Publications by authors named "Caleb Gonshen Chen"

5 Publications

  • Page 1 of 1

Local ablation of gastric cancer by reconstituted apolipoprotein B lipoparticles carrying epigenetic drugs.

Nanomedicine 2021 Jul 29;37:102450. Epub 2021 Jul 29.

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Epigenetic inhibitors have shown anticancer effects. Combination chemotherapy with epigenetic inhibitors has shown high effectiveness in gastric cancer clinical trials, but severe side effect and local progression are the causes of treatment failure. Therefore, we sought to develop an acidity-sensitive drug delivery system to release drugs locally to diminish unfavorable outcome of gastric cancer. In this study, we showed that, as compared with single agents, combination treatment with the demethylating agent 5'-aza-2'-deoxycytidine and HDAC inhibitors Trichostatin A or LBH589 decreased cell survival, blocked cell cycle by reducing number of S-phase cells and expression of cyclins, increased cell apoptosis by inducing expression of Bim and cleaved Caspase 3, and reexpressed tumor suppressor genes more effectively in MGCC3I cells. As a carrier, reconstituted apolipoprotein B lipoparticles (rABLs) could release drugs in acidic environments. Orally administrated embedded drugs not only showed inhibitory effects on gastric tumor growth in a syngeneic orthotopic mouse model, but also reduced the hepatic and renal toxicity. In conclusion, we have established rABL-based nanoparticles embedded epigenetic inhibitors for local treatment of gastric cancer, which have good therapeutic effects but do not cause severe side effects.
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http://dx.doi.org/10.1016/j.nano.2021.102450DOI Listing
July 2021

BAFF-driven NLRP3 inflammasome activation in B cells.

Cell Death Dis 2020 10 1;11(9):820. Epub 2020 Oct 1.

Department of Hematology, MacKay Memorial Hospital, Taipei, 10449, Taiwan.

BAFF supports B-cell survival and homeostasis by activating the NF-κB pathway. While NF-κB is also involved in the priming signal of NLRP3 inflammasome, the role of BAFF in NLRP3 inflammasome regulation is unknown. Here we report BAFF engagement to BAFF receptor elicited both priming and activating signals for NLRP3 inflammasomes in primary B cells and B lymphoma cell lines. This induction of NLRP3 inflammasomes by BAFF led to increased NLRP3 and IL-1β expression, caspase-1 activation, IL-1β secretion, and pyroptosis. Mechanistically, BAFF activated NLRP3 inflammasomes by promoting the association of cIAP-TRAF2 with components of NLRP3 inflammasomes, and by inducing Src activity-dependent ROS production and potassium ion efflux. B-cell receptor (BCR) stimulation on the Lyn signaling pathway inhibited BAFF-induced Src activities and attenuated BAFF-induced NLRP3 inflammasome activation. These findings reveal an additional function of BAFF in B-cell homeostasis that is associated with BCR activities.
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http://dx.doi.org/10.1038/s41419-020-03035-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529748PMC
October 2020

NKG2A Down-Regulation by Dasatinib Enhances Natural Killer Cytotoxicity and Accelerates Effective Treatment Responses in Patients With Chronic Myeloid Leukemia.

Front Immunol 2018 17;9:3152. Epub 2019 Jan 17.

Department of Hematology, MacKay Memorial Hospital, Taipei, Taiwan.

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of (9;22) chromosomal translocation that results in fusion gene. ABL tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, are currently the front-line treatment options for CML. Recently, natural killer (NK) cell activation and expansion have been shown to be associated with optimal treatment responses for CML. To investigate the effects and mechanisms of these TKIs on NK cells, here we characterized activating and inhibitory NK receptors in CD3CD16CD56 NK cells isolated from CML patients in chronic phase (CP). The expressions of activating NK receptors, such as NKG2D, natural cytotoxicity receptor (NCR) and DNAM-1, rebounded after successful TKI treatments for CML. In contrast, among the three surveyed inhibitory receptors (NKG2A, KIR2DL1, and KIR3DL1), only the expression of NKG2A was reverted and suppressed to a very low level by dasatinib, and not by imatinib or nilotinib. CML patients treated with dasatinib indeed expressed fewer NKG2A+ NK cells, which send negative signals for induction of NK cytotoxicity. For these dasatinib-treated patients, the duration to reach major molecular response (MMR) was shorter, and significantly correlated with individual's NKG2A+ NK cell number. This clinical relevance to NKG2A was not observed in treatments with imatinib or nilotinib. In line with dasatinib-specific down-regulation of NKG2A, NK cytotoxicity evaluated by the killing assay was also significantly higher in patients treated with dasatinib than in those treated with imatinib or nilotinib. The lower NK cytotoxicity from imatinib or nilotinib treatments could be reverted by NKG2A blockade using anti-NKG2A antibody. Further experiments revealed mechanistically that dasatinib could inactivate p38 mitogen-activated protein kinase (MAPK), and consequently affect nuclear import of GATA-3 and GATA-3 transcriptional activities for NKG2A. Our results highlight the dual effects of dasatinib in direct inhibition of ABL kinase and in immunomodulation through NKG2A down-regulation, contributing to accelerated molecular responses (MR) in CML.
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http://dx.doi.org/10.3389/fimmu.2018.03152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6344416PMC
October 2019

Upfront maintenance therapy with arsenic trioxide in acute promyelocytic leukemia provides no benefit for non-t(15;17) subtype.

Asia Pac J Clin Oncol 2012 Dec 12;8(4):330-6. Epub 2012 Mar 12.

Department of Hematology-Oncology, Mackay Memorial Hospital, Taipei, Taiwan.

Aims: The optimal maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved complete remission (CR) and complete consolidation chemotherapy is still controversial. Whether the use of arsenic trioxide (ATO) alone or along with all-trans retinoic acid (ATRA) improves overall survival (OS) or disease-free survival (DFS) is still debated.

Methods: A retrospective reivew was conducted of 20 patients diagnosed with APL according to the French - American - British system. After achieving CR and receiving consolidation chemotherapy, nine patients were given maintenance therapy for 1 year (ATRA 45 mg/m(2) /day p.o., mercaptopurine 60 mg/m(2) /day p.o. and ATO 0.15 mg/kg/day × 5 days/week for six cycles in five patients; ATRA 45 mg/m(2) /d p.o. alternating with ATO 0.15 mg/kg/day × 5 days/week in 1 patient; ATRA only in three patients).

Results: In all patients the rates of CR, 3-year OS and 5-year OS were 75, 71 and 57%, respectively. For patients treated with ATO maintenance, the rates were 100% for both 5-year OS and 5-year DFS. Four of six patients on ATO maintenance had grade 1 or grade 2 adverse events. Excluding the two patients who died from intracerebral hemorrhage within 4 days after diagnosis, these rates were 85, 82 and 78%, respectively.

Conclusion: Upfront ATO maintenance therapy for one year is safe and appears to be effective, with the benefits restricted to patients with APL with t(15;17) translocation. Larger studies will be required to confirm this observation.
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http://dx.doi.org/10.1111/j.1743-7563.2011.01496.xDOI Listing
December 2012

Synthesis and evaluation of [18F]Fluorobutyl ethacrynic amide: a potential PET tracer for studying glutathione transferase.

Bioorg Med Chem Lett 2012 Jun 30;22(12):3998-4003. Epub 2012 Apr 30.

Department of Biomedical Engineering and Environmental Sciences, National Tsing-Hua University, Hsinchu 300, Taiwan.

[(18)F]Flurobutyl ethacrynic amide ([(18)F]FBuEA) was prepared from the precursor tosylate N-Boc-N-[4-(toluenesulfonyloxy)butyl]ethacrynic amide with a radiochemical yield of 3%, a specific activity of 48 GBq/μmol and radiochemical purity of 98%. Chemical conjugation of [(18)F]FBuEA with glutathione (GSH) via a self-coupling reaction and enzymatic conjugation under catalysis of glutathiontransferase alpha (GST-α) and π provided about 41% yields of radiochemical conjugated product [(18)F]FBuEA-GSH, 85% and 5-16%, respectively. The catalytic selectivity of this tracer toward GST-alpha was addressed. Positron emission tomography (PET) imaging of [(18)F]FBuEA in normal rats showed that a homogeneous pattern of radioactivity was distributed in the liver, suggesting a catalytic role of GST. By contrast, PET images of [(18)F]FBuEA in rats with thioacetamide-induced cholangiocarcinoma displayed a heterogeneous pattern of radioactive accumulation with cold spots in tumor lesions. PET imaging with [(18)F]FBuEA could be used for early diagnosis of hepatic tumor with a low GST activity as well as liver function.
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http://dx.doi.org/10.1016/j.bmcl.2012.04.091DOI Listing
June 2012
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