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Antioxidant Activity Of Growth Hormone-Releasing Hormone Antagonists In LNCaP Human Prostate Cancer Line

Dr. Nektarios Barabutis and Nobel Laureate Dr. Andrew Schally reported in the Proceedings of the National Academy of Sciences that inhibition of oxidative stress in prostate cancer (CaP) cell lines decreases tumor cell proliferation. This is an original observation with therapeutic implications.

The research used the LNCaP cell line. Growth hormone-releasing hormone (GHRH) functions as a growth factor in CaP and Dr. Schally's group has developed antagonistic analogues of GHRH to include JMR-132. The effect of GHRH analogues in the reduction/oxidative (redox) status of cancer are uninvestigated. Reactive oxygen species (ROS) are oxygen radicals and non-radical derivatives of oxygen and react rapidly with intracellular functions to cause oxidative stress. ROS plays a role in tumor initiation and progression and is associated with the aggressive phenotype.

In this work, the investigators demonstrated expression of GHRH receptors in the LNCaP cell line by Western blotting. Next they showed that exogenous addition of GHRH stimulated LNCaP proliferation and JMR-132 inhibited this by 32-37%. p53 protein participates as a defense against cancer and exposure to GHRH decreased p53 expression while JMR-132 increased it. NF-κB is enhanced by oxidative stress and inhibited by overexpression of wild-type p53. GHRH increased the activated form of NF-κB and JMR-132 decreased concentrations. A host of antioxidant enzymes that tumor cells are highly dependent on for survival were also assessed. These enzymes were lower when exposed to JMR-132. COX 2 enzymes are also an important source in intracellular ROS and JMR-132 decreased the expression of COX 2 and blocked downstream signaling. As another measure of oxidative status of LNCaP cells, protein and lipid oxidative status was assessed and GHRH increased the oxidative status while JMR-132 decreased it.

These data suggest that GHRH antagonists could be used as anticancer therapy and potentially in other cellular processes that are altered by oxidative stress.

Barabutis N, Schally AV
Proc Natl Acad Sci U S A. 2008 Dec 23;105(51):20470-5.
doi:10.1073/pnas.0811209106