Last update 01 Nov 2024

BSG x Na/K-ATPase

Last update 01 Nov 2024

Basic Info

Related Targets

BSGNa/K-ATPase

Drugs associated with BSG x Na/K-ATPase

EDC-2

Target

BSG x Na/K-ATPase

Mechanism

BSG inhibitors [+1]

Active Org.

The University of Alabama at Birmingham [+1]

Originator Org.

Wisconsin Alumni Research Foundation

Active Indication

Squamous Cell Carcinoma of Head and Neck

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BSG x Na/K-ATPase

100 Translational Medicine associated with BSG x Na/K-ATPase

0 Patents (Medical) associated with BSG x Na/K-ATPase

Literatures (Medical) associated with BSG x Na/K-ATPase

01 Oct 2016·Molecular TherapyQ1 · MEDICINE

Extracellular Antibody Drug Conjugates Exploiting the Proximity of Two Proteins

Q1 · MEDICINE

Article

Author: Thorson, Jon S ; Harried, Scott S ; Chillemi, Antonella ; Hall, Chad A ; Murphy, John L ; Shekhani, Mohammed S ; Pearce, Homer L ; Lyons, Conner A ; Pain, Christophe ; Malavasi, Fabio ; Marshall, David J ; Prudent, James R

The human Na⁺/K⁺-ATPase (NKA) is a plasma membrane ion pump that uses ATP to help maintain the resting potential of all human cells. Inhibition of the NKA leads to cell swelling and death. The results of this investigation show that on cancer cells, the NKA either comes in close proximity to, associate with or complexes to important cancer-related proteins, and thus can be targeted with a new type of precision therapy called the extracellular drug conjugate or EDC. The EDCs reported here exhibit EC₅₀ values in the low to mid-picomolar range, and signal to noise ratios > 1,000:1, both of which are dependent on the cell surface expression of the NKA and corresponding cancer-related target. We demonstrate that a potent small molecule inhibitor of the NKA can be covalently attached to antibodies targeting CD20, CD38, CD56, CD147, or dysadherin, to create a series of selective and powerful EDCs that kill cancer cells extracellularly by a mechanism resembling necrosis. This is therefore a framework for the development of a new type of precision therapy wherein exquisite selectivity is achieved for targeting extracellular disease-related proteins.

01 Oct 2013·Oral OncologyQ2 · MEDICINE

A novel extracellular drug conjugate significantly inhibits head and neck squamous cell carcinoma

Q2 · MEDICINE

Article

Author: Yolanda E. Hartman ; James R. Prudent ; Kurt R. Zinn ; David J. Marshall ; Mohammed S. Shekhani ; Eben L. Rosenthal ; Larissa Sweeny

OBJECTIVESDespite advances in treatment modalities, head and neck squamous cell carcinoma (HNSCC) remains a challenge to treat with poor survival and high morbidity, necessitating a therapy with greater efficacy. EDC22 is an extracellular drug conjugate of the monoclonal antibody targeting CD147 (glycoprotein highly expressed on HNSCC cells) linked with a small drug molecule inhibitor of Na, K-ATPase. In this study, EDC22's potential as a treatment modality for HNSCC was performed.MATERIALS AND METHODSHNSCC cell lines (FADU, OSC-19, Cal27, SCC-1) were cultured in vitro and proliferation and cell viability were assessed following treatment with a range of concentrations of EDC22 (0.25-5.00μg/mL). Mice bearing HNSCC xenografts (OSC-19, SCC-1) were treated with either EDC22 (3-10mg/kg), anti-CD147 monoclonal antibody, cisplatin (1mg/kg) or radiation therapy (2Gy/week) monotherapy or in combination.RESULTSIn vitro, treatment with minimal concentration of EDC22 (0.25μg/mL) significantly decreased cellular proliferation and cell viability (p<0.0001). In vivo, systemic treatment with EDC22 significantly decreased primary tumor growth rate in both an orthotopic mouse model (OSC-19) and a flank tumor mouse model (SCC-1) (p<0.05). In addition, EDC22 therapy resulted in a greater reduction in tumor growth in vivo compared to radiation monotherapy (p<0.05) and a similar reduction in tumor growth compared to cisplatin monotherapy. Combination therapy provided no significant further reduction in tumor growth relative to EDC22 monotherapy.CONCLUSIONEDC22 is a potent inhibitor of HNSCC cell proliferation in vitro and in vivo, warranting further investigations of its clinical potential in the treatment of HNSCC.

01 Jul 2010·American Journal of Physiology-Renal PhysiologyQ3 · MEDICINE

Ouabain stimulates Na-K-ATPase through a sodium/hydrogen exchanger-1 (NHE-1)-dependent mechanism in human kidney proximal tubule cells

Q3 · MEDICINE

Article

Author: Holthouser, Kristine A. ; Schelling, Jeffrey R. ; Lederer, Eleanor D. ; Mandal, Amritlal ; Khundmiri, Syed J. ; Delamere, Nicholas A. ; Tyagi, Suresh C. ; Merchant, Michael L. ; Valdes, Ronald R.

Recent investigations demonstrate increased Na/H exchanger-1 (NHE-1) activity and plasma levels of ouabain-like factor in spontaneously hypertensive rats. At nanomolar concentrations, ouabain increases Na-K-ATPase activity, induces cell proliferation, and activates complex signaling cascades. We hypothesize that the activity of NHE-1 and Na-K-ATPase are interdependent. To test whether treatment with picomolar ouabain regulates Na-K-ATPase through an NHE-1-dependent mechanism, we examined the role of NHE-1 in ouabain-mediated stimulation of Na-K-ATPase in kidney proximal tubule cell lines [opossum kidney (OK), HK-2, HKC-5, and HKC-11] and rat kidney basolateral membranes. Ouabain stimulated Na-K-ATPase activity and tyrosine phosphorylation in cells that express NHE-1 (OK, HKC-5, and HKC-11) but not in HK-2 cells that express very low levels of NHE-1. Inhibition of NHE-1 with 5 μM EIPA, a NHE-1-specific inhibitor, prevented ouabain-mediated stimulation of86Rb uptake and Na-K-ATPase phosphorylation in OK, HKC-5, and HKC-11 cells. Expression of wild-type NHE-1 in HK2 cells restored regulation of Na-K-ATPase by picomolar ouabain. Treatment with picomolar ouabain increased membrane expression of Na-K-ATPase and enhanced NHE-1-Na-K-ATPase α1-subunit association. Treatment with ouabain (1 μg·kg body wt−1·day−1) increased Na-K-ATPase activity, expression, phosphorylation, and association with NHE-1 increased in rat kidney cortical basolateral membranes. Eight days' treatment with ouabain (1 μg·kg body wt−1·day−1) resulted in increased blood pressure in these rats. These results suggest that the association of NHE-1 with Na-K-ATPase is critical for ouabain-mediated regulation of Na-K-ATPase and that these effects may play a role in cardioglycoside-stimulated hypertension.

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