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

Sanchareeka Dey,Ralph P Mason,Heling Zhou,Sarada Preeta Kalainayakan,James Campbell,Poorva Ghosh,Li Liu,Li Zhang,Maoping Li,Sharda Kumari,Keely E Fitzgerald

doi:10.18632/oncotarget.23734

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.

Highlights

Tumors cannot grow beyond 2 mm3 without a vascular structure to supply tumor core cells with oxygen and nutrients [1]
Using Multispectral approach Optoacoustic Tomography (MSOT), we found that Combretastatin A-4 phosphate (CA4P) caused a significant reduction in vascular oxygen saturation and hypoxia at 1 and 3 hours post-Vascular disrupting agents (VDAs) treatment
Consistent with previous studies of CA4P [8, 9, 14], MSOT showed that CA4P caused significant reduction of perfusion and oxygenation in tumors (Figures 1 & 2)

Summary

Introduction

Tumors cannot grow beyond 2 mm without a vascular structure to supply tumor core cells with oxygen and nutrients [1]. Vascular disrupting agents (VDAs) act on tumor endothelial cells and induce a vascular shutdown, leading to reduction in blood flow, ischemia, and cell death [2, 3]. While VDA treatment causes acute ischemia leading to extensive central necrosis in many tumors, a peripheral rim of viable tumor cells remains, which allows re-growth and re-vascularization of the tumor [20,21,22,23]. Further understanding of the mode of CA4P action may help to improve the anti-tumor efficacy of VDAs, through rational combination with additional therapy

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