Design of Hypoxia-Targeting Drugs as New Cancer Chemotherapeutics

Abstract

The tumor microenvironment is now recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also helps define the potential for malignant progression and metastasis. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment. Furthermore, discovery of the hypoxia inducible factor 1a a (HIF-1a a) has led to a rapidly increasing understanding of the molecular mechanisms involved in tumor hypoxia. This in turn has led to the current extensive interest in the signal molecules related to tumor hypoxia as potential molecular targets for cancer therapeutics. In this paper we give an overview of recent advances in hypoxia research, including cancer treatments that target tumor hypoxia. Progress in the development of hypoxia-targeting drugs will be discussed, including antiangiogenic hypoxic cell radiosensitizers and hypoxic cytotoxins, hypoxia targeting boron carriers and p53-inhibiting bifunctional radiosensitizers. We will also review our own recent research results in these areas. For example, we have found that certain of the 2-nitroimidazole radiosensitizers and heterocycle-N-oxide hypoxic cytotoxins we developed have antiangiogenic activity and antimetastatic activity. We propose that these activities are based on the inhibition of signal transduction mediated by HIF-1a a. The anti-tumor activities of hypoxia response are considered to be cytostatic (tumor dormancy-inducing) effects in contrast to cytotoxic DNA damaging effects. The combinaiton of these cytostatic effects that are related to radiosensitization with the cytotoxic effects of radiation should improve the prognosis and QOL of patients receiving radiation and lead to an overall response to treatment. Based on these considerations, we developed the antiangiogenic hypoxic cell radiosensitizers, TX-1877, TX-1898 and the hypoxic cytotoxin TX-402 that inhibits the HIF-1a a pathway We will also discuss our research involved with the development of other drugs to exploit tumor hypoxia, including a hypoxia-targeting boron carrier for boron neutron capture therapy (BNCT) and a p53 inhibiting radiosensitizer.Key words tumor hypoxia; angiogenic inhibitor; hypoxia inducible factor (HIF)-1a inhibitor; hypoxic cell radiosensitizer; boron neutron capture therapy; p53 inhibitor Review

Hypoxia-targeting by tirapazamine (TPZ) induces preferential growth inhibition of nasopharyngeal carcinoma cells with Chk1/2 activation

“…HIF-1α, as well as its target genes are known contribute to tumor cell survival, invasiveness and metabolic adaptation under hypoxia. The observed hypoxia-selective down-modulation of HIF-1α by TPZ in NPC cells was consistent with the previous study in non-small cell lung cancer cell lines, H1299 [36]. The mechanism of TPZinduced downregulation of HIF-1α is unclear.…”

“…4A). In both HONE-1 and HK1 cells, high dose of TPZ (50µM) resulted in complete abrogation of HIF-1α expression under hypoxia, which is consistent with the previous observation in non-small cell lung cancer cells [36]. However, for reasons unclear, lower dose of TPZ (5 and 10µM) seemed to result in a mild induction of HIF-1α under hypoxia in HK1 cells (Fig.…”

Pathophysiological Response to Hypoxia — From the Molecular Mechanisms of Malady to Drug Discovery: Drug Discovery for Targeting the Tumor Microenvironment

“…At first, strategies of cancer therapy that target hypoxia focused on sensitizing the tumor response to cancer therapy by developing oxygen-mimic chemical modifiers and hypoxia-selective cytotoxic prodrugs (4,5). Key mechanisms of hypoxia selectivity are bioreductions to generate active species in hypoxic tissue, which have long been studied ( Fig.…”

Targeting Tumor Hypoxia with Prodrugs: Challenges and Opportunities

“…Several recent reviews describe the preclinical and clinical development of HAP (10,(18)(19)(20)(21)(22). Th e attempt to exploit or overcome hypoxia with HAP dates back to pioneering studies with quinones and nitro compounds in the 1980s (23)(24)(25)(26).…”