MPT0G413, A Novel HDAC6-Selective Inhibitor, and Bortezomib Synergistically Exert Anti-tumor Activity in Multiple Myeloma Cells

In multiple myeloma (MM), homeostasis is largely maintained by misfolded protein clearance via the proteasomal and aggresomal pathways. Histone deacetylase 6 (HDAC6) binds polyubiquitinated proteins and dynein motors and transports this protein cargo to the aggresome for further degradation. Accordingly, a combination of an HDAC6 inhibitor and bortezomib (BTZ) could increase ubiquitinated protein accumulation, leading to further apoptosis. Here we evaluated the anti-MM activity of MPT0G413, a novel specific HDAC6 inhibitor, using in vitro and in vivo models. MPT0G413 treatment more significantly inhibited cell growth in MM cells than in normal bone marrow cells. Furthermore, the combination of MPT0G413 and BTZ enhanced polyubiquitinated protein accumulation and synergistically reduced MM viability, increased caspase-3, caspase-8, caspase-9 levels, and cleaved poly (ADP) ribosome polymerase and also inhibited adherence of MM cells to bone marrow stromal cells (BMSC) and reduced VEGF and IL-6 levels and cell growth in a co-culture system. The combination treatment disturbed the bone marrow microenvironment and induced synergic, caspase-dependent apoptosis. Xenograft tumor growth significantly decreased in combination-treated SCID mice. In conclusion, MPT0G413 and BTZ synergistically inhibit MM viability, providing a framework for the clinical evaluation of combined therapies for MM

Coenzyme Q10 Reduces Ethanol-Induced Apoptosis in Corneal Fibroblasts

Dilute ethanol (EtOH) is a widely used agent to remove the corneal epithelium during the modern refractive surgery. The application of EtOH may cause the underlying corneal fibroblasts to undergo apoptosis. This study was designed to investigate the protective effect and potential mechanism of the respiratory chain coenzyme Q10 (CoQ10), an electron transporter of the mitochondrial respiratory chain and a ubiquitous free radical scavenger, against EtOH-induced apoptosis of corneal fibroblasts. Corneal fibroblasts were pretreated with CoQ10 (10 µM) for 2 h, followed by exposure to different concentrations of EtOH (0.4, 2, 4, and 20%) for 20 s. After indicated incubation period (2–12 h), MTT assay was used to examine cell viability. Treated cells were further assessed by flow cytometry to identify apoptosis. Reactive oxygen species (ROS) and the change in mitochondrial membrane potential were assessed using dichlorodihydrofluorescein diacetate/2′,7′-dichlorofluorescein (DCFH-DA/DCF) assays and flow-cytometric analysis of JC-1 staining, respectively. The activity and expression of caspases 2, 3, 8, and 9 were evaluated with a colorimetric assay and western blot analysis. We found that EtOH treatment significantly decreased the viability of corneal fibroblasts characterized by a higher percentage of apoptotic cells. CoQ10 could antagonize the apoptosis inducing effect of EtOH. The inhibition of cell apoptosis by CoQ10 was significant at 8 and 12 h after EtOH exposure. In EtOH-exposed corneal fibroblasts, CoQ10 pretreatment significantly reduced mitochondrial depolarization and ROS production at 30, 60, 90, and 120 min and inhibited the activation and expression of caspases 2 and 3 at 2 h after EtOH exposure. In summary, pretreatment with CoQ10 can inhibit mitochondrial depolarization, caspase activation, and cell apoptosis. These findings support the proposition that CoQ10 plays an antiapoptotic role in corneal fibroblasts after ethanol exposure

Effect of Intracameral Injection of Lidocaine and Carbachol on the Rabbit Corneal Endothelium

Purpose: To determine the effect of intracameral injection of preservative-free lidocaine 1% and carbachol 0.01% on corneal endothelial cells of rabbits. Setting: Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan. Methods: Forty eyes of 20 New Zealand White rabbits were divided into 2 equal groups. In the first group, 1 eye was injected with 0.02 mL of preservative-free lidocaine 1% and the fellow eye was injected with 0.02 mL of normal saline as a control. In the second group, 1 eye was injected with 0.02 mL of carbachol 0.01% and the fellow eye was injected with 0.02 mL of normal saline. Specular microscopy was used to evaluate corneal endothelial cell loss and corneal thickness 1 week and 1 month postinjection. For morphologic studies, corneal buttons were excised and stained with alizarin red with trypan blue. Scanning electron microscopy (SEM) examination was performed. Results . Specular microscopy revealed no significant endothelial cell loss and normal endothelial thickness with the intracameral injection of preservative-free lidocaine 1% and carbachol 0.01% compared with the control eye. Alizarin red with trypan blue stain and SEM examinations revealed smooth , distinct , and intact intercellular borders and normal viability of corneal endothelial cells in both groups. Conclusions. Intracameral injections of preservative-free lidocaine 1% and carbachol 0.01% do not produce morphologic and functional changes in the corneal endothelial cells of rabbits

Bilateral bulbar subconjunctival hemorrhage associated with H1N1 vaccination

AbstractSubconjunctival hemorrhage (SCH) is a common eye disorder that is characterized by the sudden onset of a flat area of bleeding under the conjunctiva. Although SCH is a well-known and relatively common disease, the cause in a number of cases remains unknown. Here, we report an unusual ocular presentation of bulbar SCH in a patient who had received an influenza vaccine. Patients who present with SCH other than trauma episode should be evaluated with metabolic diseases or coagulopathy. Although there are rare cases of SCH related to vaccination, we should closely follow a patient if there is a risk of the SCH becoming bleeding disorder. To our knowledge, the features of SCH related to vaccination have not been reported

Herpetic keratouveitis mixed with bilateral Pseudomonas corneal ulcers in vitamin A deficiency

A 56-year-old woman complained of blurred vision and pain in her right eye for several days. Slit lamp examination revealed a large epithelial defect and disciform stromal edema with ring infiltration in her right cornea. Unfortunately, hypopyon and purulent discharge subsequently developed in both eyes. Herpetic keratouveitis and a superimposed pseudomonas infection were diagnosed. A systemic review on the patient showed malnutrition due to her dietary preference and vegetarianism. After the infection was controlled, bilateral epithelial defects persisted for a long time. We performed amniotic membrane transplantation on both eyes and the clinical status improved with administration of vitamin and protein supplements. Although rare in Taiwan, vitamin A deficiency should be kept in mind when conjunctival and corneal xerosis occurred. Vitamin A supplements are suggested because of the increased susceptibility to infection in patients with this clinical status

Intraocular lens opacification after Descemet's stripping automated endothelial keratoplasty

Compared with conventional penetrating keratoplasty, Descemet's stripping automated endothelial keratoplasty (DSAEK) more effectively maintain global integrity and rapid vision rehabilitation with less ocular surface disorders in patients with endothelial dysfunction. Here, we report a case of a 76-year-old woman who experienced opacification of a hydrophilic intraocular lens (IOL) approximately 10 months after DSAEK. The patient with no history of systemic disease developed pseudophakic bullous keratopathy in the right eye 2 years after undergoing cataract surgery. The best-corrected visual acuity (BCVA) of the right eye was Snellen 0.01 when presented to our hospital. DSAEK was arranged and performed smoothly. However, the graft detached over the upper part of the cornea on postoperative day 1. Thus, rebubbling was performed immediately. After the procedure, the graft was well attached, and the cornea became clear gradually. The BCVA returned to Snellen 0.6. However, progressive opacification over the anterior surface of the IOL was observed 10 months postoperatively. Vision deteriorated to 0.5 with various refractive errors during 2-year follow-up. IOL exchange may be considered if the vision is getting worse. IOL opacification may result from a direct contact between the IOL surface and exogenous air, particularly in a hydrophilic IOL, and can be a rare but significant complication after DSAEK. Clinicians planning to perform DSAEK should consider the composition of the IOL, the amount of intracameral air, duration of air filling, and high intraocular pressure

A Novel Dual HDAC6 and Tubulin Inhibitor, MPT0B451, Displays Anti-tumor Ability in Human Cancer Cells in Vitro and in Vivo

The combination cancer therapy is a new strategy to circumvent drug resistance for the treatment of high metastasis and advanced malignancies. Herein, we developed a synthesized compound MPT0B451 that display inhibitory effect against histone deacetylase (HDAC) 6 and tubulin assembly. Our data demonstrated that MPT0B451 significantly inhibited cancer cell growths in HL-60 and PC-3 cells due to inhibition of HDAC activity. MPT0B451 also markedly increased caspase-mediated apoptosis in these cells. The cell cycle analysis showed mitotic arrest induced by MPT0B451 with enhanced expression of G2/M transition proteins. Moreover, molecular docking analysis supported MPT0B451 as a dual HDAC6 and tubulin inhibitor. Finally, MPT0B451 led to tumor growth inhibition (TGI) in HL-60 and PC-3 xenograft models. These findings indicated that MPT0B451 has dual inhibition effects for HDAC6 and tubulin, and also contributed to G2/M arrest followed by apoptotic induction. Together, our results suggested that MPT0B451 may serve as a potent anti-cancer treatment regimen in human prostate cancer and acute myeloid leukemia

The anticancer effects of MPT0G211, a novel HDAC6 inhibitor, combined with chemotherapeutic agents in human acute leukemia cells

Abstract Background There are some limitations of standard chemotherapy for acute leukemia. Vincristine and doxorubicin are commonly used for acute leukemia, but they may induce serious side effects such as cardiomyopathy and neurotoxicity. Furthermore, chemotherapy resistance occurs more and more frequently. Therefore, effective treatment strategies are needed. Histone deacetylase 6 inhibition is considered as a potential therapeutic strategy for acute leukemia, since it is observed that HDAC6 is overexpressed in acute leukemia and regulates tumor survival. Combination therapy for cancer is used to minimize adverse drug effects, reduce drug dosage, enhance efficacy, and prevent drug resistance. In order to improve efficacy of chemotherapy agents of acute leukemia, this study will investigate the effects of combination MPT0G211, a novel histone deacetylase 6 inhibitor, with doxorubicin or vincristine on human acute leukemia cells. Results MPT0G211 combined with doxorubicin induces DNA damage response on human acute myeloid leukemia cells. MPT0G211 can additionally increase Ku70 acetylation and release BAX to mitochondria. Ectopic expression of HDAC6 successively reversed the apoptosis triggered by the combined treatment. Moreover, co-treatment of MPT0G211 and vincristine may alter microtubule dynamics, triggering acute lymphoblastic leukemia cells arrest in mitotic phase followed by induction of the apoptotic pathway. Finally, MPT0G211 plus doxorubicin or vincristine can significantly improve the tumor growth delay in a tumor xenograft model. Conclusions Collectively, our data highlighted that MPT0G211 in combination with chemotherapy drugs has significant anticancer activity, suggesting a novel strategy for the treatment of acute leukemia