The heterogeneous distribution of hypoxic regions within solid tumors renders them refractive to chemo- and radio-therapies and contributes positively to tumor invasion and metastasis. Moreover, hypoxia favors the enrichment of cancer stem cells by interacting with differentiation signals via the maintenance of stem cell properties of undifferentiated cells or via the induction of cellular dedifferentiation. The discovery of the hypoxia inducible factor 1alpha (HIF-1α) has led to the current extensive interest in the signal molecules related to tumor hypoxia and the major regulatory pathways that control the family of hypoxia-inducible factors as potential molecular targets for cancer therapeutics. Multiple approaches have been developed to circumvent hypoxia-induced resistance, such as oxygenating tumors, using radiosensitizers and more recently using bio-reductively activated pro-drugs. Recent evidence suggests that radio-sensitization has undergone a paradigm shift from compounds that enhance the effect of radiation via mimicking oxygen, to compounds that target HIF-mediated signaling pathways eventually reducing radio-resistance. In this paper, we give an overview of our recent understandings in hypoxia research, discuss the mechanisms of resistance of hypoxic tumors and of hypoxia-induced cancer stem cells and highlight the latest advances in cancer treatments that target tumor hypoxia and the resistant populations of cancer stem cells. Classical and novel radio-sensitization methods, mainly the molecular inhibition of HIFs and downstream targets and the use of hypoxia-activated drugs are compared and contrasted. Such multi-faceted targeted therapies ultimately enhance treatment outcomes and reduce normal tissue toxicity by the selective targeting of solid tumors.
BackgroundAlthough tumor hypoxia poses challenges against conventional cancer treatments, it provides a therapeutic target for hypoxia-activated drugs. Here, we studied the effect of the hypoxia-activated synthetic quinoxaline di-N-oxide DCQ against breast cancer metastasis and identified the underlying mechanisms.MethodsThe human breast cancer cell lines MCF-7 (p53 wildtype) and MDA-MB-231 (p53 mutant) were treated with DCQ under normoxia or hypoxia. Drug toxicity on non-cancerous MCF-10A breast cells was also determined. In vitro cellular responses were investigated by flow cytometry, transfection, western blotting, ELISA and migration assays. The anti-metastatic effect of DCQ was validated in the MDA-MB-231 xenograft mouse model.ResultsDCQ selectively induced apoptosis in both human breast cancer cells preferentially under hypoxia without affecting the viability of non-cancerous MCF-10A. Cancer cell death was associated with an increase in reactive oxygen species (ROS) independently of p53 and was inhibited by antioxidants. DCQ-induced ROS was associated with DNA damage, the downregulation of hypoxia inducible factor-1 alpha (HIF-1α), and inhibition of vascular endothelial growth factor (VEGF) secretion. In MCF-7, HIF-1α inhibition was partially via p53-activation and was accompanied by a decrease in p-mTOR protein, suggesting interference with HIF-1α translation. In MDA-MB-231, DCQ reduced HIF-1α through proteasomal-dependent degradation mechanisms. HIF-1α inhibition by DCQ blocked VEGF secretion and invasion in MCF-7 and led to the inhibition of TWIST in MDA-MB-231. Consistently, DCQ exhibited robust antitumor activity in MDA-MB-231 breast cancer mouse xenografts, enhanced animal survival, and reduced metastatic dissemination to lungs and liver.ConclusionDCQ is the first hypoxia-activated drug showing anti-metastatic effects against breast cancer, suggesting its potential use for breast cancer therapy.
Acid catalyzed Friedlander reactions of a number of 2,3-dihydro-1H-cyclopenta[b]quinoxaline-1-ones with 2-aminobenzaldehyde yield, unexpectedly, 8H-indolo[3,2-a]phenazine and quinolino[2,3-c]cyclopentadienone[2,3-b]quinoxalines, the structures of derivatives of which were confirmed by X-ray crystallography. Easy routes to novel quinoxaline-based indoles, quinolones, and quinoxaline-1,4-dioxides are reported and proposed mechanisms for the unexpected products are discussed.
The method allows the preparation of different types of polycyclic N‐heterocyclic systems which may be important in medicinal chemistry.
Although tumor hypoxia is associated with the complex processes of tumor metastasis and resistance, and poses significant challenges against traditional cancer treatments, it provides a target for therapy by bioreductive drugs with enhanced cytotoxic activity in the reduced microenvironment of tumors. We identified a potent synthetic quinoxaline di-N-oxide (DCQ) which preferentially targets hypoxic tumors. Here we show that DCQ: 1) Reduces the viability of breast cancer cell lines (MDA-MB-231, MCF-7), 2) Induces reactive oxygen species (ROS)-dependent p53-independent apoptosis, 3) Inhibits the accumulation of hypoxia inducible factor (HIF-1α) via distinct mechanisms in the two cell lines and 4) Significantly reduces hypoxia-induced invasion of breast cancer cell lines in vitro and in vivo. DCQ-induced ROS was associated with increased DNA damage in MDA-MB-231 and MCF-7 cells. The inhibition of HIF-1α accumulation in MCF-7 was in part via the activation of p53 and was accompanied by a decrease in the levels of phosphorylated mTOR, indicating that DCQ-induced reduction of HIF-1α is possibly occurring at the translational level of the protein. HIF-1α reduction was associated with a decrease in p21 and a reversal of the hypoxia-induced VEGF secretion and invasion, which are key processes in tumor metastasis. In MDA-MB-231 cells; however, DCQ reduced HIF-1α through proteasomal degradation, which was accompanied by a reduction of TWIST, a major player in epithelial to mesenchymal transition (EMT). The inhibitory effect of DCQ on hypoxia induced breast cancer invasion was validated in the xenograft model of subdermally injected MDA-MB-231 cells in immune-compromised mice. DCQ significantly increased the survival rate of treated animals. This increase was associated with a reduction of the metastatic dissemination of breast cancer cells into the liver and lungs of DCQ treated mice. Citation Format: Khaled I. Ghattass, Sally El Sitt, Kazem Zibara, Makhlouf MJ Haddadin, Marwan El-Sabban, Hala Ghali-Muhtasib. DCQ is a hypoxia-activated quinoxaline 1,4-dioxide that reduces breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A99.
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