The vascular disrupting agent combretastatin A-4 phosphate causes prolonged elevation of proteins involved in heme flux and function in resistant tumor cells
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Sanchareeka Dey1, Sharda Kumari2, Sarada Preeta Kalainayakan1, James Campbell III2, Poorva Ghosh1, Heling Zhou2, Keely E. FitzGerald1, Maoping Li2,3, Ralph P. Mason2, Li Zhang1 and Li Liu2
1Department of Biological Sciences, The University of Texas at Dallas, Richardson, TX, USA
2Department of Radiology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
3Visiting Fellow from Department of Ultrasound, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
Li Zhang, email: [email protected]
Li Liu, email: [email protected]
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
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.
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