Redox Proteins as Cytotoxic Factors
In collaboration with the Department of Microbiology and Immunology, we have identified several bacterial secretory product(s) which are cytotoxic to a variety of cancer cells. Studies are in progress to ascertain their in vivo efficacy and subsequent clinical potential.
The basic research being done at UIC is becoming extremely exciting as a result of its potential to allow identification and characterization of new types of bacterial proteins that have never been known to have anticancer activity or even to enter mammalian cells. These bacterial proteins have been shown to enter various human cancer cells such as those of breast cancer, melanoma, colon cancer, etc., and to kill such cells by multiple mechanisms. For example, one of these bacterial proteins, azurin, previously known only to be involved in electron transfer, has now been shown to have the ability not only to enter cancer cells in preference to normal cells but to form complexes with the tumor suppressor protein p53, stabilizing it and raising its levels and thereby inducing apoptosis in such cells. Nothing happens to normal cells because the protein is extremely inefficient in entering normal breast epithelial cells. Other groups outside UIC have published papers confirming such complex formations or anticancer activity. Azurin, however, was found to have much less activity against brain tumors such as glioblastomas or astrocytomas. Interestingly, we found out that the azurin gene exists in the genome of another pathogen, Neisseria meningitidis, in a slightly bigger size, which encodes an azurin protein with an additional peptide in its N-terminal called an H.8 epitope. Azurin is produced by Pseudomonas aeruginosa, a pathogen that cannot cross the blood-brain barrier to infect brain tissues. Neisseria meningitidis, however, is known to cause meningitis in humans by entering the meningeal space in the cerebrospinal axis, causing inflammation of the meninges. To see if the H.8 epitope might allow N. Meningitidis azurin, called LAZ protein, to enter brain tumors and kill such tumors, we have cloned the H.8 epitope gene upstream of the P. aeruginosa azurin gene, called H.8-azurin, and checked the ability of azurin, H.8-azurin, and LAZ protein, to enter glioblastoma and astrocytoma cells and kill them. Indeed, we found that H.8-azurin and LAZ enter brain tumor cells much more efficiently and exert much higher cytotoxicity. Another exciting finding with regard to azurin, H.8 azurin and LAZ is that all three proteins can greatly reduce parasitemia in infected human red blood cells, thus acting as potential antimalarial drugs. There are very few new antimalarial drugs coming to the market and most of the malarial parasites are becoming resistant to the old drugs, thus causing major concerns. Cerebral malaria is a major problem in Asia and Africa where the infected erythrocytes reenter brain capillaries and cause coma and rapid death. The ability of LAZ and H.8 azurin to cross the blood-brain barrier and significantly reduce (~80%) parasitemia in human infected erythrocytes provides potential treatment opportunities for cerebral malaria.
Principal Investigators and Key personnel:
Rajeshwari R. Mehta, Ph.D.
Ananda Chakrabarty, Ph.D.
Craig W. Beattie, Ph.D.
Tohru Yamada, Ph.D.