Recent research out of Yongli Guan's laboratory at the Baylor College of Medicine, with the consultation of Gregg Semenza at the Hopkins School of Medicine, has demonstrated the creation of short strands of DNA nucleotides, abundant in the base guanine, as a possible mechanism to prevent cancer-related tumor growth.
This result may have a groundbreaking influence on possible human cancer therapies.Causing nearly 13 percent of all human deaths, cancer remains one of science's greatest unsolved dilemmas. And while there may not ever be one simple vaccine to cure all the different types of cancers, research such as Guan's sheds light on possible therapies to control this killer.
Specifically, Guan's study demonstrates the ability of these guanine-rich nucleotide strands, or oligodeoxynucleotides, to inhibit Hypoxia-inducible factor-1 (HIF-1), a transcription factor in cells. A transcription factor is a protein that binds to specific DNA sequences and thereby controls the transcription of genetic information from DNA to mRNA.
Thus, transcription factors regulate countless processes in the human body, including negative ones such as tumor formation. Think of the process of tumor growth as an assembly line. If one of the first steps of this line is faulty, the end product will be severely affected.
HIF-1 is a transcription factor that plays crucial roles in tumor promotion by up-regulating the expression of genes that increase the tumor's energy metabolism, facilitate the growth of nutrient-supplying blood vessels, promote metastasis and confer drug resistance.
The same approach is utilized in this study to prevent the growth of cancer related tumors. If some molecule "X" prevents the transcription of target genes that stimulate tumor growth, then the whole process of tumor formation is halted. Therefore, if the transcription factors that promote tumor growth can be suppressed, science may be well on its way to controlling cancer.
Even more promising is the observation that HIF-1 has been demonstrated to be over-expressed in many human cancers, including colon, brain, breast, gastric, lung, skin, ovarian, prostate, renal and pancreatic carcinomas. Poor prognosis and treatment failure for many cancers in the past may be attributed to a lack of consideration of HIF-1 and HIF-2 transcription factors, so targeting these molecules could one day constitute a potent cancer therapy.
Several anti-cancer drugs, which were not originally created as HIF-1 inhibitors, have been found to slow HIF-1 activity. However, Guan's oligodeoxynucleotides (ODNs) selectively inhibit HIF-1 and HIF-2 both in vivo (in living organisms) and in vitro (in cultured cells). These ODNs can be thought of as the molecule "X," the mechanism capable of stopping the assembly line before it can make a final product.
The mechanism of this inhibition by ODNs can be broken down into three steps. First, ODNs interact and bind to a drug carrier PEI, which facilitates the delivery of ODNs into cells. Once inside the cell, ODNs are released by PEI and selectively target HIF-1? and HIF-2? to help degrade them.
To test the therapeutic aspect of ODNs, mice with prostate, breast and pancreatic cancer were tested with this method. The results demonstrated that compared with tumors treated with the PEI molecule alone, the ODNs/PEI complexes suppressed, and in some cases even eliminated, these three tumor types.
It may not be long until we see this ODN/PEI complex being utilized as a promising anticancer agent that can target HIF-1 and HIF-2, block HIF-1 transcription, and in turn, significantly suppress tumor growth in multiple types of cancer.
