Oxygen-enhanced optoacoustic tomography reveals the effectiveness of targeting heme and oxidative phosphorylation at normalizing tumor vascular oxygenation

Poorva Ghosh, Yihang Guo, Adnin Ashrafi, Jingyu Chen, Sanchareeka Dey, Shigen Zhong, Jie Liu, James Campbell, Purna Chaitanya Konduri, Jeni Gerberich, Massoud Garrossian, Ralph P. Mason, Li Zhang, Li Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Multispectral optoacoustic tomography (MSOT) is an emerging noninvasive imaging modality that can detect real-time dynamic information about the tumor microenvironment in humans and animals. Oxygen enhanced (OE)-MSOT can monitor tumor vasculature and oxygenation during disease development or therapy. Here, we used MSOT and OE-MSOT to examine in mice the response of human non-small cell lung cancer (NSCLC) xenografts to a new class of antitumor drugs, heme-targeting agents heme-sequestering peptide 2 (HSP2) and cyclopamine tartrate (CycT). HSP2 inhibits heme uptake, while CycT inhibits heme synthesis in NSCLC cells, where heme is essential for ATP generation via oxidative phosphorylation. HSP2 and CycT can inhibit ATP generation and thereby suppress NSCLC cell tumorigenic functions. MSOT showed that treatment of NSCLC tumors with HSP2 or CycT reduced total hemoglobin, increased oxygen saturation, and enhanced the amplitude of response to oxygen gas breathing challenge. HSP2 and CycT normalized tumor vasculature and improved tumor oxygenation, where levels of several hypoxia markers in NSCLC tumors were reduced by treatment with HSP2 or CycT. Furthermore, treatment with HSP2 or CycT reduced levels of angiogenic factor VEGFA, its receptor VEGFR1, and vascular marker CD34. Together, our data show that heme-targeting drugs HSP2 and CycT elicit multiple tumor-suppressing functions, such as inhibiting angiogenic function, normalizing tumor vasculature, alleviating tumor hypoxia, and inhibiting oxygen consumption and ATP generation.

Original languageEnglish (US)
Pages (from-to)3542-3555
Number of pages14
JournalCancer research
Volume80
Issue number17
DOIs
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Oxygen-enhanced optoacoustic tomography reveals the effectiveness of targeting heme and oxidative phosphorylation at normalizing tumor vascular oxygenation'. Together they form a unique fingerprint.

Cite this