[Rich66]

Ann N Y Acad Sci. 2009 Oct;1177:2-8.
Regulation of vascularization by hypoxia-inducible factor 1.

Semenza GL.
Vascular Program, Institute for Cell Engineering; McKusick-Nathans Institute of Genetic Medicine, Baltimore, Maryland 21205, USA. gsemenza@jhmi.edu
Vascularization and vascular remodeling represent critical adaptive responses to tissue hypoxia that are mediated by hypoxia-inducible factor 1 (HIF-1). In patients with peripheral arterial disease, these responses are impaired by aging and diabetes, leading to critical limb ischemia and amputation. Intramuscular injection of an adenovirus encoding a constitutively active form of the HIF-1alpha subunit (CA5) increases the recovery of blood flow following femoral artery ligation in a mouse model of age-dependent critical limb ischemia. Intradermal injection of a plasmid encoding CA5 promotes healing of cutaneous wounds in a mouse model of diabetes. In cancer, vascularization is required for tumors to grow beyond microscopic size, a process that involves HIF-1-dependent production of angiogenic growth factors. Daily treatment of prostate cancer xenograft-bearing mice with low-dose anthracycline (doxorubicin or daunorubicin) chemotherapy inhibits HIF-1 DNA-binding activity, HIF-1-dependent expression of angiogenic growth factors, mobilization of circulating angiogenic cells, and tumor vascularization, thereby arresting tumor growth.

PMID: 19845601 [PubMed - indexed for MEDLINE]



Low-dose anthracyclines may block HIF-1 and stop tumor growth.

Hede K.
PMID: 19276456 [PubMed - indexed for MEDLINE]Free Article

Includes inset "Digoxin as Anticancer Agent: The HIF-1 Connection"

A recent study suggests that the well-known anthracycline chemotherapeutic agents doxorubicin and daunorubicin, when given in small doses, can reduce tumor vascularization in animal models. The discovery, by Gregg Semenza, M.D., Ph.D., and his colleagues at Johns Hopkins University School of Medicine in Baltimore, reveals a new mechanism of action for these mainstays of chemotherapy and explains why smaller doses of chemotherapy agents given over a longer period can sometimes inhibit formation of new blood vessels.
Anthracyclines kill cancer cells by interfering with DNA replication in actively dividing cells. But Semenza and his colleagues demonstrate that the drugs also interfere with a key regulator of oxygen metabolism, hypoxia-inducible factor 1 (HIF-1), a crucial regulator of vascularization.
Semenza discovered HIF-1 in 1992 in cells grown in low-oxygen (hypoxic) conditions and demonstrated that HIF-1 regulated the adaptation to the hypoxic growth conditions common in many solid tumors. HIF-1, a transcription factor, is a master regulator that activates vascular endothelial growth factor (VEGF) and many other adaptive proteins, allowing cells to generate fuel under hypoxic conditions.
In the present study, published in late January 2009 in the Proceedings of the National Academy of Sciences online edition, he shows that chronic inhibition of HIF-1 can effectively block tumor growth by blocking angiogenesis in a mouse xenograft model.
"When we treat [mice] with these drugs, almost immediately we inhibit HIF-1 activity, we inhibit the production of angiogenic cytokines such as VEGF, we inhibit the mobilization of angiogenic cells into the circulation, and we block tumor vascularization," said Semenza. "At least in these xenograft models, when you block tumor vascularization, you block tumor growth."
Master Regulator
In recent years, HIF-1 has emerged as a critical regulator of cancer growth, progression, and metastasis. High HIF-1 levels in tumor cells have been linked to poor patient outcomes in bladder, breast, cervical, endometrial, lung, and pancreatic cancers, among others. HIF-1 enables tumor cells to thrive under the hypoxic conditions that have been the bane of oncologists trying to wipe out cancer cells remaining after radiation and chemotherapy.

The Angiogenesis Foundation Website includes education and video presentations on angiogenesis