Oncotarget

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A novel small-molecule arylsulfonamide causes energetic stress and suppresses breast and lung tumor growth and metastasis

Xin Dai, Stefan Kaluz, Ying Jiang, Lei Shi, DeAngelo Mckinley, Yingzhe Wang, Binghe Wang, Erwin G. Van Meir and Chalet Tan _

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Oncotarget. 2017; 8:99245-99260. https://doi.org/10.18632/oncotarget.22104

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Abstract

Xin Dai1, Stefan Kaluz2,4, Ying Jiang5, Lei Shi 6, DeAngelo Mckinley5, Yingzhe Wang5, Binghe Wang7, Erwin G. Van Meir2,3,4 and Chalet Tan1

1 Department of Pharmaceutics and Drug Delivery, University of Mississippi, Oxford, MS, USA

2 Department of Neurosurgery, Emory University, Atlanta, GA, USA

3 Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA

4 Winship Cancer Institute, Emory University, Atlanta, GA, USA

5 Department of Pharmaceutical Sciences, Mercer University, Atlanta, GA, USA

6 Department of Biology, Georgia State University, Atlanta, GA, USA

7 Department of Chemistry, Georgia State University, Atlanta, GA, USA

Correspondence to:

Binghe Wang, email:

Erwin G. Van Meir, email:

Chalet Tan, email:

Keywords: arylsulfonamide; AMPK; mTORC1; HIF-1; metastasis

Received: September 04, 2017 Accepted: October 10, 2017 Published: October 29, 2017

Abstract

Neoplastic cells display reprogrammed metabolism due to the heightened energetic demands and the need for biomass synthesis of a growing tumor. Targeting metabolic vulnerabilities is thus an important goal for cancer therapy. Here, we describe a novel small-molecule arylsulfonamide (N-cyclobutyl-N-((2,2-dimethyl-2H-pyrano[3,2-b]pyridin-6-yl)methyl)-3,4-dimethoxybenzenesulfonamide) that exerts potent cytotoxicity and energetic stress on tumor cells while largely sparing non-cancerous human cells. In tumor cells, it stimulates glycolysis and accelerates glucose consumption. Consequently, intracellular ATP levels plummet, triggering activation of AMP-activated protein kinase (AMPK), and diminishing the mammalian target of rapamycin complex 1 (mTORC1) and hypoxia-inducible factor 1 (HIF-1) signaling. In orthotopic triple-negative breast cancer and subcutaneous lung cancer mouse models, this arylsulfonamide robustly suppresses primary tumor growth, inhibits the formation of distant metastases to the lung, and extends mouse survival while being very well tolerated. These therapeutic effects are further potentiated by co-administration of 2-deoxy-D-glucose (2-DG), a glucose analog and glycolysis inhibitor. Collectively, our findings provide preclinical proof of concept for the further development of this arylsulfonamide in combination with 2-DG towards cancer treatment.


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