Abstract
SummaryTumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% O2) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% O2). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis, and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub-micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our pre-clinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.
Highlights
Insufficient O2, or hypoxia, is a common feature of the tumor microenvironment arising from abnormal tumor vasculature and high metabolic demand
Hypoxia is associated with resistance to chemotherapy, radiotherapy, and poor patient prognosis across a broad range of tumor types (Hammond et al, 2014)
Hypoxia leads to cell-cycle arrest and inhibition of proliferation, and as anti-cancer drugs often preferentially target rapidly dividing cells, hypoxia results in resistance to chemotherapy (Tredan et al, 2007)
Summary
Insufficient O2, or hypoxia, is a common feature of the tumor microenvironment arising from abnormal tumor vasculature and high metabolic demand. Hypoxia is associated with resistance to chemotherapy, radiotherapy, and poor patient prognosis across a broad range of tumor types (Hammond et al, 2014). O2binds covalently to radiation-induced DNA radicals fixing the damage which can lead to DNA double-strand breaks (Bristow and Hill, 2008; Gatti and Zunino, 2005). The mechanisms that underlie resistance to anti-cancer drugs in hypoxic cells are complex and include drug efflux, autophagy, metabolic reprogramming, DNA damage, and mitochondrial activity (Bristow and Hill, 2008; Hammond et al, 2014). Hypoxia leads to extracellular changes in the tumor microenvironment such as acidosis, which can lead to extracellular ion trapping of weakly basic drugs such as doxorubicin (Gatti and Zunino, 2005). Hypoxia leads to cell-cycle arrest and inhibition of proliferation, and as anti-cancer drugs often preferentially target rapidly dividing cells, hypoxia results in resistance to chemotherapy (Tredan et al, 2007)
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