Neratinib reverses ATP-binding cassette B1-mediated chemotherapeutic drug resistance in vitro, in vivo, and ex vivo

Neratinib, an irreversible inhibitor of epidermal growth factor receptor and human epidermal receptor 2, is in phase III clinical trials for patients with human epidermal receptor 2-positive, locally advanced or metastatic breast cancer. The objective of this study was to explore the ability of neratinib to reverse tumor multidrug resistance attributable to overexpression of ATP-binding cassette (ABC) transporters. Our results showed that neratinib remarkably enhanced the sensitivity of ABCB1-overexpressing cells to ABCB1 substrates. It is noteworthy that neratinib augmented the effect of chemotherapeutic agents in inhibiting the growth of ABCB1-overexpressing primary leukemia blasts and KBv200 cell xenografts in nude mice. Furthermore, neratinib increased doxorubicin accumulation in ABCB1-overexpressing cell lines and Rhodamine 123 accumulation in ABCB1-overexpressing cell lines and primary leukemia blasts. Neratinib stimulated the ATPase activity of ABCB1 at low concentrations but inhibited it at high concentrations. Likewise, neratinib inhibited the photolabeling of ABCB1 with [(125)I]iodoarylazidoprazosin in a concentration-dependent manner (IC(50) = 0.24 μM). Neither the expression of ABCB1 at the mRNA and protein levels nor the phosphorylation of Akt was affected by neratinib at reversal concentrations. Docking simulation results were consistent with the binding conformation of neratinib within the large cavity of the transmembrane region of ABCB1, which provides computational support for the cross-reactivity of tyrosine kinase inhibitors with human ABCB1. In conclusion, neratinib can reverse ABCB1-mediated multidrug resistance in vitro, ex vivo, and in vivo by inhibiting its transport function.     

Chronic sensorimotor polyneuropathy associated with tacrolimus immunosuppression in renal transplant patients: case reports

Tacrolimus is used widely for immunosuppression following transplantation. It has rarely been linked to the development of peripheral neuropathy. However, one study also reported improvement in peripheral neuropathy after tacrolimus use. We have reported herein two patients who developed chronic sensorimotor polyneuropathy after tacrolimus use following renal transplantation. One patient had an unusual presentation with bilateral facial and extremity weakness and a relapsing course. The other patient presented with focal sensory symptoms in one hand. Electrophysiological studies confirmed widespread, predominantly demyelinating or axonal polyneuropathy. We concluded that patients on tacrolimus should be carefully monitored for symptoms suggestive of peripheral neuropathy.     

Photoregulation of drug release in azo-dextran nanogels

A simple photoresponsive azo-dextran polymer has been investigated for its ability to act as a nanogel drug carrier. Self aggregation of the azo-dextran polymer leads to the formation of nanogels, AD (5 and 10) in aqueous media, which were characterized by TEM and DLS. When examined under UV light (365 nm), the unloaded nanogels, which were observed to be in the range of 120-290 nm, show dependence on the degree of crosslinking, pH and ionic concentration of the dispersed media. Nanogels, AD (5 and 10), have been loaded with a model fluorophore, rhodamine B and a drug, aspirin, by freeze drying an aqueous dispersion of the nanogels in the presence of the substrate dissolved in water or PBS buffer. The release pattern of the encapsulated bio-active molecules from these nanogels was regulated by (trans-cis) photoisomerization of the azobenzene moiety present in the crosslinker. A comparison of the release behavior of the loaded (rhodamine, aspirin) AD (5 and 10) nanogels reveal that the rate of release of the encapsulated active molecules from the nanogels was slower when the azo moiety was in E-configuration as compared to that the azo in the Z-configuration. The in vitro release behavior of drug from these polymeric micellar systems is revelative of the potential of the nanogels for targeted drug delivery in nanomedicine.     

Aortic dissection and bicuspid aortic valve: an autopsy study

Medico-legal post-mortems referred to the Department of Pathology, for the histopathological examination, revealed six cases of acute aortic dissection--two in isolation, three in combination with congenital bicuspid aortic valve; and one isolated case of congenital bicuspid aortic valve. One case of isolated aortic dissection was associated with Marfan's syndrome; and one case of aortic dissection with bicuspid aortic valve was associated with polycystic kidneys. History of hypertension could be elicited in two cases. Cystic medial degeneration of aorta was seen in three cases; one of which was associated with Marfan's syndrome. All five cases of aortic dissection belonged to type II of DeBakey classification.     

Tetracycline-regulated transactivators driven by the involucrin promoter to achieve epidermal conditional gene expression

To achieve conditional gene expression in the differentiated layers of the epidermis, we generated transgenic mice with the tetracycline-regulated transactivator proteins, tTA (tetracycline transactivator) and rtTA (reverse tetracycline transactivator), expressed from the human involucrin promoter. Interaction with tetracycline turns off or turns on the tTA and rtTA molecules, respectively, allowing for regulation of downstream target genes during development and postnatally. These transactivator lines were crossed with reporter mice driving LacZ expression from a tetracycline response element to analyze the specificity and levels of target gene expression. Quantitative beta-galactosidase experiments demonstrate a 30-fold induction, specific to epithelial tissues. Immunohistochemistry results illustrate that the beta-galactosidase staining follows that of endogenous involucrin expression. Induction initiates at embryonic day 14.5 with expression over the entire epidermal surface by E16.5. Together with other driver lines, expressing tetracycline transactivators in the mitotically active layers of the epidermis, these mice will allow investigators to specifically modulate expression of target genes to specific stages of epidermal differentiation.     

Hypertensive Encephalopathy Presenting with Isolated Brain Stem and Cerebellar Edema

Hypertensive encephalopathy typically presents with headache and confusion and bilateral parietooccipital vasogenic edema. Brain stem and cerebellar edema in hypertensive encephalopathy usually occurs in association with these typical supratentorial changes and is usually asymptomatic. We report here an uncommon hypertensive patient with isolated, severe, and symptomatic brain stem and cerebellar edema with fourth ventricular obstruction and mild hydrocephalus. Rapid treatment of hypertension resulted in clinical and radiological improvement. Prompt recognition of the cause and aggressive treatment of hypertension in such patients are crucial to relieve edema and prevent life‐threatening progression.     

Telatinib reverses chemotherapeutic multidrug resistance mediated by ABCG2 efflux transporter in vitro and in vivo

Multidrug resistance (MDR) is a phenomenon where cancer cells become simultaneously resistant to anticancer drugs with different structures and mechanisms of action. MDR has been shown to be associated with overexpression of ATP-binding cassette (ABC) transporters. Here, we report that telatinib, a small molecule tyrosine kinase inhibitor, enhances the anticancer activity of ABCG2 substrate anticancer drugs by inhibiting ABCG2 efflux transporter activity. Co-incubation of ABCG2-overexpressing drug resistant cell lines with telatinib and ABCG2 substrate anticancer drugs significantly reduced cellular viability, whereas telatinib alone did not significantly affect drug sensitive and drug resistant cell lines. Telatinib at 1 μM did not significantly alter the expression of ABCG2 in ABCG2-overexpressing cell lines. Telatinib at 1 μM significantly enhanced the intracellular accumulation of [³H]-mitoxantrone (MX) in ABCG2-overexpressing cell lines. In addition, telatinib at 1 μM significantly reduced the rate of [³H]-MX efflux from ABCG2-overexpressing cells. Furthermore, telatinib significantly inhibited ABCG2-mediated transport of [³H]-E₂17βG in ABCG2 overexpressing membrane vesicles. Telatinib stimulated the ATPase activity of ABCG2 in a concentration-dependent manner, indicating that telatinib might be a substrate of ABCG2. Binding interactions of telatinib were found to be in transmembrane region of homology modeled human ABCG2. In addition, telatinib (15 mg/kg) with doxorubicin (1.8 mg/kg) significantly decreased the growth rate and tumor size of ABCG2 overexpressing tumors in a xenograft nude mouse model. These results, provided that they can be translated to humans, suggesting that telatinib, in combination with specific ABCG2 substrate drugs may be useful in treating tumors that overexpress ABCG2.