EphB4: A promising target for upper Aerodigestive malignancies.

EphB4: A promising target for upper Aerodigestive malignancies.

Biochim Biophys Acta. 2018 Jan 21;:

Authors: Salgia R, Kulkarni P, Gill PS

Abstract
The erythropoietin-producing hepatocellular carcinoma (Eph) receptors are the largest family of receptor tyrosine kinases (RTKs) that include two major subclasses, EphA and EphB. They form an important cell communication system with critical and diverse roles in a variety of biological processes during embryonic development. However, dysregulation of the Eph/ephrin interactions is implicated in cancer contributing to tumour growth, metastasis, and angiogenesis. Here, we focus on EphB4 and review recent developments in elucidating its role in upper aerodigestive malignancies to include lung cancer, head and neck cancer, and mesothelioma. In particular, we summarize information regarding EphB4 structure/function and role in disease pathobiology. We also review the data supporting EphB4 as a potential pharmacological and immunotherapy target and finally, progress in the development of new therapeutic strategies including small molecule inhibitors of its activity is discussed. The emerging picture suggests that EphB4 is a valuable and attractive therapeutic target for upper aerodigestive malignancies.

PMID: 29369779 [PubMed - as supplied by publisher]

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Breast cancer amelioration by Butea monosperma in-vitro and in-vivo.

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Breast cancer amelioration by Butea monosperma in-vitro and in-vivo.

J Ethnopharmacol. 2018 Jan 20;:

Authors: Karia P, Patel KV, Rathod SSP

Abstract
ETHNOPHARMACOLOGICAL RELEVANCE: Butea monosperma belonging to family Fabaceae is used in the Indian traditional medicine (Ayurveda) for various ailments including abdominal tumors and possess anti-estrogenic activity.
AIM OF THE STUDY: The present study is aimed at investigating the chemo-preventive potential of Butea monosperma in breast cancer and elucidating it's mechanism of action by assessing its effect on key processes like apoptosis, angiogenesis and metastasis.
METHODS: Cytotoxic potential of methanol extract of Butea monosperma flower (MEBM) was tested in MCF-7 (estrogen receptor positive), MDA-MB-231 (triple negative) and MDA-MB-453 (HER2 positive) human breast cancer cells by MTT assay. Chemo-preventive potential was evaluated in-vivo in Methylnitrosourea (MNU) induced mammary cancer in nulliparous Sprague-Dawley rats.The mechanism for anticancer potential was screened by in-vitro studies involving Annexin V- FITC assay (apoptosis), Chick Chorioallantoic Membrane assay (angiogenesis) and Migration assay (metastasis). Statistical analysis was done by one way and two way ANOVA (for Growth Rate and feed consumption efficiency) followed by post hoc Bonferroni's test respectively with P value <0.05.
RESULTS: It is observed that the exposure of MEBM, at various concentrations and time intervals to different cell lines, resulted in decreased cell proliferation. The IC50 value of MCF-7 cells was found significantly less than that of MDA-MB-231 and MDA-MB-453 cells, which indicated that the extract of said medicinal plant were more potent inhibitors of estrogen positive breast cancer cells than other types of breast cancer cells in vitro. Corroborative evidences were acquired in MNU actuated mammary carcinogenesis where MEBM constricted tumor parameters, decreased expression of estrogen and progesterone, nucleic acid content and increased latency period. MEBM also induced apoptosis, inhibited angiogenesis and metastasis in-vitro.
CONCLUSION: Selective cytotoxic activity in MCF-7 estrogen positive breast cancer cells and inhibition of growth of mammary carcinoma in-vivo by methanol extract of Butea monosperma flowers (MEBM) suggests chemo-prevention through modulation of estrogen and progesterone receptor, apoptotic, anti-angiogenesis and anti-metastatic activity.

PMID: 29366766 [PubMed - as supplied by publisher]

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Urokinase-type plasminogen activator (uPA) is critical for progression of tuberous sclerosis complex 2 (TSC2)-deficient tumors.

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Urokinase-type plasminogen activator (uPA) is critical for progression of tuberous sclerosis complex 2 (TSC2)-deficient tumors.

J Biol Chem. 2017 Dec 15;292(50):20528-20543

Authors: Stepanova V, Dergilev KV, Holman KR, Parfyonova YV, Tsokolaeva ZI, Teter M, Atochina-Vasserman EN, Volgina A, Zaitsev SV, Lewis SP, Zabozlaev FG, Obraztsova K, Krymskaya VP, Cines DB

Abstract
Lymphangioleiomyomatosis (LAM) is a fatal lung disease associated with germline or somatic inactivating mutations in tuberous sclerosis complex genes (TSC1 or TSC2). LAM is characterized by neoplastic growth of smooth muscle-α-actin-positive cells that destroy lung parenchyma and by the formation of benign renal neoplasms called angiolipomas. The mammalian target of rapamycin complex 1 (mTORC1) inhibitor rapamycin slows progression of these diseases but is not curative and associated with notable toxicity at clinically effective doses, highlighting the need for better understanding LAM's molecular etiology. We report here that LAM lesions and angiomyolipomas overexpress urokinase-type plasminogen activator (uPA). Tsc1-/- and Tsc2-/- mouse embryonic fibroblasts expressed higher uPA levels than their WT counterparts, resulting from the TSC inactivation. Inhibition of uPA expression in Tsc2-null cells reduced the growth and invasiveness and increased susceptibility to apoptosis. However, rapamycin further increased uPA expression in TSC2-null tumor cells and immortalized TSC2-null angiomyolipoma cells, but not in cells with intact TSC. Induction of glucocorticoid receptor signaling or forkhead box (FOXO) 1/3 inhibition abolished the rapamycin-induced uPA expression in TSC-compromised cells. Moreover, rapamycin-enhanced migration of TSC2-null cells was inhibited by the uPA inhibitor UK122, dexamethasone, and a FOXO inhibitor. uPA-knock-out mice developed fewer and smaller TSC2-null lung tumors, and introduction of uPA shRNA in tumor cells or amiloride-induced uPA inhibition reduced tumorigenesis in vivo These findings suggest that interference with the uPA-dependent pathway, when used along with rapamycin, might attenuate LAM progression and potentially other TSC-related disorders.

PMID: 28972182 [PubMed - indexed for MEDLINE]

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Controlled Antibody Release from Degradable Thermoresponsive Hydrogels Cross-Linked by Diels-Alder Chemistry.

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Controlled Antibody Release from Degradable Thermoresponsive Hydrogels Cross-Linked by Diels-Alder Chemistry.

Biomacromolecules. 2017 Aug 14;18(8):2410-2418

Authors: Gregoritza M, Messmann V, Abstiens K, Brandl FP, Goepferich AM

Abstract
Amine-modified four- and eight-armed poloxamines were prepared and subsequently functionalized with maleimide or furyl groups. Aqueous solutions of these polymers exhibited an immediate gelation at a temperature above 37 °C. Concomitantly, Diels-Alder reactions gradually cross-linked and cured the gels. Different ratios between four- and eight-armed macromonomers were used to tune hydrogel stability and mechanical properties. In this way, hydrogel stability could be precisely controlled in the range of 14 to 329 days. Controlled release of the model antibody bevacizumab was achieved over a period of 7, 21, and 115 days. Release profiles were triphasic with a low burst; approximately 87% of the released antibody was intact and displayed functional binding. The hydrogels presented in this study are degradable, nontoxic, rapidly gelling, stable, and provide controlled antibody release. They can be tailored to match the demands of various applications and present an attractive platform for antibody delivery.

PMID: 28639788 [PubMed - indexed for MEDLINE]

http://ift.tt/2rEwxCV

Identification and characterization of process-related substances and degradation products in apremilast: Process optimization and degradation pathway elucidation.

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Identification and characterization of process-related substances and degradation products in apremilast: Process optimization and degradation pathway elucidation.

J Pharm Biomed Anal. 2017 Jul 15;141:70-78

Authors: Lu Y, Shen X, Hang T, Song M

Abstract
This study aims at investigating the separation, identification and characterization of related substances in apremilast by LC-MS hyphenated techniques, as well as the synthesis optimization and the degradation pathways elucidation. Forced degradation studies were conducted under the ICH prescribed stress conditions. The chromatographic separation was achieved on XBridge C18 column (4.6mm×150mm, 3.5μm) using a mobile phase consisting of water adjusted to pH 3.0 with formic acid as solvent A and acetonitrile as solvent B in linear gradient elution program. Twelve related substances were detected all together in apremilast and its stress samples. Their structures were identified mainly through positive ESI high-resolution TOF-MS analysis of the parent ions' accurate masses and elemental compositions, and the corresponding MS/MS spectra elucidation. There were three process-related substances and nine degradation products, seven of them were first reported. Two degradation products and one process-related substance were further verified by semi-preparation and NMR determination. Their origins and formation mechanisms were also discussed, based on which effective approaches for the synthesis optimization were conducted. Therefore, the related substances investigation are valuable for apremilast manufacturing process optimization and quality control.

PMID: 28454058 [PubMed - indexed for MEDLINE]

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Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production.

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Rabex-5 is a lenalidomide target molecule that negatively regulates TLR-induced type 1 IFN production.

Proc Natl Acad Sci U S A. 2016 09 20;113(38):10625-30

Authors: Millrine D, Tei M, Gemechu Y, Kishimoto T

Abstract
Immunomodulatory drugs (IMiDs) are a family of compounds derived from thalidomide. Binding of the IMiD molecule to the Lon protease Cereblon initiates the degradation of substrates via the ubiquitin proteasome pathway. Here, we show that Cereblon forms a complex with Rabex-5, a regulator of immune homeostasis. Treatment with lenalidomide prevented the association of Cereblon with Rabex-5. Conversely, mutation of the IMiD binding site increased Cereblon-Rabex-5 coimmunoprecipitation. The thalidomide binding region of Cereblon therefore regulates the formation of this complex. Knockdown of Rabex-5 in the THP-1 macrophage cell line up-regulated Toll-like receptor (TLR)-induced cytokine and type 1 IFN production via a STAT1/IRF activating pathway. Thus, we identify Rabex-5 as a IMiD target molecule that functions to restrain TLR activated auto-immune promoting pathways. We propose that release of Rabex-5 from complex with Cereblon enables the suppression of immune responses, contributing to the antiinflammatory properties of IMiDs.

PMID: 27601648 [PubMed - indexed for MEDLINE]

http://ift.tt/2rJqrBc

Quality Control of Therapeutic Monoclonal Antibodies at the Hospital After Their Compounding and Before Their Administration to Patients.

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Quality Control of Therapeutic Monoclonal Antibodies at the Hospital After Their Compounding and Before Their Administration to Patients.

Methods Mol Biol. 2016;1466:179-84

Authors: Jaccoulet E, Smadja C, Taverna M

Abstract
Monoclonal antibodies (mAbs) are widely used in cancer therapy and recently many new mAbs have gained EMA and FDA approvals for oncology indications. Here we describe a highly reproducible CZE method, relying on a cationic coating allowing separation and identification of a complex mixture of four compounded mAbs widely used in cancer therapy (cetuximab, rituximab, bevacizumab, and trastuzumab).

PMID: 27473490 [PubMed - indexed for MEDLINE]

http://ift.tt/2GihbqV