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Sabine Wächter, Alexander I Damanakis, Moritz Elxnat, Silvia Roth, Annette Wunderlich, Frederik A Verburg, Sebastian A Fellinger, Detlef K Bartsch, Pietro Di Fazio
Epigenetic modifications have been identified as being responsible for the de-differentiation of thyroid tissue and its malignant transformation. Cell proliferation inhibitory effects of the pan-deacetylase inhibitors panobinostat, SAHA and Trichostatin A (TSA), the modulation of the sodium iodide symporter (NIS; SLC5A5), thyroid transcription factor 1 (TTF1), high mobility group A2 (HMGA2), and H19 and their putative targeting miRNAs have been evaluated in vitro. The cell viability was measured in five thyroid cancer cell lines (FTC133, TPC1, BCPAP, 8505C, C643) by real time cell analyzer xCELLigence...
March 21, 2018: Journal of Clinical Medicine
Andoni Garitano-Trojaola, Edurne San José-Enériz, Teresa Ezponda, Juan Pablo Unfried, Arantxa Carrasco-León, Nerea Razquin, Marina Barriocanal, Amaia Vilas-Zornoza, Bruno Sangro, Victor Segura, Felipe Prósper, Puri Fortes, Xabier Agirre
Long Non-Coding RNAs (lncRNAs) are functional RNAs longer than 200 nucleotides in length. Several lncRNAs are involved in cell proliferation and are deregulated in several human tumors. Few lncRNAs have been described to play a role in Acute Lymphoblastic Leukemia (ALL). In this study, we carried out a genome wide lncRNA expression profiling in ALL samples and peripheral blood samples obtained from healthy donors. We detected 43 lncRNAs that were aberrantly expressed in ALL. Interestingly, among them, linc-PINT showed a significant downregulation in T and B-ALL...
February 27, 2018: Oncotarget
Alanna Sedgwick, M Olivia Balmert, Crislyn D'Souza-Schorey
Aberrant cellular cholesterol accumulation contributes to the pathophysiology of many diseases including neurodegenerative disorders such as Niemann-Pick Type C (NPC) and Alzheimer's Disease1-4 . Many aspects of cholesterol efflux from cells remain elusive. Here we describe the utility of cholesterol-rich giant plasma membrane vesicles (GPMVs) as a means to monitor cholesterol that is translocated to the plasma membrane for secretion. We demonstrate that small molecules known to enhance lipid efflux, including those in clinical trials for lipid storage disorders, enhance this GPMV formation...
March 6, 2018: Experimental Cell Research
Bingqing Cheng, Sishi Tang, Nana Zhe, Dan Ma, Kunlin Yu, Danna Wei, Zheng Zhou, Tingting Lu, Jishi Wang, Qin Fang
To improve the treatment outcomes of acute myeloid leukemia (AML), epigenetic modification has been widely tested and used in recent years. However, drug-resistance is still a choke point to cure the malignancy. The growth factor independent 1 transcriptional repressor (GFI-1), as a zinc-finger transcriptional repressor, can bind histone deacetylases to allow the transcriptional repression. According to the finding of our study, AML patients with low level of GFI-1 not only implicated poor prognosis but also caused Panobinostat-resistance...
February 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Sin Young Choi, Hae Jin Kee, Li Jin, Yuhee Ryu, Simei Sun, Gwi Ran Kim, Myung Ho Jeong
Histone deacetylase (HDAC) inhibitors are gaining increasing attention as potential therapeutics for cardiovascular diseases as well as cancer. We recently reported that the class II HDAC inhibitor, MC1568, and the phytochemical, gallic acid, lowered high blood pressure in mouse models of hypertension. We hypothesized that class II HDACs may be involved in the regulation of hypertension. The aim of this study was to determine and compare the effects of well-known HDAC inhibitors (TMP269, panobinostat, and MC1568), phytochemicals (gallic acid, sulforaphane, and piceatannol), and anti-hypertensive drugs (losartan, carvedilol, and furosemide) on activities of class IIa HDACs (HDAC4, 5, 7, and 9)...
February 23, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Christel Rothe Brinkmann, Jesper Falkesgaard Højen, Thomas Aagaard Rasmussen, Anne Sofie Kjær, Rikke Olesen, Paul W Denton, Lars Østergaard, Zhengyu Ouyang, Mathias Lichterfeld, Xu Yu, Ole Schmeltz Søgaard, Charles Dinarello, Martin Tolstrup
Histone deacetylase inhibitors (HDACi) modulate the transcriptional activity of all cells, including innate and adaptive immune cells. Therefore, we aimed to evaluate immunological effects of treatment with the HDACi panobinostat in HIV-infected patients during a clinical phase IIa latency reversal trial. Using flow cytometry, we investigated changes in T cell activation (CD69, CD38, HLA-DR) and the expression of CD39 and CTLA4 on regulatory T cells (Tregs). Whole-blood stimulations were performed and cytokine responses measured using Luminex...
January 2018: MSphere
Harikrishna Kommidi, Umberto Tosi, Uday B Maachani, Hua Guo, Christopher S Marnell, Benedict Law, Mark M Souweidane, Richard Ting
Histone deacetylase (HDAC) inhibition is becoming an increasingly popular approach to treat cancer, as HDAC overexpression is common in many malignancies. The blood-brain barrier (BBB) prevents systemically delivered drugs from reaching brain at effective concentration, making small-molecule-HDAC inhibition in brain tumors particularly challenging. To circumvent the BBB, novel routes for administering therapeutics are being considered in the clinic, and a need exists for drugs whose deliveries can be directly imaged, so that effective delivery across the BBB can be monitored...
February 8, 2018: ACS Medicinal Chemistry Letters
Andrew J Yee, Noopur S Raje
No abstract text is available yet for this article.
February 14, 2018: Oncologist
Benigno C Valdez, Yang Li, David Murray, Yan Liu, Yago Nieto, Richard E Champlin, Borje S Andersson
Combination of drugs that target different aspects of aberrant cellular processes is an efficacious treatment for hematological malignancies. Hypomethylating agents (HMAs) and inhibitors of poly(ADP-ribose) polymerases (PARPis) and histone deacetylases (HDACis) are clinically active anti-tumor drugs. We hypothesized that their combination would be synergistically cytotoxic to leukemia and lymphoma cells. Exposure of AML and lymphoma cell lines to the combination of the PARPi niraparib (Npb), the HMA decitabine (DAC) and the HDACi romidepsin (Rom) or panobinostat (Pano) synergistically inhibited cell proliferation by up to 70% via activation of the ATM pathway, increased production of reactive oxygen species, decreased mitochondrial membrane potential, and activated apoptosis...
January 9, 2018: Oncotarget
Benet Pera, Jan Krumsiek, Sarit E Assouline, Rossella Marullo, Jayeshkumar Patel, Jude M Phillip, Lidia Román, Koren K Mann, Leandro Cerchietti
Despite the proven clinical antineoplastic activity of histone deacetylase inhibitors (HDACI), their effect has been reported to be lower than expected in B-cell lymphomas. Traditionally considered as "epigenetic drugs", HDACI modify the acetylation status of an extensive proteome, acting as general lysine deacetylase inhibitors (KDACI), and thus potentially impacting various branches of cellular metabolism. Here, we demonstrate through metabolomic profiling of patient plasma and cell lines that the KDACI panobinostat alters lipid metabolism and downstream survival signaling in diffuse large B-cell lymphomas (DLBCL)...
January 25, 2018: EBioMedicine
Kai-Wen Hsu, Chien-Yu Huang, Ka-Wai Tam, Chun-Yu Lin, Li-Chi Huang, Ching-Ling Lin, Wen-Shyang Hsieh, Wei-Ming Chi, Yu-Jia Chang, Po-Li Wei, Shou-Tung Chen, Chia-Hwa Lee
Breast cancer is the most common malignancy in women and the second leading cause of cancer death in women. Triple negative breast cancer (TNBC) subtype is a breast cancer subset without ER (estrogen receptor), PR (progesterone receptor) and HER2 (human epidermal growth factor receptor 2) expression, limiting treatment options and presenting a poorer survival rate. Thus, we investigated whether histone deacetylation inhibitor (HDACi) could be used as potential anti-cancer therapy on breast cancer cells. In this study, we found TNBC and HER2-enriched breast cancers are extremely sensitive to Panobinostat, Belinostat of HDACi via experiments of cell viability assay, apoptotic marker identification and flow cytometry measurement...
February 2, 2018: International Journal of Molecular Sciences
Maria Lorenzo Pisarello, Tatyana V Masyuk, Sergio A Gradilone, Anatoliy I Masyuk, Jingyi Francess Ding, Pui-Yuen Lee, Nicholas F LaRusso
Hepatic cystogenesis in polycystic liver disease (PLD) is associated with abnormalities in multiple cellular processes, including elevated cAMP and overexpression of histone deacetylase 6 (HDAC6). Disease progression in polycystic kidney (PCK) rats (an animal model of PLD) is attenuated by inhibition of either cAMP production or HDAC6. Therefore, we hypothesized that concurrent targeting of HDAC6 and cAMP would synergistically reduce cyst growth. Changes in hepatorenal cystogenesis were examined in PCK rats treated with a pan-HDAC inhibitor, panobinostat; three specific HDAC6 inhibitors, ACY-1215, ACY-738, and ACY-241; and a combination of ACY-1215 and the somatostatin receptor analogue, pasireotide...
January 31, 2018: American Journal of Pathology
Hak-Min Lee, Eunmyong Lee, So-Young Yeo, Sang Shin, Hyun-Kyu Park, Do-Hyun Nam, Seok-Hyung Kim
Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval...
January 18, 2018: Investigational New Drugs
Sishi Tang, Dan Ma, Bingqing Cheng, Qing Fang, Xinyi Kuang, Kunling Yu, Weili Wang, Bo Hu, Jishi Wang
Inhibition of histone deacetylase (HDAC) is a promising therapeutic strategy for various hematologic cancers. Panobinostat has been approved for treating patients with multiple myeloma (MM) by the FDA. Since the mechanism for the resistance of panobinostat to MM remains elusive, we aimed to clarify this mechanism and the synergism of panobinostat with lenalidomide. The mRNA and protein of transcription factor IRF4 were overexpressed in CD138+ mononuclear cells from MM patients compared with in those from healthy donors...
January 6, 2018: Experimental Cell Research
Lingzhi Wang, Nicholas Li-Xun Syn, Vinod Vijay Subhash, Yijia Any, Win Lwin Thuya, Esther Cheow, Liren Kong, Fenggang Yu, Praveen C Peethala, Andrea Li-Ann Wong, Hirpara J Laljibhai, Arunachalam Chinnathambi, Pei Shi Ong, Paul Chi-Lui Ho, Gautam Sethi, Wei Peng Yong, Boon Cher Goh
Accumulating evidence has implicated the aberrant regulation of histone deacetylases (HDACs) as a nexus for multiple cancer hallmarks and in mediating tumor adaptation and resistance to genotoxic chemotherapy, suggesting a rational pairing of HDAC inhibitors with DNA damaging chemotherapeutic agents in the treatment of human malignancies. Here we report that panobinostat (LBH589), a potent pan-HDAC inhibitor, effectively curbed the proliferation of non-small cell lung cancer (NSCLC) cell lines A549, Calu-1, H226, H460, H838 and SKMES-1 at IC50 concentrations between 4 and 31 nmol/L via pleiotropic mechanisms, including crosstalk with EGFR signal transduction cascades...
January 3, 2018: Cancer Letters
Ajai Chari, Hearn J Cho, Amishi Dhadwal, Gillian Morgan, Lisa La, Katarzyna Zarychta, Donna Catamero, Erika Florendo, Nadege Stevens, Daniel Verina, Elaine Chan, Violetta Leshchenko, Alessandro Laganà, Deepak Perumal, Anna Huo-Chang Mei, Kaity Tung, Jami Fukui, Sundar Jagannath, Samir Parekh
Phase 3 studies combining histone deacetylase inhibitors with bortezomib were hampered by gastrointestinal (GI) intolerance, which was not observed when combined with immunomodulatory drugs. This study is a single-center phase 2 study of panobinostat with lenalidomide and dexamethasone (FRD). Twenty-seven relapsed multiple myeloma patients were enrolled. Twenty-two patients (81%) were lenalidomide refractory and 9 (33%), 14 (52%), and 7 (26%) were refractory to pomalidomide, bortezomib, and carfilzomib, respectively...
August 22, 2017: Blood Advances
Josh J Carlson, Gregory F Guzauskas, Richard H Chapman, Patricia G Synnott, Shanshan Liu, Elizabeth T Russo, Steven D Pearson, Elizabeth D Brouwer, Daniel A Ollendorf
BACKGROUND: New 3-drug regimens have been developed and approved to treat multiple myeloma (MM). The absence of direct comparative data and the high cost of treatment support the need to assess the relative clinical and economic outcomes across all approved regimens. OBJECTIVE: To evaluate the cost-effectiveness of treatments for relapsed and/or refractory MM from a U.S. health system perspective. METHODS: We developed a partition survival model with 3 health states (progression-free, progression, and death) to evaluate the following regimens: carfilzomib (CFZ), elotuzumab (ELO), ixazomib (IX), daratumumab (DAR), and panobinostat (PAN) in combination with lenalidomide (LEN) or bortezomib (BOR) plus dexamethasone (DEX) in the second and/or third line of therapy...
January 2018: Journal of Managed Care & Specialty Pharmacy
Lubna Wasim, Madhu Chopra
PURPOSE: Various combinations of drugs may be effective in the treatment of different types of cancer. Previously, we have shown that combinations of the histone deacetylase inhibitor panobinostat and the topoisomerase inhibitors topotecan or etoposide act synergistically, but the underlying mode of action has remained unknown. Here, we aimed at uncovering the mechanisms underlying this synergism. METHODS: The effects of (combinations of) panobinostat and topotecan or etoposide on cervical cancer-derived HeLa and SiHa cells were assessed using morphological evaluations, scratch wound healing assays, cell cycle analyses, AO/EB staining assays, Annexin V/PI staining assays, reactive oxygen species (ROS) and mitochondrial membrane potential measurements and Western blotting...
December 19, 2017: Cellular Oncology (Dordrecht)
Rosalie M Sterner, Kimberly N Kremer, Aref Al-Kali, Mrinal M Patnaik, Naseema Gangat, Mark R Litzow, Scott H Kaufmann, Jennifer J Westendorf, Andre J van Wijnen, Karen E Hedin
The bone marrow microenvironment protects acute myeloid leukemia (AML) cells during chemotherapy and is a major factor in relapse. Here, we examined which type(s) of bone marrow cells are responsible for the relapse of AML following treatment with cytarabine (Ara-C), and we identified a means to inhibit this protection. To determine the protective cell type(s), AML cells were treated with Ara-C, and AML cell survival in the presence or absence of osteoblast lineage cells was assessed. Cultured AML cells and patient bone marrow isolates were each significantly protected from Ara-C-induced apoptosis by co-culture with differentiating osteoblasts...
November 7, 2017: Oncotarget
Stuart J Gallagher, Dilini Gunatilake, Kimberley A Beaumont, Danae M Sharp, Jessamy C Tiffen, Anja Heinemann, Wolfgang Weninger, Nikolas K Haass, James S Wilmott, Jason Madore, Peter M Ferguson, Helen Rizos, Peter Hersey
Mutations in BRAF activate oncogenic MAPK signalling in almost half of cutaneous melanomas. Inhibitors of BRAF (BRAFi) and its target MEK are widely used to treat melanoma patients with BRAF mutations but unfortunately acquired resistance occurs in the majority of patients. Resistance results from mutations or non-genomic changes that either reactivate MAPK signalling or activate other pathways that provide alternate survival and growth signalling. Here, we show the histone deacetylase inhibitor (HDACi) panobinostat overcomes BRAFi resistance in melanoma, but this is dependent on the resistant cells showing a partial response to BRAFi treatment...
May 1, 2018: International Journal of Cancer. Journal International du Cancer
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