance, highlighting the urgent need for new treatments. High throughput screening in clinically-informative cell-based models represents an attractive strategy for identifying candidate treatment options for prioritisation in clinical studies.
METHODS
We performed a high throughput drug screen of 1610 agents across a panel of 6 LGSOC cell lines (3 RAS/RAF-mutant, 3 RAS/RAF-wildtype) to identify novel candidate therapeutic approaches. Validation comprised dose-response analysis across 9 LGSOC models and 5 high grade serous comparator lines.
RESULTS
16 hits of 1610 screened compounds were prioritised for validation based on >50% reduction in nuclei counts in over half of screened cell lines at 1000 nM concentration. 11 compounds passed validation, and the four agents of greatest interest (dasatinib, tyrosine kinase inhibitor; disulfiram, aldehyde dehydrogenase inhibitor; carfilzomib, proteasome inhibitor; romidepsin, histone deacetylase inhibitor) underwent synergy profiling with the recently approved MEK inhibitor trametinib. Disulfiram demonstrated excellent selectivity for LGSOC versus high grade serous ovarian carcinoma comparator lines (P = 0.003 for IC50 comparison), while the tyrosine kinase inhibitor dasatinib demonstrated favourable synergy with trametinib across multiple LGSOC models (maximum zero interaction potency synergy score 46.9). The novel, highly selective Src family kinase (SFK) inhibitor NXP900 demonstrated a similar trametinib synergy profile to dasatinib, suggesting that SFK inhibition is the likely driver of synergy.
CONCLUSION
Dasatinib and other SFK inhibitors represent novel candidate treatments for LGSOC and demonstrate synergy with trametinib. Disulfiram represents an additional treatment strategy worthy of investigation.
Topics: Humans; Female; Ovarian Neoplasms; Pyridones; Pyrimidinones; Drug Synergism; High-Throughput Screening Assays; Cell Line, Tumor; Dasatinib; Cystadenocarcinoma, Serous; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Grading; Protein Kinase Inhibitors; Disulfiram; Drug Screening Assays, Antitumor
PubMed: 38582027
DOI: 10.1016/j.ygyno.2024.03.029 -
Clinical & Translational Immunology 2024The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase...
OBJECTIVES
The rapid recognition of epigenetic manipulation's potential in restricting cancer cell capabilities spurred translational initiatives, including histone deacetylase inhibitors (HDACis). Clinical trials on multiple myeloma (MM) demonstrated substantial benefits of HDACis, coupled with promising outcomes from cytokine-induced killer cell (CIK) immunotherapy. Intriguingly, the unexplored synergy of HDACis and CIK cell immunotherapy in MM prompted our study.
METHODS
We examined clinically relevant HDACis (panobinostat/LBH589 and romidepsin) alongside CIK cells derived from peripheral blood mononuclear cells across diverse MM cell lines (U266, RPMI8226, OPM-2 and NCI-H929). Utilising various methodologies, we investigated how HDACis enhance CIK cell lysis of myeloma cells through NKG2D/NKG2D ligand interactions.
RESULTS
The results of our analysis indicated several key findings. (1) Enhanced cytotoxicity of CIK cells in MM cells when combined with HDACis. (2) Significant increase in apoptosis, suggesting HDACis and CIK may together enhance apoptotic effects in specific MM cell lines. (3) Elevated IFN-γ secretion and alterations in granzyme B secretion because of the independent activity of HDACis. (4) Notably, HDACis increased the expression of MICA/B and ULBP2, crucial for inducing antitumor cytotoxicity of NKT cells. Validation through NKG2D receptor blocking in CIK cells with a purified mouse antihuman NKG2D antibody further supported our findings.
CONCLUSIONS
Our analyses provide sufficient evidence to consider this clinically forgotten instance (HDACis-CIK cell combination) as a therapeutic priority for MM treatment. Furthermore, we suggest that NKG2D/NKG2D-ligand interactions activating NK/NKT cells may contribute to enhanced myeloma cell lysis in response to HDACis treatment by CIK cells.
PubMed: 38529413
DOI: 10.1002/cti2.1500 -
The Journal of Physiology May 2024Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity...
Adverse experiences in early life can induce maladaptive responses to acute stress in later life. Chronic social isolation during adolescence is an early life adversity that can precipitate stress-related psychiatric disorders. We found that male mice after 8 weeks of adolescent social isolation (SI) have markedly increased aggression after being exposed to 2 h of restraint stress (RS), which was accompanied by a significant increase of AMPA receptor- and NMDA receptor-mediated synaptic transmission in prefrontal cortex (PFC) pyramidal neurons of SI males. Compared to group-housed counterparts, SI males exhibited a significantly decreased level of histone H3 acetylation in PFC. Systemic administration of class I histone deacetylase inhibitors, romidepsin or MS-275, ameliorated the aggressive behaviour, as well as general social interaction deficits, of SI males. Electrophysiological recordings also found normalization of PFC glutamatergic currents by romidepsin treatment of SI male mice. These results revealed an epigenetic mechanism and intervention avenue for aggression induced by chronic social isolation. KEY POINTS: Adolescent chronic social isolation can precipitate stress-related psychiatric disorders. A significant increase of glutamatergic transmission is found in the prefrontal cortex (PFC) of socially isolated male mice exposed to an acute stress (SI). Treatment with class I histone deacetylase (HDAC) inhibitors ameliorates the aggressive behaviour and social interaction deficits of SI males, and normalizes glutamatergic currents in PFC neurons. It provides an epigenetic mechanism and intervention avenue for aberrant stress responses induced by chronic social isolation.
Topics: Animals; Male; Histone Deacetylase Inhibitors; Stress, Psychological; Social Isolation; Prefrontal Cortex; Aggression; Mice; Mice, Inbred C57BL; Depsipeptides; Pyridines; Benzamides; Restraint, Physical; Synaptic Transmission; Pyramidal Cells
PubMed: 38500302
DOI: 10.1113/JP285875 -
Human Cell May 2024Giant cell tumor of bone (GCTB) is a rare osteolytic bone tumor consisting of mononuclear stromal cells, macrophages, and osteoclast-like giant cells. Although GCTB...
Giant cell tumor of bone (GCTB) is a rare osteolytic bone tumor consisting of mononuclear stromal cells, macrophages, and osteoclast-like giant cells. Although GCTB predominantly exhibits benign behavior, the tumor carries a significant risk of high local recurrence. Furthermore, GCTB can occasionally undergo malignant transformation and distal metastasis, making it potentially fatal. The standard treatment is complete surgical resection; nonetheless, an optimal treatment strategy for advanced GCTB remains unestablished, necessitating expanded preclinical research to identify appropriate therapeutic options. However, only one GCTB cell line is publicly available from a cell bank for research use worldwide. The present study reports the establishment of two novel cell lines, NCC-GCTB8-C1 and NCC-GCTB9-C1, derived from the primary tumor tissues of two patients with GCTB. Both cell lines maintained the hallmark mutation in the H3-3A gene, which is associated with tumor formation and development in GCTB. Characterization of these cell lines revealed their steady growth, spheroid-formation capability, and invasive traits. Potential therapeutic agents were identified via extensive drug screening of the two cell lines and seven previously established GCTB cell lines. Among the 214 antitumor agents tested, romidepsin, a histone deacetylase inhibitor, and mitoxantrone, a topoisomerase inhibitor, were identified as potential therapeutic agents against GCTB. Conclusively, the establishment of NCC-GCTB8-C1 and NCC-GCTB9-C1 provides novel and crucial resources that are expected to advance GCTB research and potentially revolutionize treatment strategies.
Topics: Humans; Giant Cell Tumor of Bone; Cell Line, Tumor; Antineoplastic Agents; Bone Neoplasms
PubMed: 38466561
DOI: 10.1007/s13577-024-01042-5