The vascular disrupting agent combretastatin A-4 phosphate causes prolonged elevation of proteins involved in heme flux and function in resistant tumor cells

Abstract

// Sanchareeka Dey 1 , Sharda Kumari 2 , Sarada Preeta Kalainayakan 1 , James Campbell III 2 , Poorva Ghosh 1 , Heling Zhou 2 , Keely E. FitzGerald 1 , Maoping Li 2, 3 , Ralph P. Mason 2 , Li Zhang 1 and Li Liu 2 1 Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA 2 Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA 3 Visiting Fellow from Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China Correspondence to: Li Zhang, email: li.zhang@utdallas.edu Li Liu, email: Li.Liu@UTSouthwestern.edu Keywords: combretastatin A-4 phosphate (CA4P); multispectral optoacoustic tomography (MSOT); vascular disrupting agent (VDA); heme; lung tumor Received: October 02, 2017      Accepted: December 15, 2017      Published: December 28, 2017 ABSTRACT Vascular disrupting agents (VDAs) represent a promising class of anti-cancer drugs for solid tumor treatment. Here, we aim to better understand the mechanisms underlying tumor reccurrence and treatment resistance following the administration of a VDA, combretastatin A-4 phosphate (CA4P). Firstly, we used photoacoustic tomography to noninvasively map the effect of CA4P on blood oxygen levels throughout subcutaneous non-small cell lung cancer (NSCLC) tumors in mice. We found that the oxygenation of peripheral tumor vessels was significantly decreased at 1 and 3 hours post-CA4P treatment. The oxygenation of the tumor core reduced significantly at 1 and 3 hours, and reached anoxia after 24 hours. Secondly, we examined the effect of CA4P on the levels of proteins involved in heme flux and function, which are elevated in lung tumors. Using immunohistochemistry, we found that CA4P substantially enhanced the levels of enzymes involved in heme biosynthesis, uptake, and degradation, as well as oxygen-utilizing hemoproteins. Furthermore, measurements of markers of mitochondrial function suggest that CA4P did not diminish mitochondrial function in resistant tumor cells. These results suggest that elevated levels of heme flux and function contribute to tumor regrowth and treatment resistance post-VDA administration.